Microbiota in health and diseases 22년 nature review

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• Review Article
• Open access
• Published: 23 April 2022

Microbiota in health and diseases

• Kaijian Hou, 
• Zhuo-Xun Wu, 
• Xuan-Yu Chen, 
• Jing-Quan Wang, 
• Dongya Zhang, 
• Chuanxing Xiao, 
• Dan Zhu, 
• Jagadish B. Koya, 
• Liuya Wei, 
• Jilin Li & 
• Zhe-Sheng Chen 

Signal Transduction and Targeted Therapy volume 7, Article number: 135 (2022) Cite this article

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Abstract

The role of microbiota in health and diseases is being highlighted by numerous studies since its discovery. Depending on the localized regions, microbiota can be classified into gut, oral, respiratory, and skin microbiota. The microbial communities are in symbiosis with the host, contributing to homeostasis and regulating immune function. However, microbiota dysbiosis can lead to dysregulation of bodily functions and diseases including cardiovascular diseases (CVDs), cancers, respiratory diseases, etc. In this review, we discuss the current knowledge of how microbiota links to host health or pathogenesis. We first summarize the research of microbiota in healthy conditions, including the gut-brain axis, colonization resistance and immune modulation. Then, we highlight the pathogenesis of microbiota dysbiosis in disease development and progression, primarily associated with dysregulation of community composition, modulation of host immune response, and induction of chronic inflammation. Finally, we introduce the clinical approaches that utilize microbiota for disease treatment, such as microbiota modulation and fecal microbial transplantation.

건강과 질병에서 미생물총의 역할은 

발견 이후 수많은 연구를 통해 그 중요성이 강조되고 있습니다. 

미생물은 국소화된 부위에 따라 

장내, 

구강, 

호흡기, 

피부 미생물로 분류할 수 있습니다. 

미생물 군집은 

숙주와 공생하며 항상성을 유지하고 

면역 기능을 조절하는 데 기여합니다. 

그러나 

미생물 군집의 불균형은 

심혈관 질환(CVD), 

암, 

호흡기 질환 등 신체 기능 및 질병의 조절 장애로 이어질 수 있습니다. 

이 리뷰에서는 

미생물총이 숙주의 건강 또는 발병과 어떻게 연관되는지에 대한 최신 지식을 논의합니다. 

먼저 

장-뇌 축, 

colonization resistance, 

면역 조절 등 건강한 상태에서의 미생물총에 대한 연구를 요약합니다. 

그런 다음 

주로 커뮤니티 구성의 조절 장애, 

숙주 면역 반응의 조절, 

만성 염증 유발과 관련된 질병 발생 및 진행에서 미생물군집의 이상균총의 발병 기전을 강조합니다. 

마지막으로 

미생물군집 조절 및 대변 미생물 이식 등 

질병 치료를 위해 미생물군을 활용하는 임상적 접근법을 소개합니다.

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Introduction

The origin of “microbiota” can be dated back to early 1900s. It was found that a vast number of microorganisms, including bacteria, yeasts, and viruses, coexist in various sites of the human body (gut, skin, lung, oral cavity).1 In addition, the human microbiota, also known as “the hidden organ,” contribute over 150 times more genetic information than that of the entire human genome.2 Although “microbiota” and “microbiome” are often interchangeable, there are certain differences between the two terms. Microbiota describes the living microorganisms found in a defined environment, such as oral and gut microbiota. Microbiome refers to the collection of genomes from all the microorganisms in the environment, which includes not only the community of the microorganisms, but also the microbial structural elements, metabolites, and the environmental conditions.3 In this regard, microbiome encompasses a broader spectrum than that of microbiota. In the current review, we mainly focus on the function of microbiota in human health and diseases.

'미생물총'의 기원은 1900년대 초로 거슬러 올라갑니다. 박테리아, 효모, 바이러스 등 수많은 미생물이 장, 피부, 폐, 구강 등 인체의 다양한 부위에 공존하는 것으로 밝혀졌습니다.1 또한 '숨겨진 장기'로도 알려진 인체 미생물총은 전체 인간 게놈보다 150배 이상의 유전 정보를 제공합니다.2 "미생물총"과 "마이크로바이옴"은 종종 혼용되지만, 두 용어 간에는 분명한 차이가 있습니다. 

Microbiota 미생물총은

구강 및 장내 미생물과 같이 정해진 환경에서 발견되는

살아있는 미생물을 의미합니다. 

마이크로바이옴은 

환경에 존재하는 모든 미생물의 유전체 집합을 의미하며, 

여기에는 미생물 군집뿐만 아니라 

미생물 구조 요소, 대사산물 및 환경 조건도 포함됩니다.3 

이러한 점에서 

마이크로바이옴은 

마이크로비오타보다 더 광범위한 스펙트럼을 포괄합니다. 이번 리뷰에서는 주로 인간의 건강과 질병에 대한 마이크로바이옴의 기능에 초점을 맞춥니다.

The composition of microbiota varies from site to site (depicted in Fig. 1). Gut microbiota is considered the most significant one in maintaining our health.4 The gut bacteria serve several functions, such as fermentation of food, protection against pathogens, stimulating immune response, and vitamin production.5 Generally, the gut microbiota is composed of 6 phyla including Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, among which Firmicutes and Bacteroidetes are the major types.6 The most studied fungi (gut mycobiota) are Candida, Saccharomyces, Malassezia, and Cladosporium.7 In addition to bacteria and fungi, the human gut microbiota also contain viruses, phages, and archaea, mainly M. smithii.8

마이크로바이옴의 구성은 부위마다 다릅니다(그림 1 참조). 

장내 미생물은 

건강 유지에 가장 중요한 미생물로 간주됩니다.4 

장내 세균은 

음식물의 발효, 

병원균으로부터의 보호, 

면역 반응 자극, 

비타민 생산 등 여러 기능을 수행합니다.5 

일반적으로 장내 미생물은 

정장균, 박테로이데테스, 액티노박테리아, 프로테오박테리아, 푸소박테리아, 베루코마이크로바이러스를 포함한 6개의 문으로 구성되며, Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia,

그 중 정장균과 박테로이데테스가 주요한 종류입니다.6 

가장 많이 연구된 진균(장내 미생물)은 칸디다, 사카로마이세스, 말라세지아, 클라도스포리움입니다.7 인간의 장내 미생물에는 박테리아와 진균 외에도 바이러스, 파지, 고세균(주로 M. 스미티)도 포함되어 있습니다.8

Fig. 1

Human microbiota composition in different locations. Predominant bacterial genera in the oral cavity, respiratory tract, skin, gut, and vagina are highlighted

While less well established compared with gut, microbiota is also localized in other regions including the oral cavity, lung, vagina, and skin. Oral microbiota is considered the second largest microbial community in human.9 The oral cavity can be further divided into multiple habitats of microbiota, including saliva, tongue, tooth surfaces, gums, buccal mucosa, palate, and subgingival/supragingival plaque, which may exhibit substantial and rapid changes in composition and activity, owing to the factors such as changes in pH, gene mutations, and interactions among the bacteria.10 The microbiota composition in all seven sites shares overall similarities but with small scale differences. In general, the major bacteria present in oral microbiota are Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria.

장에 비해 잘 알려지지는 않았지만 구강, 폐, 질, 피부 등 다른 부위에도 미생물이 존재합니다. 구강 미생물은 인체에서 두 번째로 큰 미생물 군집으로 간주됩니다.9 구강은 침, 혀, 치아 표면, 잇몸, 협측 점막, 입천장, 치은/치태하 플라그를 포함한 여러 미생물 서식지로 더 나눌 수 있으며, pH 변화, 유전자 변이, 세균 간의 상호작용 등의 요인으로 인해 구성과 활성에 실질적이고 빠른 변화가 나타날 수 있습니다.10 7곳 모두에서 미생물 구성은 전체적으로 유사하지만 작은 규모의 차이가 있습니다. 

일반적으로 

구강 미생물총에 존재하는 주요 박테리아는 

펌미쿠테스, 프로테오박테리아, 박테로이데테스, 액티노박테리아, 푸소박테리아입니다.

Although healthy human lungs were long considered sterile, numerous studies have demonstrated that microbiota is also present in lung tissues.11 The core lung microbiota included Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. The composition of lung microbiota is primarily determined by three factors: 1) microbial immigration, 2) the elimination of microorganisms, and 3) the reproduction rates of microorganisms.12

건강한 사람의 폐는 오랫동안 무균 상태로 여겨졌지만, 수많은 연구를 통해 폐 조직에도 미생물이 존재한다는 사실이 밝혀졌습니다.11 

폐 미생물의 핵심에는 

방선균, 박테로이데테스, 펌미쿠테스, 프로테오박테리아가 포함됩니다. 

Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria

폐 미생물총의 구성은 주로 세 가지 요인에 의해 결정됩니다: 

1) 미생물 이동, 2) 미생물 제거, 3) 미생물의 번식률입니다.12

In human skin, the distribution and variety of glands and hair follicles vary among each geographic region. The physical and chemical differences of skin regions create distinct composition of microbiota.13 Generally, the skin microbiota is composed of Actinobacteria, Bacteroidetes, Cyanobacteria, Firmicutes, and Proteobacteria.

사람의 피부에서는 

땀샘과 모낭의 분포와 종류가 지역마다 다릅니다. 

피부 부위의 물리적, 화학적 차이로 인해 미생물총의 구성이 달라집니다.13 

일반적으로 피부 미생물총은 

방선균, 박테로이데테스, 시아노박테리아, 퍼미큐테스, 프로테오박테리아로 구성됩니다.
Actinobacteria, Bacteroidetes, Cyanobacteria, Firmicutes, and Proteobacteria.

In recent decades, tremendous amount of work has highlighted the relationship between microbiota and diseases such as cancers, diabetes, and neurological disorders. Moreover, manipulating microbiota in human body can be key for disease treatment. Here, we summarize and discuss the current state of knowledge of human microbiota in development of diseases, mediating health conditions, and the potential clinical application in disease treatments.

최근 수십 년 동안 엄청난 양의 연구가 

암, 

당뇨병, 

신경 장애와 같은 질병과 미생물총의 관계를 조명했습니다. 

또한 인체 내 미생물을 조작하는 것이 질병 치료의 핵심이 될 수 있습니다. 여기에서는 질병의 발생과 건강 상태를 매개하는 인체 미생물에 대한 지식의 현재 상태와 질병 치료에서의 임상 적용 가능성에 대해 요약하고 논의합니다.

Microbiota in health

The “healthy” gut microbiota

Intestinal microbial balance is closely relevant to human diseases and health. Compared with other regions of the body, the human gastrointestinal (GI) tract contains an abundant microbial community which gathers ~100 trillion microorganisms.14 Extensive studies have been performed to reveal the important relationship between gut microbiota and basic human biological processes. For example, current advances have shown that human microbiota is closely involved in nutrient extraction, metabolism, and immunity.15 Microbiota may affect biological processes via several mechanisms. For energy and nutrient extraction from food, microbiota plays crucial roles due to the versatile metabolic genes which provide independent unique enzymes and biochemical pathways.16 Moreover, the biosynthesis of bioactive molecules such as vitamins, amino acids and lipids, are also highly dependent on the gut microbiota.17 Regarding the immune system, the human microbiota not only protects the host from external pathogens by producing antimicrobial substances but also serves as a significant component in the development of intestinal mucosa and immune system.

장내 미생물 균형은 인간의 질병 및 건강과 밀접한 관련이 있습니다. 

신체의 다른 부위에 비해 인간의 위장관은 

약 100조 개의 미생물이 모여 있는 풍부한 미생물 군집을 포함하고 있습니다.14 

장내 미생물과 인간의 기본적인 생물학적 과정 사이의 중요한 관계를 밝히기 위해 광범위한 연구가 수행되었습니다. 

예를 들어, 최근의 연구 결과에 따르면 

인체 미생물은 영양소 추출, 신진대사 및 면역에 밀접하게 관여합니다.15 

미생물은 여러 가지 메커니즘을 통해 생물학적 과정에 영향을 미칠 수 있습니다. 음식물에서 에너지와 영양소를 추출하는 데 있어 미생물은 독립적인 고유 효소와 생화학 경로를 제공하는 다양한 대사 유전자로 인해 중요한 역할을 합니다.16 

또한 

비타민, 

아미노산, 지질과 같은 생리 활성 분자의 생합성도 

장내 미생물에 크게 의존합니다.17 

면역 체계와 관련하여 인체 미생물은 

항균 물질을 생산하여 

외부 병원균으로부터 숙주를 보호할 뿐만 아니라 

장 점막과 면역 체계 발달에 중요한 구성 요소로 작용하기도 합니다.

In healthy conditions, the gut microbiota exhibits stability, resilience, and symbiotic interaction with the host. There is a lot of research into the definition of a “healthy” gut microbiota and its link to host physiological functions. Gut microbiota is composed of bacteria, yeasts, and viruses. A healthy microbiota community often demonstrates high taxonomic diversity, high microbial gene richness and stable core microbiota.18 However, it should be noted that the relative distribution of microorganisms is unique between individuals and may undergo variations within the same individual. In human, gut microbiota may vary due to age and environmental factors (for example, medication usage). Additionally, gut microbiota varies in different anatomical parts of the GI tract. For example, Proteobacteria such as Enterobacteriaceae are found in the small intestine but not the colon. Instead, Bacteriodetes such as Bacteroidaceae, Prevotellaceae and Rikenellaceae are often found in the colon.19 Such variations are majorly due to the different environments.

건강한 상태의 장내 미생물은 

안정성과 회복력, 

숙주와의 공생적 상호 작용을 나타냅니다. 

"건강한" 장내 미생물의 정의와 숙주의 생리적 기능과의 연관성에 대한 많은 연구가 진행 중입니다. 

장내 미생물은 

박테리아, 

효모, 

바이러스로 구성됩니다. 

bacteria, yeasts, and viruses. 

건강한 미생물 군집은 높은 분류학적 다양성, 높은 미생물 유전자 풍부도, 안정적인 핵심 미생물 군집을 보이는 경우가 많습니다.18 그러나 미생물의 상대적 분포는 개체마다 고유하며 같은 개체 내에서도 변이가 있을 수 있다는 점에 유의해야 합니다. 사람의 장내 미생물은 나이와 환경적 요인(예: 약물 사용)에 따라 달라질 수 있습니다. 또한 장내 미생물은 위장관의 해부학적 부위에 따라 달라집니다. 예를 들어, 장내 세균과 같은 프로테오박테리아는 소장에서는 발견되지만 결장에서는 발견되지 않습니다. 대신 박테로이데테아과, 프레보텔라과, 리케넬라과와 같은 박테리오데테스는 결장에서 발견되는 경우가 많습니다.19 이러한 차이는 주로 서로 다른 환경 때문이라고 할 수 있습니다.

In the small intestine, the transit time is short and bile concentration is high, while in the colon, which has slower flow rates and milder pH, as well as larger microbial communities, especially anaerobic types, are commonly observed.20 Besides spatial distribution, gut microbiota also differs by age. Generally, the microbiota diversity increases in the time between childhood and adulthood and decreases at older age (over 70).21 Before the formation of a relatively stable gut microbiota composition, the diversity of children’s microbiota is dominated by Akkermansia muciniphila, Bacteroides, Veillonella, Clostridium coccoides spp., and Clostridium botulinum spp.22 At about age 3, children’s gut microbiota becomes comparable to that of adults, with three major microbial phyla including Firmicutes, Bacteroidetes and Actinobacteria becoming dominant.23 Subsequently at older age, dietary and immune system change potentially affect the composition of the human gut microbiota. Specifically, elder people tend to exhibit decreased Bifidobacterium and increased Clostridium and Proteobacteria.24 The decrease in the anaerobic bacteria Bifidobacterium is considered relevant to deteriorated inflammatory status due to its role in stimulating the immune system. Since the microbiota plays an important role in human well-being, also proactively involves in multiple biological processes and disease development, the research on human microbiota is going beyond compositional studies and investigation on members’ associations. Specifically, more attention has been paid on explaining the causality of microbiota functions, especially with the boom of new techniques of high-throughput sequencing, microbiota interactive modeling and simulation. Overall, further investigations are still necessary to unveil the roles of human microbiota, in order to support the development of microbiome-based diagnosis and personalized medicine (Table 1).

소장은 

통과 시간이 짧고 담즙 농도가 높은 반면, 

대장은 

유속이 느리고 pH가 약하며 

미생물 군집, 

특히 혐기성 미생물이 더 많이 관찰됩니다.20 

장내 미생물은 공간적 분포 외에도 연령에 따라 차이가 있습니다. 일반적으로 장내 미생물 다양성은 유년기와 성인기 사이에 증가하고 노년기(70세 이상)에는 감소합니다.21 

비교적 안정적인 장내 미생물 구성이 형성되기 전, 

어린이 미생물의 다양성은 

아커만시아 뮤시니필라, 

박테로이데스, 

베일로넬라, 

클로스트리디움 코코이데스(Clostridium coccoides spp.), 및 

클로스트리듐 보툴리눔균.22 

3세가 되면 

어린이의 장내 미생물총은 성인과 비슷해지며 

펌미쿠테스, 박테로이데테스, 액티노박테리아 등 3가지 주요 미생물 문이 우세해집니다.23 

이후 나이가 들면 

식이 및 면역 체계 변화가 장내 미생물총 구성에 잠재적으로 영향을 미칠 수 있습니다. 

특히 노인은 

비피더스균이 감소하고 

클로스트리디움과 프로테오박테리아가 증가하는 경향이 있습니다.24 

혐기성 세균인 비피더스균의 감소는 

면역 체계를 자극하는 역할로 인해 

염증 상태 악화와 관련이 있는 것으로 간주됩니다. 

미생물은 인간의 웰빙에 중요한 역할을 하고 여러 생물학적 과정과 질병 발생에도 적극적으로 관여하기 때문에 인체 미생물에 대한 연구는 구성 연구와 구성원의 연관성에 대한 조사를 넘어서고 있습니다. 특히 고처리량 시퀀싱, 미생물총 상호작용 모델링 및 시뮬레이션이라는 새로운 기술이 붐을 이루면서 미생물총 기능의 인과관계를 설명하는 데 더 많은 관심을 기울이고 있습니다. 전반적으로 마이크로바이옴 기반 진단 및 개인 맞춤형 의학 개발을 지원하기 위해 인간 미생물총의 역할을 밝히기 위해서는 아직 더 많은 연구가 필요합니다(표 1).

Table 1 Mouse models in microbiota research

Rodent models for human microbiota research

The human microbiota has attracted more and more research in recent decades. However, the studies of local microbiota require invasive sampling methods, with practical or ethical reasons in concern. Animal models, particularly mouse and rat models, have also been used to study the pathogenic and therapeutic potential of microbiota with varies diseases.25 With a majority of microbiota research is focusing on gut microbiota, the use of germ-free (GF) mouse model has become popular due to its translatability. It should be noted that, in order to translate such generated knowledge from rodent to human, the similarities and differences between their microbiota profile need to be considered. In Table 2, we summarized some commonly used rodent models and their role in microbiota research.

최근 수십 년 동안 인체 미생물총에 대한 연구가 점점 더 많이 이루어지고 있습니다. 그러나 인체 미생물을 연구하려면 침습적인 샘플링 방법이 필요하며, 실용적 또는 윤리적 문제가 우려됩니다. 동물 모델, 특히 마우스와 쥐 모델은 다양한 질병에 대한 미생물의 병원성 및 치료 가능성을 연구하는 데 사용되었습니다.25 대부분의 미생물 연구가 장내 미생물에 초점을 맞추고 있는 가운데, 무균(GF) 마우스 모델의 사용은 번역 가능성으로 인해 널리 사용되고 있습니다. 이렇게 생성된 지식을 설치류에서 인간으로 번역하기 위해서는 미생물총 프로필의 유사점과 차이점을 고려해야 한다는 점에 유의해야 합니다. 표 2에는 일반적으로 사용되는 설치류 모델과 미생물군 연구에서의 역할이 요약되어 있습니다.

Table 2 Summary of pathogenic microbiota and the related signaling pathways

The genome data showed that more than 85% of the genomic sequences between human and mouse are conserved, while the main difference is found in the primary sequence of regulatory elements. Cheng et al. reported that, in murine genome, half of the transcription factor binding sites may not have orthologous sequences in human genome.26 Moreover, the genomic studies have shown a significant difference in the immune system and its regulation in different species. Since gut microbiota has major impact to host innate and adaptive immune responses, the translation of findings from rodents to human should be carefully validated before drawing definite conclusions. While human and murine gut microbiota has 90% overlapping in phyla and genera levels, the composition and abundance of microbes have key discrepancies.27 For instance, the major difference is the Firmicutes/Bacteroidetes ratio, where it is significantly higher in human than mice. Particularly, human Bacteroidetes is mainly composed of Prevotellaceae and Bacteroidaceae, while mice Bacteroidetes are primarily composed of S24-7. Regarding the Firmicutes, Ruminococcaceae is the major phylum observed in human and Clostridiales is the major one observed in mice. Moreover, human and mouse each carries specific genera, such as Faecalibacterium, Megasphera, Asteroleplasma, Succinivibrio, Paraprevotella in human and Mucispirillum in mouse.28

게놈 데이터에 따르면 인간과 생쥐의 게놈 서열의 85% 이상이 보존되어 있으며, 주요 차이점은 조절 요소의 주요 서열에서 발견됩니다. Cheng 등은 쥐 게놈에서 전사 인자 결합 부위의 절반이 인간 게놈에서 상동 서열을 갖지 않을 수 있다고 보고했습니다.26 또한 게놈 연구에 따르면 종에 따라 면역 체계와 그 조절에 상당한 차이가 있는 것으로 나타났습니다. 

장내 미생물은 

선천성 및 후천성 면역 반응에 큰 영향을 미치기 때문에 

설치류의 연구 결과를 인간에게 적용하려면 확실한 결론을 도출하기 전에 신중하게 검증해야 합니다. 

사람과 쥐의 장내 미생물은 

문과 속 수준에서 90%가 겹치지만, 

미생물의 구성과 풍부도에는 중요한 차이가 있습니다.27 

예를 들어, 

가장 큰 차이점은 

피르미쿠테스/박테로이데테스 비율로, 

사람이 쥐보다 훨씬 더 높다는 것입니다. 

특히 사람의 박테로이데테스는 

주로 프리보텔라과와 박테로이드과로 구성되어 있는 반면, 

생쥐의 박테로이데테스는 주로 S24-7로 구성되어 있습니다. 

Firmicutes의 경우, 

사람에서 관찰되는 주요 문은 루미노코카세아과이고 생쥐에서 관찰되는 주요 문은 클로스트리디움과입니다. 또한 인간과 마우스는 각각 특정 속을 가지고 있는데, 인간은 Faecalibacterium, Megasphera, Asteroleplasma, Succinivibrio, Paraprevotella를, 마우스는 Mucispirillum을 가지고 있습니다.28

Colonization resistance

Humans are born with and form a large community of symbiotic and pathogenic microbes, which inhabit our gut, skin, mucosal passages, and form a stable community that is resistant to external pathogens. The term “colonization resistance” was initially coined in the 1950s when Bohnhoff et al. found that mice became significantly sensitive to a specific type of bacterial infection after antibiotic treatment.29 Later, such conclusion was further applied to the phenomenon that current microbiota could provide resistance the colonization of invading pathogenic species, also from which researchers recognize. As a result, the microbiota is crucial shield in protecting us from exogenous microorganisms. Despite the fact that microbiota colonization resistance has not been fully elucidated, with the advent of GF animal models, researchers have discovered several potential mechanisms such as nutrient competition,30 antimicrobial production, and bacteriophage deployment. Another example of colonization resistance is the interaction of symbolic and pathogenic E. coli., where indigenous E. coli strains compete with pathogenic E. coli O157:H7 for the amino acid proline in consuming nutrients.In this section, we focus on the gut microbiota and colonization resistance. The vaginal and skin microbiota and their colonization resistance are also discussed.

인간은 

장, 피부, 점막 통로에 서식하는 공생 및 병원성 미생물의 대규모 군집을 가지고 태어나며 

외부 병원균에 저항하는 안정된 군집을 형성합니다. 

"군집화 저항성"이라는 용어는 1950년대에 본호프 등이 생쥐가 항생제 치료 후 특정 유형의 박테리아 감염에 상당히 민감해지는 것을 발견하면서 처음 만들어졌습니다.29 이후 이러한 결론은 현재의 미생물 군집이 침입한 병원성 종의 군집화에 저항성을 제공할 수 있다는 현상에도 적용되어 연구자들이 인식하고 있습니다. 

결과적으로 

미생물 총은 외래 미생물로부터 우리를 보호하는 중요한 방패입니다. 

미생물 군집화 저항성이 완전히 밝혀지지는 않았지만, GF 동물 모델의 등장으로 연구자들은 영양소 경쟁,30 항균제 생산, 박테리오파지 배치와 같은 몇 가지 잠재적인 메커니즘을 발견했습니다. 군집화 저항성의 또 다른 예로는 토착 대장균과 병원성 대장균의 상호작용이 있는데, 토착 대장균 균주가 병원성 대장균 O157:H7과 영양소 섭취 시 아미노산 프롤린을 놓고 경쟁하는 것으로, 이 섹션에서는 장내 미생물과 식민지화 저항성에 초점을 맞추고 있습니다. 질과 피부 미생물총과 이들의 식민지화 저항성에 대해서도 설명합니다.

The GI tract digests proteins as well as sugars from foods. Metabolizing polysaccharides and specific proteins requires multiple enzymes produced by various bacteria. For example, Bacteroides species in the large intestine are responsible for sugar harvest.31 Pathogenic Enterobacteriaceae also utilizes sugar and amino acids in gut.32 Freter et al. proposed a niche hypothesis which has been supported by in vitro and in vivo studies. The hypothesis states that the composition and abundance of gut microbiota is determined by one or a few nutritional substrates.33 In mouse models, when a single type of sugar is removed, both the microbiota composition and the ability of resistance to pathobiont were altered.34

위장관은 

음식에서 단백질과 당분을 소화합니다. 

다당류와 특정 단백질을 대사하려면 

다양한 박테리아가 생산하는 여러 효소가 필요합니다. 

예를 들어, 

대장에 있는 박테로이데스 종은 당 수확을 담당합니다.31 

병원성 장내 세균도 장에서 

당과 아미노산을 이용합니다.32 

프레터 등은 시험관 및 생체 내 연구에서 뒷받침된 틈새 가설을 제안했습니다. 이 가설에 따르면 장내 미생물의 구성과 풍부함은 하나 또는 몇 가지 영양 기질에 의해 결정됩니다.33 마우스 모델에서 한 가지 유형의 당을 제거하면 미생물 구성과 병원성 장내 세균에 대한 저항 능력이 모두 변경되었습니다.34

Probably due to the necessity of competing with foreign bacteria, gut bacteria have developed various ways of suppressing competitors, including the secretion of diverse bacteriocins. A contact-dependent competition in the gut, namely type 6 secretion system, was originally identified in the bacteria secretion system involved with eukaryotic cells,35 which was later found relevant to intraspecies killing. The system works by contact cells delivering effectors, such as degraders of nucleotide, cell walls and membranes, into the cytoplasm.36 Moreover, this system may also contribute to the abundance of Bacteroides species in the mouse and human gut.37 Besides the type 6 system, other systems such as type 7 (or ESX system), also mediate the intra- and interspecies killing.38 Currently, the contact-dependent systems of gut microbiota inhibition and growth are being increasingly discovered. The intermediate genes, immunity and effectors may serve as amenable factors which are modifiable via bioengineering methods. Additionally, they are valuable for studying the interactions, structure, and dynamics of the gut microbiota. However, the exact role of bactericidal mechanisms remain poorly understood and further studies are still necessary.

장내 세균은 

외부 박테리아와 경쟁해야 할 필요성 때문에 

다양한 박테리오신 분비를 포함하여 경쟁자를 억제하는 다양한 방법을 개발해 왔습니다. 

장내에서 접촉에 의존하는 경쟁, 즉 6형 분비 시스템은 원래 진핵세포와 관련된 박테리아 분비 시스템에서 확인되었으며,35 나중에 종내 사멸과 관련이 있는 것으로 밝혀졌습니다. 이 시스템은 접촉 세포가 뉴클레오타이드, 세포벽 및 세포막의 분해제와 같은 효과제를 세포질로 전달함으로써 작동합니다.36 또한 이 시스템은 마우스와 사람의 장에서 박테로이데스 종의 풍부함에도 기여할 수 있습니다.37 6형 시스템 외에도 7형(또는 ESX 시스템)과 같은 다른 시스템도 종내 및 종간 사멸을 매개합니다.38 현재 장내 미생물의 억제 및 성장의 접촉 의존적 시스템이 점점 더 많이 발견되고 있습니다. 중간 유전자, 면역 및 이펙터는 생명 공학적 방법을 통해 수정할 수 있는 인자로 작용할 수 있습니다. 또한 장내 미생물총의 상호작용, 구조 및 역학을 연구하는 데에도 유용합니다. 그러나 살균 메커니즘의 정확한 역할은 아직 제대로 이해되지 않았으며 추가 연구가 필요합니다.

Bacteriophage deployment is another mechanism of colonization resistance in the gut; however relevant research is still in an immature stage.32 It has been revealed that two cycles, namely the lytic cycle and the lysogenic cycle, are involved in bacteriophage infection. Phages duplicate by injecting genomic segment into the bacterial cytoplasm, after which the two cycles start to branch. Phages in lysogenic stage insert their genome into bacteria genome and render prophages, which guarantees the replication of phage DNA and entrance into the lytic cycle. In the lytic cycle, phage DNA starts replication, modification and expression‎, resulting in new phage assembly, cell lysis and phage spreading.39 There are several potential mechanisms to prevent bacteriophage infection including the blockage of surface receptor recognition, superinfection exclusion system and abortive infection. For infection prevention, resistant strains exhibit compositions similar to bacterial surface and thereby could serve as decoys for attacking phages.40 DNA replication could be prevented by “restriction-modification” system, mainly by methyltransferase and restriction endonucleases. This system serves as the primitive inner bacteria defense system in the human body, despite the disadvantage of this system that it also damages the host DNA.41 The defense system of bacteria also inspired the discovery of Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, which has been extensively reviewed.42 Later, newer defense systems, such as bacteriophage exclusion have been discovered to work by preventing DNA replication.43 The third potential mechanism is the abortive infection, where the infected cells are killed, and surrounding ones are protected. This mechanism is not yet fully elucidated, and still needs further exploration.

박테리오파지 배치는 장내 식민지화 저항의 또 다른 메커니즘이지만 관련 연구는 아직 미성숙 단계에 있습니다.32 박테리오파지 감염에는 두 가지 주기, 즉 용해 주기와 용해 주기가 관여하는 것으로 밝혀졌습니다. 파지는 게놈 세그먼트를 박테리아 세포질에 주입하여 복제하고, 그 후 두 주기가 분기되기 시작합니다. 용해 단계의 파지는 게놈을 박테리아 게놈에 삽입하고 파지 DNA의 복제와 용해 주기로의 진입을 보장하는 프로파지를 렌더링합니다. 용해 주기에서 파지 DNA는 복제, 변형 및 발현을 시작하여 새로운 파지 조립, 세포 용해 및 파지 확산을 초래합니다.39 표면 수용체 인식 차단, 슈퍼감염 배제 시스템, 감염 중단 등 박테리오파지 감염을 방지하는 몇 가지 잠재적 메커니즘이 있습니다. 감염 예방을 위해 내성 균주는 박테리아 표면과 유사한 구성을 나타내어 파지를 공격하는 미끼 역할을 할 수 있습니다.40 DNA 복제는 주로 메틸 트랜스퍼라제 및 제한 엔도뉴클레아제에 의한 "제한 변형" 시스템에 의해 방지될 수 있습니다. 이 시스템은 숙주 DNA도 손상시킨다는 단점이 있지만 인체의 원시적인 박테리아 내부 방어 시스템으로 작용합니다.41 박테리아의 방어 시스템은 또한 광범위하게 검토되고 있는 CRISPR(Clustered 정기적으로 간격을 둔 짧은 팔린드로믹 반복)-Cas9의 발견에 영감을 주었습니다.42 이후 박테리오파지 배제와 같은 새로운 방어 시스템이 DNA 복제를 방지하는 것으로 밝혀졌습니다.43 세 번째 가능한 메커니즘은 감염된 세포가 죽고 주변 세포가 보호되는 중단 감염입니다. 이 메커니즘은 아직 완전히 밝혀지지 않았으며 더 많은 연구가 필요합니다.

Besides the gut, the vaginal microbiota also plays crucial in resisting the colonization of invading pathogenic microbiomes, which is important for preventing sexually transmitted infections, urinary tract infections and vulvovaginal candidiasis.44 Traditionally, the cultivation methods suggested the vaginal microbiota as a community that lacks species that produce lactic acid (e.g., Lactobacillus species).45 Moreover, the vaginal microbial community is overabundant with anaerobic bacteria including Gardnerella vaginalis, Prevotella spp., Mobiluncus spp., Ureaplasma urealyticum, and Mycoplasma hominis.46 Later studies identified Lactobacilli as important members of vaginal microbiota.

질 미생물은 

장 외에도 침입하는 병원성 미생물의 군집에 저항하는 데 중요한 역할을하며, 

이는 성병, 요로 감염 및 외음 질 칸디다증 예방에 중요합니다 .44 

전통적으로 배양 방법은 질 미생물을 젖산을 생성하는 종 (예 :, 락토바실러스 종).45 또한, 질 미생물 군집에는 가드네렐라 바지날리스, 프레보텔라 종, 모빌룬쿠스 종, 우레아플라즈마 우레알리티움, 마이코플라즈마 호미니스 등 혐기성 박테리아가 풍부합니다.46 이후 연구에서는 락토바실리가 질 미생물의 중요한 구성원인 것으로 밝혀졌습니다.

To better understand the vaginal microbiota, researchers have grouped the vaginal bacteria community into five types known as community state types (CSTs) I–V. All five communities are dominated by L. crispatus, L. gasseri, L. iners, polymicrobial flora including Lactobacillus and bacterial vaginosis-associated bacteria (BVAB), and L. jensenii. The CST I, III and IV are commonly found in women and have been extensively studied, while the other two types are rare.47 The Lactobacillus species are believed to provide protective functions by generating bactericidal and virucidal agents, including lactic acid and bacteriocins.48 As a result, the vaginal Lactobacilli is considered a risk factor of sexually transmitted infections such as human immunodeficiency virus (HIV),49 human papillomavirus,50 and herpes simplex virus infections.51 In a previous randomized clinical study, Schwebke et al. found that women treated with atypical gram positive stain smears showed lower risk for incident chlamydial genital infection.52 In another study which involves 3620 nonpregnant women, Brotman et al. found a strong association between bacterial vaginosis and elevated risk of genital infection.53 So far, only limited studies are available regarding vaginal colonization resistance, but it has been widely agreed upon that the vaginal colonization resistance plays crucial protective roles in preventing pathogenic infections.

질내 미생물을 더 잘 이해하기 위해 연구자들은 질내 박테리아 커뮤니티를 커뮤니티 상태 유형(CST) I-V로 알려진 다섯 가지 유형으로 분류했습니다. 다섯 가지 커뮤니티 모두 L. 크리스파투스, L. 가세리, L. 이너, 락토바실러스와 세균성 질염 관련 박테리아(BVAB)를 포함한 다균총, 그리고 L. 젠세니가 주류를 이루고 있습니다. CST I, III, IV는 여성에게서 흔히 발견되며 광범위하게 연구된 반면, 나머지 두 유형은 드물다.47 락토바실러스 종은 젖산과 박테리오신을 포함한 살균 및 바이러스 살균제를 생성하여 보호 기능을 제공하는 것으로 여겨진다.48 

결과적으로 

질내 락토바실러스는 

인간 면역결핍 바이러스(HIV)49 인유두종 바이러스50 및 

단순 포진 바이러스 감염과 같은 성병의 위험 요소로 간주된다.51 

이전의 무작위 임상 연구에서 슈웹케 등은 비정형 그람 양성 도말 검사로 치료받은 여성이 클라미디아 생식기 감염 위험이 낮다는 것을 발견했습니다.52 임신하지 않은 여성 3620명을 대상으로 한 다른 연구에서 브로트만 등은 세균성 질염과 생식기 감염 위험 증가 사이의 강력한 연관성을 발견했습니다.53 지금까지 질 군집화 저항성에 관한 연구는 제한적이었지만 질 군집화 저항성은 병원성 감염 예방에 중요한 보호 역할을 한다는 데 널리 동의하고 있습니다.

The skin, as the largest organ in human body, is colonized by dense microbiome communities. Healthy skin with balanced microbiota is believed to contribute to colonization resistance against pathogenic infections. Changes in the skin microbiota (dybiosis) are highly associated with many common skin diseases, such as acne, a chronic inflammatory skin condition mediated by Propionibacterium acnes.54 Severity of P. acnes pathophysiology is correlated with the level of sebum secretion. As a result, acne is preval‎ent in teenager and a minor portion of adults. Also, the production of bacteriocins by current residing microbiome provides further protection against invading species.55 For example, S. epidermidis was suggested to destroy S. aureus biofilms via a serine protease.56 In addition, S. lugdunensis was discovered to produce lugdunin, an inhibitor of nasal colonization with S. aureus. Lugdunin also inhibits other pathogens including Enterococcus faecalis, Listeria monocytogenes, Streptococcus pneumoniae, and Pseudomonas aeruginosa.57 Overall, understanding the interactions among skin microbiota communities will be beneficial to the control of skin diseases or disorders.

인체에서 가장 큰 기관인 피부는 

밀집된 미생물 군집으로 이루어져 있습니다. 

균형 잡힌 미생물 군집을 가진 건강한 피부는 

병원성 감염에 대한 군집화 저항력에 기여하는 것으로 알려져 있습니다. 

피부 미생물총의 변화(이바이오시스)는 

프로피오니박테리움 아크네스가 매개하는 

만성 염증성 피부 질환인 여드름과 같은 많은 일반적인 피부 질환과 관련이 깊습니다.54 P. 

아크네스 병리 생리의 심각성은 피지 분비 수준과 상관관계가 있습니다. 그 결과 여드름은 청소년과 일부 성인에게 널리 퍼져 있습니다. 또한 현재 상주하는 마이크로바이옴에 의한 박테리오신의 생산은 침입 종에 대한 추가적인 보호 기능을 제공합니다.55 

예를 들어, S. 에피더미디스는 세린 프로테아제를 통해 S. 아우레우스 바이오필름을 파괴하는 것으로 제안되었습니다.56 또한 S. 루그두넨시스는 S. 아우레우스 비강 집락화 억제제인 루그두닌을 생성하는 것으로 밝혀졌습니다. 루그두닌은 또한 엔테로코커스 페칼리스, 리스테리아 모노사이토제네스, 스트렙토코커스 뉴모니아에, 녹농균 등 다른 병원균을 억제합니다.57 전반적으로 피부 미생물 군집 간의 상호작용을 이해하면 피부 질환이나 장애를 관리하는 데 도움이 될 것입니다.

The microbiota–gut–brain axis

In the 1980s, with the development of brain imaging, our understanding of the critical roles of the gut–brain axis in homeostasis was established.58 Researchers then reached consensus that this axis is bidirectional. On the one hand, gut distension activates key pathways within the brain, while on the other hand, such pathways are involved with gut disorders, for example irritable bowel syndrome (IBS).59 In the past decades, gut microbiota was identified as a key regulator of the gut–brain axis. Multiple animal models as well as human studies have been used to model the gut-brain axis. The factors contributing to gut–brain axis balance are summarized in Fig. 2. A recent study by Chen et al.60 found that, due to the loss of histone demethylases (eg, KDM5), fruit flies (Drosophila melanogaster) showed intestinal barrier dysfunction and change in social behaviors such as mating. This is one of the direct pieces of evidence that mating behavior is likely relevant to the enteric bacteria. Similarly, in mouse models, Bravo et al. performed chronic feeding with lactic acid bacteria Lactobacillus rhamnosus on mice and found region-dependent alterations in the brain such as GABA gene upregulation in cortical regions and downregulation in the hippocampus, amygdala, and locus coeruleus.61 Thus, it indicates that gut microbiota could influence neurophysiology and behavior.

1980년대에 뇌 영상이 발달하면서 항상성에서 장-뇌 축의 중요한 역할에 대한 이해가 확립되었습니다.58 이후 연구자들은 이 축이 양방향적이라는 데 동의하게 되었습니다. 

한편으로는 

장의 팽창이 뇌의 주요 경로를 활성화하고, 

다른 한편으로는 이러한 경로가 과민성 대장 증후군(IBS)과 같은 

장 질환에 관여한다는 것입니다.59 

지난 수십 년 동안 

장내 미생물이 

장-뇌 축의 주요 조절자로 밝혀졌습니다. 

장-뇌 축을 모델링하기 위해 여러 동물 모델과 인간 연구가 사용되었습니다. 장-뇌 축의 균형에 기여하는 요인은 그림 2에 요약되어 있습니다. Chen 등.60의 최근 연구에 따르면 히스톤 탈메틸화 효소(예: KDM5)의 손실로 인해 초파리(Drosophila melanogaster)는 장 장벽 기능 장애와 짝짓기와 같은 사회적 행동의 변화를 보였습니다. 이는 짝짓기 행동이 장내 세균과 관련이 있을 수 있다는 직접적인 증거 중 하나입니다. 마찬가지로 마우스 모델에서 브라보 등은 쥐에게 유산균인 락토바실러스 람노수스를 만성적으로 먹인 결과 피질 영역의 GABA 유전자 상향 조절과 해마, 편도체, 코에룰루스 유전자 하향 조절 등 뇌에서 영역 의존적인 변화를 발견했습니다.61 따라서 장내 미생물이 신경 생리와 행동에 영향을 줄 수 있음을 시사합니다.

Moreover, Buffington et al.62 reported that maternal high-fat diet induces gut microbiota shifts and physiological change in the offspring brain, such as fewer oxytocin immunoreactive neurons in the hypothalamus. Additionally, offspring social deficits and gut microbiota shifts could be prevented by co-housing with offspring of regular-diet mothers.62 This finding further supports that gut microbiota negatively impacts offspring social behavior. Gut microbiota also affects the wound-healing process. Mice fed with lactic acid bacteria Lactobacillus reuteri showed enhanced wound-healing properties via upregulation of oxytocin, which is a regulatory factor that activates host CD4 + Foxp3 + CD25 + immune T regulatory cells.63 Other studies also showed that gut microbiota impacts cognition, anxiety, depression-related behavior, and reward/addiction pathways of mice.64 Studies in chimpanzees (Pan troglodytes) revealed the other direction of microbiota in the gut-brain axis: composition of gut microbiota is impacted by various social interactions.65 Studies of gut–brain axis in humans showed similar results regarding the connection between brain physiology and gut microbial ecology. In 2016, Allen et al. performed a preclinical study on healthy volunteers to test if psychobiotic consumption could affect neurophysiological responses such as stress response, cognition, and brain activity.66 

또한, 버핑턴 등.62은 모체의 고지방 식단이 시상하부의 옥시토신 면역 반응 뉴런이 줄어드는 등 새끼의 뇌에서 장내 미생물의 변화와 생리적 변화를 유도한다고 보고했습니다. 또한, 일반 다이어트를 하는 어미의 새끼와 함께 살면 새끼의 사회적 결핍과 장내 미생물총 변화를 예방할 수 있습니다.62 이 발견은 장내 미생물이 새끼의 사회적 행동에 부정적인 영향을 미친다는 사실을 뒷받침합니다. 장내 미생물은 상처 치유 과정에도 영향을 미칩니다. 유산균인 락토바실러스 루테리를 먹인 쥐는 숙주 CD4 + Foxp3 + CD25 + 면역 T 조절 세포를 활성화하는 조절 인자인 옥시토신의 상향 조절을 통해 상처 치유력이 강화된 것으로 나타났습니다.63 

다른 연구에서도 

장내 미생물이 쥐의 인지, 불안, 우울증 관련 행동, 보상/중독 경로에 영향을 미치는 것으로 나타났습니다.64 

침팬지(팬 트로글로디테스)를 대상으로 한 연구에서는 장-뇌 축에서 미생물의 다른 방향, 즉 장내 미생물 구성이 다양한 사회적 상호작용에 영향을 받는다는 사실이 밝혀졌습니다.65 인간의 장-뇌 축에 대한 연구에서도 뇌 생리와 장내 미생물 생태 사이의 연관성에 관한 유사한 결과가 나타났습니다. 2016년에 Allen 등은 건강한 지원자를 대상으로 전임상 연구를 수행하여 항생제 섭취가 스트레스 반응, 인지 및 뇌 활동과 같은 신경생리학적 반응에 영향을 미칠 수 있는지 테스트했습니다.66 

Results indicated that consumption of B. longum 1714 is associated with reduced stress and improved memory. However, in this study, the number of samples was small (N = 11) and confounding factors such as the environment, diet, lifestyles, and genetic variations were not fully considered. In another study using mouse models, gut microbiota was discovered to be necessary for motor deficits, microglia activation, and αSyn pathology.67 The authors transplanted the microbiota from Parkinson’s disease patients and found that the mice showed enhanced physical impairments compared with mice with microbiota from healthy donors. Thus, it suggests that gut microbes are potentially relevant to neurodegenerative diseases such as Parkinson’s disease and could be used as a therapeutic marker. Furthermore, researchers found there is significant difference in the component of microbes in the gut of children with and without autism spectrum disorders, a pervasive developmental disorder characterized by social abnormalities, communication impairments, and repetitive behaviors.68 This is indeed another evidence showing the relationship between GI microbiota and neurophysiology.

연구 결과, B. 롱검 1714의 섭취는 스트레스 감소 및 기억력 개선과 관련이 있는 것으로 나타났습니다. 그러나 이 연구에서는 샘플 수가 적었고(N = 11) 환경, 식단, 생활 습관, 유전적 변이와 같은 혼란 요인을 충분히 고려하지 않았습니다. 

마우스 모델을 사용한 또 다른 연구에서 

장내 미생물은 

운동 결손, 

미세아교세포 활성화 및 αSyn 병리에 필요한 것으로 밝혀졌습니다.67 

저자들은 

파킨슨병 환자의 미생물을 이식한 결과 

건강한 기증자의 미생물을 이식한 마우스에 비해 신체 장애가 개선된 것으로 나타났습니다. 

따라서 장내 미생물이 파킨슨병과 같은 신경 퇴행성 질환과 관련이 있으며 치료 마커로 사용될 수 있음을 시사합니다. 

또한 연구자들은 사회적 이상, 의사소통 장애, 반복적인 행동을 특징으로 하는 

만연한 발달 장애인 자폐 스펙트럼 장애가 있는 아동과 없는

동의 장내 미생물 구성에 상당한 차이가 있음을 발견했습니다.68

이는 실제로 장내 미생물과 신경 생리학 사이의 관계를 보여주는 또 다른 증거입니다.

Fig. 2

Bidirectional gut-brain axis interactions and the common factors contributing to the gut–brain activity

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Many pathways have been proposed to mediate the communication within the gut-brain-axis. The signal passage along gut-brain-axis involves the interactions among autonomic nervous system (ANS), enteric neural system (ENS), central nervous system (CNS), immune system, and endocrine system. The ANS, which controls GI tract functions such as gut movement and mucus production, is a complex network that integrates the communication between the gut and the brain, as well as induces CNS effects in the gut since CNS is responsible for processing the visceral information.69 The ANS directly triggers neurological responses in the gut which further causes physiological changes. The ANS also mediates the interaction between the gut microbiota and ENS. ANS-triggered ENS activity results in the absorption and delivery of pre-/probiotics in the GI tract such as starches and other microbial nutrients.70 Microbes could affect the neural system via neuromodulatory metabolites including tryptophan, serotonins, GABA and catecholamines.58 Previous study on mice models have proved that gut microbial metabolite 4-ethylphenylsulfate induces mental disorders (such as anxiety-like behavior).71 

Additionally, the gut microbial tryptophan metabolite indole was found relevant to the activation of the vagus nerve, the 10th cranial nerve that connects the gut and brain.72 In this study, rats with acute and high indole overproduction showed decreased motor activity, while rats with chronic and moderate indole increase showed enhanced anxiety-like behavior. Similarly, the bacteria Lactobacillus rhamnosus was found to induce information transmission in vagal afferents in the mesenteric nerve bundle. Such induction could be eliminated by vagotomy.73 Also, treatment with bacteria Lactobacillus reuteri in rats models was found to help mice with social deficits; such change was also restored in mice with vagotomy.74 Recent studies also reported potential mechanisms of microbiota–ENS interaction. As one of the major serotonin producers in human, gut microbiota is linked to ENS activation by 5-HT receptors. De Vadder et al. demonstrated the interaction by pharmacological modulation of 5-HT receptors and depletion of endogenous 5-HT.75 The presence of 5-HT receptor antagonist negatively affects ENS activity. The gut microbiota also communicates with another major neuroendocrine system, the hypothalamic–pituitary–adrenal (HPA) axis, which is known to coordinate stress response.76 Signal molecules generated in HPA are distributed throughout the body and affect gut microbiota. To illustrate the connection between HPA and gut microbiota, GF mice are used. Studies revealed that GF mice exhibited elevated plasma corticosterone, indicating hyperresponsive HPA axis and the regulatory effect of gut microbiota.77 In human, it has been reported that bowel syndrome patients (with gut microbiota changes) tend to have exaggerated adrenocorticotrophic hormone response to corticotrophin releasing factor infusion.78 Despite there have been numerous of studies on the bidirectional pathways between the gut-microbiota and the brain, it is still difficult to fully understand the mechanisms.

Numerous influencing internal and external factors have been discovered to modulate the gut-brain axis of the host, including genetics, socioeconomic status, diet, medications, and environmental factors.79 Genetics and epigenetics are important in understanding the brain as well as gut health. An increasing number of studies have been performed on the relationship between host (human or mice) and microbiota genetics. One of the important components of microbiota-host genetic interaction is via the modulation of RNAs. For example, in GF mice models, researchers found that microRNAs were dysregulated in GF mice in certain brain regions, amygdala and prefrontal cortex, which suggests a close relationship between gut microbiota and brain physiology.80 In another study of gut microbiota and hippocampal RNAs using GF mice, Chen et al. found that gut microbiota significantly regulates the expression‎ level of hippocampal microRNAs and mRNAs. Specifically, re-colonizing the gut microbiota in GF mice did not reverse the behavioral change such as less latency to familiar food, but microRNAs and mRNAs were significantly restored.81

As mentioned before, lifestyles, especially diet, have been shown to be among the most critical factors in modulating the gut-brain axis. For example, a high-fat diet with only animal products will shift the microbiota composition profoundly. Specifically, animal models with high-fat diet showed reduction in Bacteroidetes levels and an increase in both Proteobacteria and Firmicute levels.82,83 Proteobacteria (Bilophila wadsworthia) abundance was also observed in another study of high-fat diet-fed animals.84 On the contrary, the Mediterranean diet composed of whole grains, nuts, vegetables, fruits, and only certain animal products (fish and poultry) showed beneficial results in hosts. In human intervention studies of diet, consumption of the Mediterranean diet has been shown to significantly reduce the occurrence of neurovegetative disorders, psychiatric conditions, cancer, and cardiovascular diseases.85 Mediterranean diet also showed correlation with reduced risk of depression.86 Though strong evidence showed that the Mediterranean diet is beneficial to the hosts, further mechanism studies are still necessary to illustrate the regulatory mechanism of such diet on the gut–brain axis. Another type of diet with high fat and low carbohydrate, namely the ketogenic diet, is popular because it forces the consumption of the body’s reserved fat. Ketogenic diet was considered to be able to inhibit apoptosis in neurodegenerative diseases because of the increase in serum ketones, which has been shown to improve mitochondrial activity.87 Studies have shown that the ketogenic diet also causes shift in microbiota abundance in the gut. Specifically, Akkermansia, Parabacteroides, Sutterella, and Erysipelotrichaceae levels were significantly higher in mice on ketogenic diets.88 Moreover, mice on ketogenic diets were better protected from acute epileptogenic seizures compared with the control group on a normal diet. Furthermore, colonization with increased microbiomes in GF mice also showed correlation with seizure protection, as well as alterations in hippocampal metabolomic profiles. All above studies support the conclusion that changes in lifestyles have marked impacts on the gut microbiota.

Finally, medications, especially antibiotics, will directly affect the gut microbiota and subsequently the gut–brain axis. Besides antibiotics, a growing number of studies also showed that nonantibiotic drugs can change the gut–microbiota composition, as well as neurophysiology and behavior.89 In a large-scale gut-microbiota project named the Belgian Flemish Gut Flora Project, antibiotics, osmotic laxatives, hormones, benzodiazepines, antidepressants, antihistamines, and inflammatory bowel disease drugs were found to be highly relevant to the variation of gut microbiota.90 Other studies also showed that proton pump inhibitors, metformin, and statins can impact gut microbiota.91 Moreover, due to the rise of interest in the gut–brain axis, more and more psychotropic medications were discovered to have antimicrobial activities. Examples are serotonin antagonists such as sertraline, paroxetine, and fluoxetine, which have antimicrobial activity against gram-positive bacteria such as Staphylococcus and Enterococcus.92 These findings indicate the potential impact of medications on the gut–brain axis.

Microbiota in the development of immune systems

Microbiota in different organs exhibits distinct characteristics and compositions. As a result, microbiota interacts with multiple biological processes of the host. In this section, we introduce the interactions between human microbiota in gut, oral cavities, lungs, skin, vagina, and the development of immune systems.

The human immune system is comprised of innate and adaptive immune responses, both of which have been shown to extensively interact with microbiota. The innate immune response has critical role in maintaining a homeostatic environment by eliminating pathogenic bacteria and regulating the adaptive response to microbiota. These effects are mediated by factors such as secretory IgA (sIgA), toll-like receptor 5 (TLR5), autophagy, and inflammasomes.93 For instance, slgA can bind and form complexes with commensal bacteria, which selectively presents the bacterial components to tolerogenic dendritic cells. As an anti-inflammatory molecule, slgA can reduce the inflammatory response that could result from the immense bacteria load in the organs. On the other hand, dysbiosis of microbiota can alter the sIgA response and lead to unregulated bacterial growth. Hapfelmeier et al. showed that microbiota-specific sIgA response was observed in GF mice using reversible microbial colonization system.94 The sIgA induction was confirmed as a gradual response to current bacterial exposure, suggesting a crosstalk between microbiota and immune system. The adaptive immune response is another important part to maintain a healthy microbiota and immune balance. Particularly, the education of adaptive immune response is achieved by differentiation and maturation of B and T cells and establishment of immune tolerance to microbiota.95 Depending on the bacteria species, the CD4 T cell responses vary significantly, which leads to the differentiation into distinct subsets and the subsequent pro-inflammatory cytokine release such as interferon-γ and interleukin IL-17A. The crosstalk between microbiota and adaptive immune response will be further discussed in the following sections.

The GI tract hosts a large number of immune cells, which constantly communicate with the gut microbiota. The maturation of the immune system needs the development of commensal microorganism. One of the mechanisms of gut microbiota affecting the immune system is by mediating neutrophil migration, which subsequently impacts T cell differentiation into various types such as helper T cells (Th1, Th2, and Th17) and regulatory T cells.96 Disorders in microbiota development during the maturation of the immune system could lead to deteriorated immunological tolerance and autoimmune diseases.97 Additionally, heterogeneous molecules produced by microbiota may induce immune response and stimulate inflammation or chronic tissue damage.98 The general interactions of microbiota and host immune response during healthy and disease states are depicted in Fig. 3.

Fig. 3

Factors affecting microbiota-associated chronic inflammation in healthy and disease state

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Human immune system is closely related to the microbiota as a complex symbolic relationship during the co-evolution of vertebrates and microbiota.99 The vertical transmission from the mother’s microbiota to the child at birth is considered the initial introduction of microbiota to the child. As a result, infants born by Cesarean section are colonized with bacteria of the epidermal origin, which might link to higher risk of developing allergies and asthma compared with infants who received initial microbiota from the maternal vaginal flora.100 Such difference in immune system and microbiota would be gradually eliminated during growth. As mentioned before, the infant’s microbiota stabilizes at ~1-year-old and resembles that of adults. The neonatal immune system also rapidly develops under the impact of dynamic microbiota.101 In addition to the microbiota transmission during birth, breastfeeding also plays crucial roles in the establishment of infant immune system as well as microbiota. Besides the required nutrients and antimicrobial proteins, breast milk provides slgA, which is specifically shaped by the maternal microbiota. As a result, infants’ microbiota is seeded not only by the maternal epidermal or virginal origin but reinforced by the sIgA shaped by maternal microbiota. Moreover, before the solidification of infant immune system, the sIgA significantly protects the newborn against pathogens.99 To summarize, the maternal-neonatal microbial bond supports the close relationship between microbiota and the immune system.

The gut microbiota has been closely connected to immunological response due to the fact that enteric microorganisms may promote macromolecules and antigens through the gut epithelium.102 The principal component of bacterial flagellum, namely flagellin, elaborates the relationship between gut epithelial integrity and host immunity. Flagellin is recognized by TLR5, which is found actively expressed in B-cells and CD4 + T-cells. Differentiated B-cells produce IgA, which neutralizes the pathogen and potential subsequent infection.103

The gut microbiota contributes to the development of immune system via the gut-associated lymphoid tissues composed of Peyer’s patches (PPs), plasma cells, and lymphocytes. Previous studies have shown that the gut bacteria interact with mucosal antibodies that are taken up by CD11 + dendritic cells in the PPs. Studies also showed that the luminal microbiota bound to SIgA increased their presence in PPs.104 The CD8 + T cells are mostly found in the intraepithelial intestine compartment, and the microbiota plays important roles in maintaining the function of CD8 + T-cells. This is supported by previous studies showing that GF mice exhibit reduced intestinal CD8 + T-cells.105 In all, understanding the relationship between the microbiota and the immune system is a critically important topic in health sciences. However, due to our innate understanding of the network of gut-immune system, greater attention will be necessary to further promote our knowledge in immune homeostasis and novel immune-microbe therapies.

The oral cavity is another important habitat where the microbiota could colonize. Different from the gut environment, the oral cavity contains both hard surface of teeth and epithelial surface of mucosal membrane. Approximately 50 species (1000 sub-species) exist in the oral microbiota. Due to the constant exposure to saliva, oral microbiota acquired the feature of avid adherence, which guarantees their colonization and resistance to the forces of fluid flow.106 Oral microbiota contains complex polymicrobial communities which have complicated interactions with the host’s diet and immunity. The colonization resistance in oral microbiota is affected by not only the lack of a single treatment for therapeutic intervention, but also due to the presence of a fluid phase which could inactivate bioactive molecules. The number of different oral sites where disease can occur and the poor retention of topical application of therapies are also hurdles to the treatment of oral disease caused by pathogens. Oral pathogens exert the ability to trigger immune response such as pro-inflammatory responses. On the other hand, alterations in host immune system also affects the oral microbiota community.

For example, gingivitis, a common disease in humans, is caused by immune-inflammatory responses where neutrophils are recruited to the gingival tissues.107 In periodontal disease, inflammation has been found to be an important driver for the growth of pathogenic microorganisms since inflammation can cause tissue destruction, which provides nutrient to microbiomes.108 However, inflammation could subsequently trigger bactericidal activity of the immune system. Thus, there exists such a paradox in dysbiosis that if the host immune system was downregulated, microbiomes will starve due to lack of nutrients. Periodontitis-associated bacteria such as the P. gingivalis is able to tackle the conundrum by triggering the host immune response without coupling bactericidal activity. Such function has been demonstrated in mice models where P. gingivalis intervened the host-microbiota homeostasis and contributed to the development of periodontitis.109 The special manipulation of the host immune system by P. gingivalis has been revealed to involve C5a receptor 1 (C5aR1) and TLR2. In human and mouse neutrophils, P. gingivalis was able to initialize a C5aR1-TLR2 signal which separates a TLR2-MyD88 pathway from a TLR2-MyD88-Mal-PI3K pathway, leading to inflammation and blocked phagocytosis. In summary, the oral microbiota could be both beneficial by potentially stabilizing the microbial diversity and harmful to cause collective pathogenic outcomes.

Like gut and oral tissues, the lungs also present a complex bacteria community. The lung microbiota is relatively dynamic as a result of the microbiome immigration and elimination via aspiration, cough, or mucociliary clearance.110 The majority of microbes in lungs belong to Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria families.111 The lung microbiota is responsible for the state of immune tolerance that protects the host from undesired inflammatory response.112 This function is mediated by the interaction between commensal bacteria and lung immune cells. Given the important role that lung microbiota plays in maintaining lung homeostasis, the lung microbiota composition is useful in monitoring lung health conditions.113 The interactions between lung microbiota and local immune cells are closely relevant to the pattern recognition receptors (PRRs), which are responsible for the recognition of microbial molecules. The above-mentioned TLRs also belong to PRRs. Activation of PRRs could stimulate the engagement of ligands and further induces immune-related genes expression‎, which promotes the immune response against pathogens.114 Additionally, the lung microbiota was also found to regulate antigen-presenting cells and regulatory T cells. In mice models, it was found that newborn mice showed excessive airway eosinophilia, Th2 cytokine release, and hyper-responsiveness after exposure to allergens. With the bacterial load increasing during the following two weeks, the microbiota composition was shifted (Gammaproteobacteria and Firmicutes toward Bacteroidetes) and responsiveness to allergens was decreased. The major mechanism includes the appearance of the Helios-regulatory T cells subset, which is promoted by changes in lung commensal bacteria community.115 Furthermore, infant mice without proper lung microbiota would suffer from excessive sensitivity to allergens until adulthood.

The human skin, like gut, is also colonized by a dense community of microbiomes composed of highly diverse communities. It has been discovered that the skin microbiota is composed of prokaryotes (bacteria and archaea) and eukaryotes (fungi, metazoic parasites). Similar to the gut microbiota, skin microbiota is also involved in the development of the innate immune system. For example, S. epidermidis produces lipoteichoic acids which prevent skin from injury-induced inflammation. The potential mechanisms include the inhibition of cytokine release and TLR2-based immune responses.116 Interestingly, S. epidermidis also promotes the expression‎ of certain antimicrobial peptides like human β-defensins (hBDs) which enhances the skin defense.117 Moreover, S. epidermidis was believed to strengthen the function of skin lymphocytes, thereby contributes to increased skin immunity.118 In summary, as a primary part of the human immune system, the skin harbors a wide range of cells that perform functions of immunity such as macrophages, dendritic cells, lymphocytes and various T-cell populations. Moreover, due to the advent of high-throughput sequencing, researchers are able to perform in-depth taxonomic analysis of the skin microbiota, which further boosts our understanding of roles that the skin microbiota plays in human wellness.

As mentioned above, vaginal microbiota is critical in protecting the host from invading pathogens via colonization resistance. It was also revealed that vaginal microbiota drives the innate immune response. Specifically, the vaginal microbiota stimulates the PRRs in and on epithelial cells lining the vagina and upper genital tract and initializes cytokine signaling cascades.119 For example, the release of interleukin (IL)-1β/6/8 and Tumour Necrosis Factor alpha (TNF-α) recruits or activates immune cells like Natural killer (NK) cells, macrophages, CD4 + helper T-cells, CD8 + cytotoxic T-lymphocytes and B-lymphocytes.120 Bacterial vaginosis (BV) is one of the most common vaginal dysbiosis due to the displacement of Lactobacillus spp and the increased concentration of BVAB. Pathogenic microbiomes in BV such as G. vaginalis and P. bivia have been found to inhibit the host inflammatory response in the vaginal epithelium.121 However, only limited number of studies examine the mechanisms of how BVAB interacts with the host immune system. Previous studies revealed that G. vaginalis infection does not trigger changes in the level of pro-inflammatory mediators including IL-1β, IL-6, MIP-3α, or TNFα,122 while A. vaginae induces a broad range of pro-inflammatory cytokines, chemokines, and antimicrobial peptides including IL-1β, IL-6, IL-8, MIP-3α, TNFα, and hBD-2; whereas P. bivia induces fewer types of immune factors including IL-1β and macrophage inflammatory protein (MIP)-3α.123 However, contradictory results have been reported that P. bivia suppressed the host immune responses.124 In all, further studies are still necessary to better understand the interaction between vaginal microbiota and host immune system.

Microbiota in the development of diseases

Microbiota are complex systems consisting of trillions of microorganisms. With advanced sequencing technologies and bioinformatics, most of microbiota–related research is focusing on the relationship between microbiota compositional changes and various disease states. When subjected to external changes, the balance of microbiota community can be affected, leading to dysregulation of bodily functions and diseases125 as summarized in Fig. 4. To date, mounting evidence has confirmed that microbiota is associated with the development of CVDs, cancer, respiratory diseases, diabetes, IBD, brain disorders, chronic kidney diseases, and liver diseases. Due to the limited studies on non-bacterial species in disease development, we majorly focus on the bacterial element of the microbiota in this section. The disease-related pathogens and the signaling pathways are summarized in Table 2 and are discussed in detail in each section.

Fig. 4

Human microbiota dysbiosis contributes to various diseases

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Cardiovascular diseases

CVDs are the leading cause of morbidity and mortality worldwide, including coronary heart disease, cerebrovascular disease, peripheral arterial disease, etc. While the general risk factors include atherosclerosis, hypertension, obesity, diabetes, dyslipidemia, and mental illness, growing evidence has suggested that microbiota play a role in maintaining cardiovascular health and its dysregulation may contribute to CVDs.126 Particularly, studies on microbiota transplantation, microbiota-dependent pathways, and downstream metabolites have all shown that microbiota may influence host metabolism and CVDs through multiple metaorganism pathways. Here, we present the potential pathogenesis of microbiota in CVDs.

Oral microbiota

Periodontal diseases, which are initiated and propagated through dysbiosis of oral microbiota, have been shown to be associated with increased risk for CVDs. In 1993, DeStefano et al. reported that subjects with periodontitis had a 25% increased risk of CVDs compared with those with minimal periodontal disease, indicating a correlation between oral microbiota with CVDs.127 Multiple bacterial phylotypes were found in both the oral cavity and atherosclerotic plaques, suggesting an association between oral microbiota and atherosclerosis. Schenkein et al. presented two major mechanisms linking periodontitis with atherosclerosis.128 The first is that some microorganisms can invade endothelial and phagocytic cells within the atheroma, causing pathogenic changes and progression of the lesion, and the second includes the release of inflammatory mediators such as C-reactive protein (CRP), fibrinogen, metalloproteinases from periodontal lesions to systemic circulation. A cohort study by Lise et al. reported that the antibody levels to periodontopathogen T. forsythia were inversely related to the increased risk for CVD mortality. Indeed, other studies also linked periodontitis with several cardiovascular risk factors. A randomized controlled trial (RCT) showed that intensive periodontal treatment achieved a reduction in systemic inflammatory markers including IL-6 and CRP, and a decreased systolic blood pressure and an improvement in lipid profiles.129 IL-6 can cause cardiac hypertrophy through the IL-6 signal-transducing receptor component, glycoprotein 130. Moreover, IL-6 is able to induce the hepatic synthesis of CRP. CRP is suggested to directly influence vascular vulnerability through several mechanisms including regulating the local expression‎ of adhesion molecules, downregulating the endothelial bioactivity of nitric oxide, altering the low-density lipoprotein ingestion of macrophages. Ramirez et al. found that, compared with the control group, periodontitis patients had higher levels of E-selectin, myeloperoxidase, and ICAM-1, which are important risk markers for CVDs.130 E-selectin is a receptor of carbohydrate ligands on the surface of leukocytes. It functions by binding with leukocytes, drawing them from the circulation toward the surface of the endothelium. Subsequently, the transmembrane glycoproteins ICAM-1 and VCAM-1, interact with integrins on the surface of the leukocyte to promote its strong binding to the endothelium, thereby contributing to CVD through their inflammatory effects on the vascular endothelium.

Gut microbiota

It is not surprising that the gut microbiota, is considered the largest endocrine organ in the body, can affect the cardiovascular system and contribute to CVDs. Gut microbiota is involved in the metabolism of choline, phosphatidylcholine, and carnitine, which eventually produce trimethylamine-N-oxide (TMAO). TMAO has been suggested to not only regulate cholesterol balance and bile acid levels but is also associated with early atherosclerosis and high long-term mortality risk of CVDs.131 Mechanistically, TMAO can activate the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways in endothelial cells and smooth muscle cells.132 The MAPK signaling pathway can be stimulated by growth factors, pathogen-associated molecules, and inflammatory cytokines, which follows by a MAPKKK-MAPKK-MAPK-TFs signaling cascade and results in the expression‎ of inflammatory cytokines IL-6, IL-8, and TNF-α. It is well-established that NF-κB is an important mediator that regulates the activation, differentiation, and effector function of inflammatory immune cells. Therefore, the dysregulation of NF-κB may contribute to pathogenesis of atherosclerosis by promoting monocyte recruitment.133 Another inflammation mediator lipopolysaccharide (LPS), also known as endotoxin, is a component of Gram-negative bacteria that are mainly distributed in gut and oral cavity. Recent studies have shown that LPS can induce vascular oxidative stress by activating the TLR4 pathway, leading to endothelial dysfunction and vascular inflammation. A retrospective analysis conducted by Yoshida et al. suggested that patients with CVDs have higher fecal LPS levels compared with those without CVDs. It is interesting that the structures of lipid A moieties of LPS differ in bacteria, which may determine LPS activity.134

신체에서 가장 큰 내분비 기관으로 간주되는 

장내 미생물이 심혈관계에 영향을 미치고 

CVD를 유발할 수 있다는 것은 놀라운 일이 아닙니다. 

장내 미생물은 

콜린, 포스파티딜콜린, 카르니틴의 대사에 관여하여 

결국 트리메틸아민-N-옥사이드(TMAO)를 생성합니다. 

TMAO는 

콜레스테롤 균형과 담즙산 수치를 조절할 뿐만 아니라 

초기 죽상 동맥 경화증 및 CVD의 높은 장기 사망 위험과도 관련이 있는 것으로 알려져 있습니다.131 

기계적으로 TMAO는 

내피 세포와 평활근 세포에서 미토겐 활성화 단백질 키나제(MAPK) 및 NF-κB 신호 경로를 활성화할 수 있습니다.132 

MAPK 신호 경로는 

성장 인자, 

병원체 관련 분자 및 염증성 사이토카인에 의해 자극될 수 있으며, 

이는 MAPKKK-MAPKK-TFs 신호 캐스케이드로 이어져 

염증성 사이토카인 IL-6, IL-8 및 TNF-α의 발현을 초래합니다. 

NF-κB가 염증성 면역 세포의 활성화, 분화 및 이펙터 기능을 조절하는 중요한 매개체라는 것은 잘 알려져 있습니다. 따라서 NF-κB의 조절 장애는 단핵구 모집을 촉진하여 죽상동맥경화증의 발병에 기여할 수 있습니다.133 

내독소라고도 알려진 

또 다른 염증 매개체인 지질 다당류(LPS)는 

주로 장과 구강에 분포하는 그람 음성 박테리아의 성분입니다. 

최근 연구에 따르면 LPS는 TLR4 경로를 활성화하여 혈관 산화 스트레스를 유발하여 내피 기능 장애와 혈관 염증을 유발할 수 있는 것으로 나타났습니다. 요시다 등이 수행한 후향적 분석에 따르면 CVD 환자는 CVD가 없는 환자에 비해 분변 LPS 수치가 더 높은 것으로 나타났습니다. 박테리아에 따라 LPS의 지질 A 분자 구조가 다르며, 이는 LPS 활성을 결정할 수 있다는 점이 흥미롭습니다.134

Gut microbiota is able to metabolize polysaccharides and proteins into short-chain fatty acids (SCFAs), another class of metabolites that is linked to CVDs. Most SCFAs are acetates, butyrates, or propionates. A large proportion of acetates is subjected to lipogenesis in adipose tissue and oxidize in muscle, with some being converted to butyrates by bacteria. As shown in Fig. 3, butyrates are involved in mediating the integrity of the intestinal barrier and are suggested to have direct salutary effects on intestinal epithelial cells.135 Propionates are mainly oxidized or metabolized in the liver. The potential role of these major SCFAs in CVDs has been extensive studied in animal models. SCFAs, particularly propionates and butyrates, were shown to protect the host from hypertensive cardiovascular damage.136 The propionate is suggested to regulate the balance of effector T cells and regulatory T cells, which is critically important in hypertension and hypertension-induced organ damage.137 Moreover, propionates reduced lateralization of gap junction protein connexin 43 in cardiomyocytes, thereby reducing susceptibility to ventricular tachycardia.136 The butyrate has been shown to modulate blood pressure by inhibiting expression‎ of renal prorenin receptors and renin in animal models.138 Recently, accumulating evidence has shown that SCFAs can act on G-protein-coupled receptors Gpr41, Gpr43, and Olfr78 to mediate blood pressure. Olfr78, expressed in smooth muscle cells of vasculature, is an olfactory receptor that mediates renin secretion in response to SCFAs. Gpr41 and Gpr43 are widely expressed in the body, which will be activated upon SCFAs binding. It is established that Olfr78 and Gpr41/43 response to SCFAs through different G protein subunits and second-messenger systems. Olfr78 will activate adenylate cyclase type 3 and Golf in the olfactory signaling pathway to induce cAMP production; while Gpr41/43 activates Gαi and/or Gαo to decrease cAMP.139 Therefore, activation of Olfr78 increases hypertension by facilitating the release of renin, while activation of Gpr41 and Gpr43 counteract the hypertensive effect of Olfr78.140 These data reinforce the important role of microbiota in blood pressure control and CVD progression.

장내 미생물은 

다당류와 단백질을 CVD와 관련된 또 다른 종류의 대사 산물인 

단쇄 지방산(SCFA)으로 대사할 수 있습니다. 

대부분의 SCFA는 

아세테이트, 부티레이트 또는 프로피온산염입니다. 

아세테이트의 대부분은 

지방 조직에서 지방 생성을 거쳐 근육에서 산화되며, 

일부는 박테리아에 의해 부티레이트로 전환됩니다. 

그림 3에서 볼 수 있듯이 

부티레이트는 장 장벽의 완전성을 매개하는 데 관여하며 

장 상피 세포에 직접적인 유익한 영향을 미치는 것으로 추정됩니다.135 

프로피온산염은 

주로 간에서 산화되거나 대사됩니다. CVD에서 이러한 주요 SCFA의 잠재적 역할은 동물 모델에서 광범위하게 연구되었습니다. 

특히 프로피온산염과 부티레이트와 같은 SCFA는 

고혈압성 심혈관 손상으로부터 숙주를 보호하는 것으로 나타났습니다.136 

프로피온산염은 고혈압과 고혈압으로 인한 장기 손상에서 매우 중요한 이펙터 T 세포와 조절 T 세포의 균형을 조절하는 것으로 추정됩니다.137 

또한 프로피오네이트는 심근 세포에서 갭 접합 단백질 코넥신 43의 측면화를 감소시켜 심실 빈맥에 대한 감수성을 감소시킵니다.136 부티레이트는 동물 모델에서 신장 프로레닌 수용체와 레닌의 발현을 억제하여 혈압을 조절하는 것으로 나타났습니다.138 최근 축적된 증거에 따르면 SCFA가 G 단백질 결합 수용체 Gpr41, Gpr43, Olfr78에 작용하여 혈압을 조절할 수 있는 것으로 밝혀졌습니다. 혈관의 평활근 세포에서 발현되는 Olfr78은 SCFA에 반응하여 레닌 분비를 매개하는 후각 수용체입니다. Gpr41과 Gpr43은 체내에서 광범위하게 발현되며, SCFA와 결합하면 활성화됩니다. Olfr78과 Gpr41/43은 서로 다른 G 단백질 서브유닛과 2차 전달체계를 통해 SCFA에 반응한다는 사실이 밝혀졌습니다. Olfr78은 후각 신호 경로에서 아데닐레이트 시클라제 3형과 Golf를 활성화하여 cAMP 생성을 유도하는 반면, Gpr41/43은 Gαi 및/Gαo를 활성화하여 cAMP를 감소시킵니다.139 따라서 Olfr78의 활성화는 레닌의 방출을 촉진하여 고혈압을 증가시키고, Gpr41 및 Gpr43의 활성화는 Olfr78의 고혈압 효과를 상쇄합니다.140 이러한 데이터는 혈압 조절 및 CVD 진행에서 미생물군의 중요한 역할을 강조합니다.

Cancer

Cancer is a disease characterized by the rapid proliferation of abnormal cells that grow uncontrollably, which can occur in almost all regions of the body. Currently, cancer is a leading cause of mortality worldwide, causing over 10 million deaths in 2020.141 Generally, the development of cancer is due to gene mutations that disrupt the cell growth or metabolic activities, and more than 100 human carcinogens are listed by the World Health Organization. Although carcinogenesis is a multifactorial process, it has been well established that tobacco, bacteria and viruses, obesity, alcohol, and radiation are the major risk factors for cancer.142 While the role of microorganisms was disregarded in cancer for a long time, the focus has shifted largely due to the finding that H. Plyori contributes to gastric cancer initiation in 1994.143 Surprisingly, recent studies have shown that microbiota plays an important role in carcinogenesis, mainly through 1) influencing the host cell proliferation and death, 2) altering immune system activity, and 3) affecting host metabolism.

Oral microbiota

Researchers have found that periodontitis, characterized by dysbiosis of oral microbiota, is involved in the initiation and progression of oral, pancreatic, genitourinary, and gastrointestinal cancers. Farrell et al. found a significant variation between the salivary microbiota of pancreatic cancer patients and healthy subjects in a retrospective case–control study.144 In cancer patients, the levels of N. elongate, and S. mitis were significantly decreased, while the level of G. adiacens was elevated compared with healthy subjects. A prospective cohort study conducted by Michaud et al. revealed that individuals with high P. gingivalis antibody levels had a twofold increased risk of pancreatic cancer compared with those with low antibody levels.145 Similarly, Fan et al. suggested that P. gingivalis was correlated with higher risk of pancreatic cancer, while Fusobacteria were associated with a decreased risk.146 Studies revealed that the abundance of T. forsythia, P. gingivalis, and F. nucleatum are significantly higher in esophageal cancer tissues compared with normal tissues.147 It is suggested that oral microbiota promote carcinogenesis by inducing chronic inflammation and producing oncometabolites.148 Since many bacteria share similar carcinogenic mechanisms, we use P. gingivalis, a pivotal periodontal bacterium, as an example to introduce the pathogenesis. Oral squamous cell carcinoma (OSCC) is the most common cancer in the head and neck region. Firstly, the presence of P. gingivalis has been shown to increase the risk of OSCC by dysregulating tissue integrity and host immune response. Cao et al. suggested that P. gingivalis can bind to TLR4 receptor, which in turn activate NF-κB pathway and overstimulate the downstream JAK1/STAT3 signaling pathway, leading to inhibition of cell apoptosis.149 TLRs are characterized as primary sensors that response to microbial components and trigger immune response. All TLR signaling pathways eventually activate NF-κB pathway, which controls the expression‎ of a wide range of inflammatory cytokines. Secondly, studies have shown that P. gingivalis can stimulate the proliferation of epithelial cells by interfering with the cell cycle regulation. Kuboniwa et al. reported that P. gingivalis can affect signaling pathways involving cyclins, p53, and PI3K.150 Cyclins are subunits of CDK complexes that regulate the progression of cell cycle and thus proliferation. p53 is a tumor suppressor gene that has been well-established in the cause of cancer. Activation of p53 can cause cell cycle arrest and apoptosis, thus mutation or loss-of-function of p53 may lead to uncontrolled cell growth.151 Moreover, P. gingivalis has been shown to interact with β-catenin, a key protein in regulating cell proliferation and tumorigenesis. The Wnt/β-catenin signaling is a versatile pathway that involved in many human diseases. Aberrant activation of Wnt/β-catenin pathway results in the accumulation of β-catenin in the cells and thus upregulating the expression‎ of oncogenes including CyclinD-1 and c-Myc. Zhou et al. suggested that P. gingivalis can induce noncanonical activation of β-catenin and dissociation of the β-catenin destruction complex via gingipain-dependent proteolytic processing.152 Thirdly, P. gingivalis may induce chronic inflammation by increasing levels of cytokines including IL-8, TGF-β1, and TNF-α. IL-8 and TGF-β1 can enhance the invasiveness of tumor cells by upregulating matrix metalloproteinases.153 TNF-α can lead to gene mutations through the generation of reactive oxygen species (ROS) or reactive nitrogen (RNS) intermediates as well as induce epithelial–mesenchymal transition, which stimulates tumor angiogenesis.154 Lastly, P. gingivalis can produce oncometabolites such as acetaldehydes and oxygen radicals. Accumulation of these metabolites are known to promote chronic inflammation and cause DNA damage and mutagenesis, leading to cancer development. Recent studies also suggested that intestinal colonization of oral microbiota contributes to several health issues including carcinogenesis.155 F. nucleatum, a periodontal pathogen, has been extensively studied in colorectal cancer (CRC). By comparing cancer and adjacent normal tissues, it was found that F. nucleatum was significantly enriched in tumor tissues and may promote CRC progression by increasing tumor multiplicity and selectively recruiting tumor-infiltrating myeloid cells.156

Respiratory microbiota

The focus of respiratory microbiota and cancer is largely on lung cancer. The lung, which was once considered sterile, is colonized by different microbiota throughout the respiratory tract. In healthy individuals, the core microorganisms in the lung are Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas. In a systematic review, Perrone et al. summarized that levels of Actinomyces, Veillonella, Streptococcus, Megasphaera, and Mycobacterium were more abundant in lung cancer patients compared with healthy individuals. In addition, Gomes et al. reported that a squamous cell carcinoma subcluster with the worst survival was correlated with several Enterobacteriaceae.157 Another study suggests that in the microbiota of patients with lung cancer, unlike in the control group, has high levels of Streptococcus, indicating it may be a possible diagnostic marker. Interestingly, Peter et al. found no relationship between tumor tissue microbiota with lung cancer recurrence, while the higher richness and diversity in adjacent normal tissue was associated with worse outcome.158 Although the underlying carcinogenesis mechanisms are not fully elucidated, dysbiosis of lung microbiota increases inflammation and host immune modulation, which are two important pathways related to cancer. Jin et al. reported that microbiota induced inflammation associated with lung adenocarcinoma via activation of lung-resident γδ T cells, facilitating the proliferation of tumor cells.159 Interestingly, previous studies suggested that γδ T cells are able to recognize cancer cells and initiate anticancer activity, largely related to cytotoxicity and interferon-γ production. Therefore, it remains inconclusive how the immune system response to lung microbial. In an epithelial cell model, exposure to Streptococcus, Prevotella, and Veillonella led to the upregulation of PI3K and ERK1/2 signaling pathways, which mediates cell proliferation, differentiation, and survival.160 PI3K/Akt/mTOR is one of the most important cell signaling pathways and a well-established mediator of cancer. Activation of PI3K/Akt/mTOR pathway, by gene mutation, inactivation of PTEN, or activation of upstream oncogenes, contributes to the development of tumor and resistance to therapeutics. The same research group used an in vivo non-small cell lung cancer mouse model to show that microbiota dysbiosis led to upregulation of PI3K/AKT, ERK/MAPK, IL17A, IL6/8, and inflammasome pathways, suggesting that microbiota can contribute to the pathogenesis of lung cancer.161

Gut microbiota

Increasing evidence suggests that gut microbiota is associated with the initiation and progression of CRC. Studies have shown that dysbiosis of gut microbiota can trigger inflammation and immune response that are indirectly related to carcinogenesis.162 Grivennikov et al. reported that microbial products may induce epithelial barrier deterioration, which trigger tumor-elicited inflammation and drive initiation and progression of CRC.163 It is suggested that gut microbiota can promote CRC progression by affecting certain signaling pathways including E-cadherin/β-catenin, TLR4/MYD88/NF-κB, and SMO/RAS/p38 MAPK.164 Chen et al. suggested that both commensal and pathogenic bacteria facilitate CRC progression via 1) exploiting tumor surface barrier defects, 2) invading normal colonic tissue and inducing local inflammation, and 3) producing genotoxic metabolites to induce oncogenic transformation of colonic epithelial cells.165 It has been characterized that the major bacteria that contribute to CRC are E. faecalis, E. coli, B. fragilis, S. bovis, F. nucleatum, and H. pylori.166 These bacteria are able to produce genotoxic substances such as colibactin, B. fragilis toxin, and typhoid toxin that cause host DNA damage. For example, intestinal F. nucleatum was eval‎uated in several CRC studies.167 The abundance of F. nucleatum was significantly higher in mucosal and fecal samples of CRC patients compared with healthy controls. These studies also indicated that F. nucleatum can invade CRC tumor cells, leading to the presumption that F. nucleatum may influence tumorigenesis.

Diabetes mellitus

Diabetes mellitus (DM) refers to a group of diseases that affect glucose regulation. DM can be classified as type 1 diabetes mellitus (T1DM), Type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). T1DM is caused by the autoimmune response against pancreatic β cells, while T2DM is characterized as the inability of the body to produce or utilize insulin properly. GDM is one of the most preval‎ent pregnancy complications and is associated with increased risk of maternal and fetal metabolic disorders. The relationship between microbiota and DM has been extensively studied and the correlation between microbiota dysbiosis and onset of DM is well established.

Type 1 diabetes mellitus

In T1DM, the microbiota is an attractive research field due to its close relationship with chronic inflammation and immune response. The composition of oral and fecal microbiota appears to be distinct in T1DM patients in multiple studies. Groot et al. found that Christensenella and Bifidobacteria were enriched in fecal samples.168 Oral Streptococcus was positively associated with T1DM, while fecal Streptococcus was inversely correlated with T1DM. In addition, T1DM patients may exhibit decreased levels of SCFA butyrate-producing bacteria, which are key factors in decreasing chronic inflammation and maintaining intestinal homeostasis.169 This finding was reinforced by other case-control studies which showed that the levels of R. faecis, F. prausnitzzi, Intestinimonas were significantly lower in T1DM patients than in healthy controls.170 However, inconsistent results were reported with other bacteria, suggesting that further research is required.171 Interestingly, Vatanen et al. analyzed data from TEDDY study and showed that healthy children contained more genes related to fermentation and the synthesis of SCFAs without significant association to specific taxa.172 Therefore, it is possible that the T1DM-related microbial factors are taxonomically diffuse but functionally coherent. The research on microbiota in T1DM was conducted mainly in animal models, therefore, the pathogenic mechanisms require further validation in human. It was first introduced that the development of T1DM may be dependent on microbiota in 1987 by Suzuki et al.173 It was suggested that microbiota can contribute to T1DM mainly through immune response modulation. T1DM is defined as an autoimmune disease by chronic inflammation of the pancreatic islets of Langerhans. Since microbiota is involved in the initiation of chronic inflammation, it is not surprising that its dysregulation may contribute to T1DM. Higuchi et al. reported that the plasma levels of IL-6 were significantly higher in T1DM patients than in healthy controls, which was correlated with the abundance of Ruminococcaceae and Ruminococcus. Leiva-Gea at al also reported that T1DM patients had increased levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α and decreased levels of anti-inflammatory cytokines IL-10 and IL-13, which were significantly correlated with the abundance of different bacteria.170 In addition, an upregulated level of LPS was observed, which is known to induce the release of proinflammatory cytokines and impair pancreatic β cells.174 Clinical data showed that T1DM patients have significantly elevated levels of TLR2 and TLR4 ligands, indicating increased TLR2 and TLR4 activity.175 As described above, TLRs play an important role in innate and adaptive immunity, which protect the body from infectious microorganisms. The role of TLR4 was further eval‎uated in mouse models. Elke et al. reported that TLR4 accelerates the development of diabetes, suggesting that TLR4 is involved in the progression of insulitis.176 The TLR4/MyD88 pathway regulates the activation of NF-κB and the levels of pro-inflammatory cytokines such as IL-6 and TNF-α.177 Wen et al. established an MyD88-negative Non-Obese Diabetic mice and found that the mice lacking MyD88 protein do not develop T1DM. Taken together, it suggests that microbiota may facilitate the progression of T1DM via TLR4/MyD88 signaling pathway.

Type 2 diabetes mellitus

In terms of T2DM, gut microbiota has been linked to disease development. Numerous studies have confirmed that the composition of gut microbiota is altered in T2DM patients.178 Larsen et al. reported that the abundance of Firmicutes and Clostridia were significantly decreased in T2DM patients compared with the control group. In addition, the ratios of Bacteroidetes to Firmicutes, Bacteroides-Prevotella group to C. coccoides-E. rectale group were positively correlated with blood glucose level.179 Almugadam et al. showed that the abundance of SCFA-producing bacteria Facalibacterium and Roseburia were significantly decreased in T2DM patients.180 Antidiabetic agents were able to improve the diversity and richness of gut microbiota and enriched gut ecosystem with beneficial bacteria. The underlying molecular mechanisms of gut microbiota contributing to T2DM may include modulation of inflammation, gut permeability, and glucose metabolism. Generally, T2DM is associated with increased levels of pro-inflammatory molecules. LPS is well documented to promote low-grade inflammation. Several studies have suggested that T2DM patients have increased level of LPS in peripheral circulation.181 LPS can bind to TLR4, triggering macrophage aggregation and activating the NF-κB signaling pathway. This interaction leads to the release of inflammatory factors, resulting in the inhibition of insulin secretion. Gut microbiota can metabolize primary bile acids into secondary bile acids. Secondary bile acids bind to the farnesoid X receptor and release fibroblast growth factor, FGF19/15, which is able to promote insulin sensitivity and glucose tolerance.182 Therefore, dysbiosis of gut microbiota may lead to abnormal bile acid metabolism by affecting glucose metabolism. Another class of important metabolites from gut microbiota are SCFAs. Studies suggest that SCFAs play an important role in mediating glucose metabolism and insulin sensitivity via multiple signaling pathways. For instance, SCFAs can bind to Free Fatty Acid Receptor FFAR2 or FFAR3 on intestinal L cells, stimulating the release of glucagon-like peptide-1 (GLP-1) and peptide YY, which are known to promote insulin secretion and reduce glucagon.183 In addition, butyrates can protect the integrity of the intestinal barrier, which may be damaged in T2DM patients due to low-grade inflammation. Moreover, SCFAs are important anti-inflammatory mediators that can limit autoimmune response by promoting the production of regulatory T cells.184 Therefore, the reduced abundance of SCFA-producing bacteria may contribute to the development of T2DM.

Oral microbiota may also play a role in T2DM. Oral bacteria can translocate to the gut, changing the composition of gut microbiota and potentially mediating immune response.185 Several studies have identified significant alterations in oral microbiota composition between T2DM patients and healthy controls. Interestingly, Xiao et al. reported that T2DM induces a shift in oral microbiota composition with enhanced IL-17 level.186 By transferring to GF mice, the DM-modified oral microbiota is more pathogenic, indicating that DM can increase the risk and severity of periodontal disease.

Gestational diabetes mellitus

In GDM, several studies reported that gut microbiota mediates insulin resistance and inflammation during pregnancy. Metabolic disorders are commonly seen in GDM women, including enhanced insulin resistance and downregulated insulin secretion.187 During pregnancy, the composition of gut microbiota undergoes substantial changes, which may account for the development of GDM. For example, positive correlation has been identified between insulin and Collinsella, gastrointestinal polypeptide and Coprococcus, and adipokine with Ruminococcaceae and Lachnospiraceae.188 Moreover, Koren et al. demonstrated that gut microbiota changed from first to third trimesters, with increased diversity and decreased richness.189 It was shown that GDM patients had increased Firmicutes to Bacteroidetes ratio, an important factor that facilitates obesity and aggravates inflammation.190 The abundance of SCFA-producing bacteria was significantly lower in GDM pregnancies compared with healthy controls, indicating that the elevated blood glucose levels may be caused by microbiota alteration.191 Studies also revealed that the gut microbiota composition in the offspring of GDM mothers were different from those in non-GDM mothers. Ponzo et al. reported that the abundance of proinflammatory bacteria was higher in GDM infants than in healthy controls.192 Other studies confirmed this finding that the GDM infants had lower α-diversity compared with the control group, and the abundance of certain lactic acid bacteria may be affected by maternal GDM status.193 Therefore, gut microbiota may play a critical role in the development of GDM and may also affect GDM infants.

Respiratory diseases

Respiratory diseases are a group of diseases that affect the lungs and other parts of the respiratory system and include chronic diseases (asthma and chronic obstructive pulmonary disease (COPD), pulmonary fibrosis) and pneumonia. Extensive studies have suggested that oral, lung, and gut microbiota are associated with the development of respiratory diseases. In this section, we will discuss the major findings demonstrating a connection between the microbiota and the development of respiratory diseases.

Chronic respiratory diseases

COPD and asthma are the two most frequently diagnosed chronic respiratory diseases. COPD is defined as a disease state characterized by the presence of airflow limitation associated with chronic bronchitis or emphysema. Asthma is a heterogeneous syndrome of chronic airway inflammation characterized by bronchial hyper-responsiveness to environmental triggers and by symptoms including wheezing, shortness of breath, and chest tightness. Accumulating data suggest that lung microbiota is actively involved in the development of chronic respiratory diseases. The composition of lung microbiota was found to be distinct between patients and healthy individuals. Using 16s rDNA sequencing technology, studies have identified that asthma patients had higher bacterial load and diversity, increased abundance of Proteobacteria, and decreased abundance of Bacteroidetes and Firmicutes.110 In addition, Woerden et al. found a different pattern of fungi, particularly Malassezia pachydermatis, in the sputum samples of asthma patients and controls. However, the research on fungi is limited and remains inconclusive.194 Other studies identified altered abundance of Pseudomonas, Moraxella, Lactobacillus, and Haemophilus during COPD exacerbations.195 Recent studies also found a potential relationship between pulmonary fibrosis and viral and bacterial infection. A clinical trial reported that the progression of pulmonary fibrosis is associated with specific Staphylococcus and Streptococcus bacterial species.196 Chronic inflammation induced by lung microbiota may be the key process in the initiation of chronic respiratory diseases. In asthma patients, Proteobacteria has been associated with hyper-responsiveness and Th17/IL-17-mediated inflammation.197 H. influenza, the most isolated pathogen from asthma patients, can induce steroid-resistant neutrophilic allergic airway diseases.198 Alnahas et al. demonstrated that Proteobacterium M catarrhalis can exaggerate allergic airway diseases by triggering a strong immune response characterized by neutrophilic infiltration, high levels of IL-6 and TNF-α, and moderate levels of Interferon (IFN)-γ and IL-17 in a mouse model.199 Furthermore, Garcia-Nuñez et al. reported that the bronchial microbe Proteobacteria may induce chronic inflammation and predict high disease severity.200 These studies highlighted that lung microbiota dysbiosis may potentially be associated with the development of chronic respiratory diseases.

Gut microbiota is a potent modulator of pro-inflammatory and autoimmune responses, leading to different inflammation-related diseases. Multiple studies have linked the dysbiosis of gut microbiota early in life to increased risk of asthma later in life, known as the gut-lung axis. The gut-lung axis in chronic respiratory diseases has been extensively studied and reviewed.112 It is suggested that gut microbiota dysbiosis in early life may lead to the development of respiratory diseases, since gut microbiota plays an important role in immune cell maturation and pathogen resistance.201 Indeed, Roussos et al. and Rutten et al. demonstrated that patients with chronic GI diseases have higher preval‎ence of chronic respiratory diseases including asthma and COPD, while the mechanisms are still unclear.202,203 Sprooten et al. reported that patients with acute COPD exacerbations had increased GI permeability, suggesting that gut microbiota is involved in exacerbations.204 Another study demonstrated that the increased levels of gut microbiota-dependent circulating TMAO were associated with all-cause mortality in COPD patients.205 Arrieta et al. discovered that the abundance of Veillonella, Faecalibacterium, and Lachnospira were significantly decreased in children at risk of asthma.206 It is suggested that the gut bacterial metabolites may contribute to asthma through its immune modulation. For example, Roduit et al. reported that children with high level of SCFAs are less likely to have asthma at later stage.207 SCFAs have been shown to promote peripheral regulatory T-cell generation208 and ameliorate inflammation in allergic asthma models.209 In addition to bacterial metabolites, it is suggested that lymphocytes with altered homing properties may contribute to asthma.210 Under normal situation, lymphocytes are thought to exhibit tissue specificity to the site where they first encounter the antigen. However, intestinal lymphocytes from IBD patients are known to lack tissue specificity and may account for the presence of inflammation in organs other than the gut. Huang et al. reported that innate lymphocytes were recruited from the gut to the lungs following inflammatory signals from IL-25.211 Interestingly, some data indicates that the gut-lung axis may have a bidirectional interaction. Perrone et al. showed that pneumonia induced intestinal epithelial apoptosis212 and decreased intestinal epithelial proliferation213 in mice.

Oral microbiota has been associated with chronic respiratory diseases due to the contiguous anatomic structure and microaspiration.214 Early studies found significant similarity between the oral and lung microbiota, while the nasal microbiota shares less similarities with lung microbiota.215 It is hypothesized that the oral microbiota may contribute to chronic respiratory diseases through aspiration and systemic inflammation. It is possible that aspiration of oral bacteria into the lung leads to lung microbiota dysbiosis and inflammation. Segal et al. reported that the enrichment of oral bacteria Veillonella and Prevotella in bronchoalveolar lavage samples has been associated with subclinical inflammation, characterized by increased neutrophils and lymphocytes.216 A RCT showed that bronchial microbiome of asthmatic subjects was uniquely enriched with two periodontal pathogens, Fusobacterium and Porphyromonas.217 Many periodontitis-related inflammatory cytokines have also been detected in chronic respiratory diseases. Aaron et al. reported that TNF-α was increased in the sputum of COPD patients.218 Substantial studies have shown that TNF-α can stimulate the generation of ROS in pulmonary tissues, accompanied by the generation of various adhesive and proinflammatory molecules such as VCAM-1, ICAM-1 and RAGE. TNF-α is also suggested to function as a pro-inflammatory cytokine in asthma that recruits neutrophils and eosinophils.219 Periodontitis is related to high levels of systemic inflammatory markers, such as CRP and IL-6. Jousilahti et al. reported that the level of CRP was significantly associated with asthma preval‎ence.220 However, the oral-lung axis has not been fully understood and deserves further investigation.

Pneumonia

The normal respiratory tract and gut microbiota protect against pneumonia by preventing pathogenic bacteria colonization and by modulating immune responses. Therefore, it is not surprising that the dysbiosis of respiratory tract microbiota is considered a risk factor of pneumonia.

The upper airways are the main source of microbes to the lower airways. Recently, researchers have shown that the reduction of nasal microbiota diversity increased susceptibility to pneumonia. Particularly, three microbiota profiles dominated by Lactobacilli, Rothia, and Streptococcus were significantly associated with pneumonia.221 In neonates, the pathogenic bacterial colonization of the airways with S. pneumonia, H. influenza, and M. catarrhalis were associated with increased risk of pneumonia and bronchiolitis.222 Regarding the lower airway microbiota, studies suggested that increased abundance of Prevotella and Veillonella predisposed pneumonia in HIV patients.223 In addition, altered immune response due to microbiota dysbiosis may increase the risk of pneumonia. For example, dysregulation of SCFA-producing bacteria may contribute to the development of pneumonia. Segal et al. suggested that pulmonary SCFAs correlated with increased anaerobic bacteria.224 Indeed, SCFAs have a direct inhibitory effect on immune response via suppression of IFN-γ and IL-17A pathways. During bacterial infection, neutrophils are rapidly migrated to lung parenchyma and alveolar. The IFN-γ released by neutrophils regulates bacterial clearance, therefore the level of IFN-γ is critical for host defense during pneumonia.225 Similarly, Th17 cells and its signature IL-17A signaling is an important immune response against pneumonia. During infection, IL-17A acts on nonimmune cells to trigger the release of antimicrobial proteins, cytokines, and chemokines, thus enhance innate immunity during microbial infection.226 By inhibiting the IFN-γ and IL-17A pathways, it allows the lung bacteria reproduction and worsen inflammation. Salk et al. reported that the influenza-specific lgA production is significantly associated with levels of Lactobacillus, Prevotella, Veillonella, Bacteroide, and Streptococcus.227 Interestingly, recent studies suggested that commensal microbes can play a crucial role in the development of pneumonia. Recently, the global pandemic COVID-19 has become a major research area in respiratory disease. Emerging data are now connecting the COVID-19 mortality with microbiota dysbiosis. Fan et al. investigated the lung microbiota characteristics from 20 deceased COVID-19 patients.228 It is suggested that the dysbiosis of lung microbiota is characterized by increased abundance of Acinetobacter spp., which are related to multidrug resistance and mortality. In addition, Cryptococcus was the dominant fungi in the lung fungal communities, along with Issatchenkia, Cladosporium, Candida, etc. Han et al. reported that COVID-19 may induce severe dysbiosis of lung microbiota, particularly with increased abundance of Klebsiella oxytoca, Faecalibacterium prausnitzii, and Rothia mucilaginosa.229 Segal et al. revealed that the enrichment of lower airways with oral bacteria Mycoplasma salivarium was associated with poor clinical outcome.230 However, no significant connection was found between increased mortality and secondary respiratory pathogens.

Gut microbiota is another major subject when studying pneumonia-microbiota interaction. Schuijt et al. identified that the gut microbiota plays a protective role against S. pneumoniae infection.231 Compared with the control group, S. pneumoniae infection in gut microbiota depleted C57BL/6 mice demonstrated increased bacterial dissemination, inflammation, organ damage and mortality. In addition, depletion of gut microbiota was associated with the upregulation of metabolic pathways, leading to reduced responsiveness to inflammatory cytokines. In accordance, Felix et al. showed that the commensal gut segmented filamentous bacteria protected immunodeficiency mice from S. pneumoniae infection. It is likely that the bacteria promoted a shift in lung neutrophil phenotype from inflammatory to pro-resolution, which is similar to heat-inactivated S. pneumoniae treatment. Recent data also suggested that gut microbiota composition may reflect disease severity in COVID-19 patients.232 In COVID-19 patients, decreased abundance of several gut commensals was observed, including Bifidobacteria, Eubacterium rectale, and Faecalibacterium prausnitzii. The dysbiosis gut microbiota was positively associated with disease severity, with elevated levels of inflammatory cytokines and blood markers such as CRP, aspartate aminotransferase, and lactate dehydrogenase. Therefore, unlike in chronic respiratory diseases, the gut-lung axis may provide additional protection for the host against pneumonia by regulating the immune response.

Inflammatory bowel disease

IBD is a chronic and remittent inflammatory condition of the GI tract, encompassing several diagnoses including Crohn’s disease (CD) and ulcerative colitis (UC).233 While UC is known as continuous, diffuse, and superficial inflammation of the colon, CD is characterized by discontinuous, transmural lesions affecting different regions of the GI tract.234

Although the development of IBD is due to complex multifactorial mechanisms, several risk factors have been extensively studied and are now well documented. The pathogenesis of IBD involves dysregulated immune response, genetic mutations, and environmental factors.235 The intestinal barrier plays an important role in maintaining homeostasis; dysfunction of the barrier may lead to ulceration. Specifically, the intestinal barrier would be susceptible to pathogen invasion without the secretion of antimicrobial peptides (AMPs) or tight junction proteins.236 During initial disease in genetically susceptible individuals, the immune response is altered, leading to loss of immune tolerance to intestinal antigens. This subsequently stimulates the differentiation of helper T cells and release of chemokines and proinflammatory cytokines, which induce chronic inflammation of the intestine.237 In addition to immune dysregulation, genetic factors are involved in determining IBD development. For example, genetic mutations associated with CD include polymorphisms for the Nucleotide Oligomerization Domain Containing 2 (NOD2/CARD15), Immunity-elated GTPase family M (IRGM), and autophagy-related 16 Like 1 (ATG16L1).238

Studies have shown that gut microbiota are highly associated with the development of IBD. Mechanistically, microbiota dysbiosis is linked to IBD through its impact on inflammation as well as the intestinal barrier. As described before, microbiota dysbiosis can induce chronic inflammation, which is associated with the development of multiple diseases such as cancer, diabetes, and heart diseases. Importantly, it is postulated that microbiota can interact with intestinal barrier and lead to IBD. For example, Kleessen et al. reported that bacterial invasion of the mucosa was detected more in IBD patients than in controls.239 It was also reported that the abundance of adherent-invasive E. coli was significantly increased in CD patients, suggesting that the pathogenic bacteria may affect the permeability of the intestine, the composition of gut microbiota, and eventually induce intestinal inflammation.240 In healthy individuals, the predominant phyla are Firmicutes and Bacteroidetes, followed by Proteobacteria and Actinobacteria. Multiple studies have revealed that the composition of gut microbiota is different between IBD patients and healthy controls.241 For example, the ratio of Bacteriodetes to Firmicutes is decreased while the abundance of gammaproteobacterial increased in IBD patients.242 The protective and normal bacteria, Bacteroides, Eubacterium, and Lactobacillus are significantly reduced in CD and UC patients.243 A meta-analysis study suggested that enterohepatic Helicobacter species, but not intestinal H. pylori infection, was significantly related to IBD.244 It should be noted that, although many studies provided the association between microbiota dysbiosis and IBD, the causation remains to be determined.245 It is possible that the microbiota dysbiosis can be considered a response to the environmental changes due to intestinal inflammation. The possible role of fungi and viruses in IBD are also being studied and reviewed, but no link has been established thus far.234,245

While most of the studies are focusing on gut microbiota, oral microbiota is gaining attention with the characterization of the oral-gut axis. Kitamoto et al. showed that pathobionts and pathogenic T cells of oral origin were able to translocate and colonize in intestines, causing IBD in periodontitis mouse models.246 Derrien et al. concluded that the bacteria residing in the oral cavity and GI tract maintain intimate relationships,247 supporting the notion of an oral-gut axis. Recently, a meta-analysis by She et al. demonstrated that periodontitis was significantly associated with IBD, while the mechanisms are undetermined.248 Another study by Kimura et al. suggested that, in the salivary microbiota of IBD patients, the abundance of Bacteroidetes was significantly increased with a concurrent decrease of Proteobacteria.249 They also found a significant correlation between inflammatory cytokine levels and the abundance of Streptococcus, Prevotella, Veillonella, and Haemophilus, implicating a possible relationship between dysbiosis of oral microbiota with inflammatory response in IBD patients. A case-control study by Vavricka et al. showed that both periodontitis and gingivitis marker levels were increased in CD patients compared with healthy controls.250 Although these studies have established an association between oral diseases with IBD, data regarding oral microbiota in IBD is still limited and require further investigation.

Brain disorders

Neuropsychiatric and neurodegenerative disorders of the brain, along with many other comorbidities, were known to be responsible in causing significant mortality in different population subsets. Extensive research over the years have shown to implicate the role of microbial diversity in brain disorders by modulating the factors linked with the development of these disorders. One example is data from a meta-analysis study which shows that depression is responsible for an increase in relative risk of mortality from all causes, specifically about 1.86 times more than non-depressed patients.251 Microbiota-induced hyperactivity of the HPA axis and inflammation are also shown to be associated with provoking depression.252

뇌의 신경정신과적 및 신경퇴행성 장애는 

다른 많은 동반 질환과 함께 다양한 인구 하위집단에서 

상당한 사망률을 유발하는 것으로 알려져 있습니다. 

수년에 걸친 광범위한 연구를 통해 이러한 장애의 발병과 관련된 요인을 조절함으로써 뇌 질환에서 미생물 다양성의 역할을 암시하는 것으로 밝혀졌습니다. 한 예로, 우울증이 모든 원인으로 인한 상대적 사망 위험의 증가, 특히 우울증이 없는 환자보다 약 1.86배 더 높다는 메타분석 연구 데이터가 있습니다.251 

미생물로 인한 

HPA 축의 과잉 활동과 

염증도 우울증 유발과 관련이 있는 것으로 나타났습니다.252

Neuropsychiatric disorders

Gut microbiota is believed to play a vital role in mediating neuronal behavior via gut-brain axis.253 Preclinical studies have established that gut microbiota affects cognitive performance, repetitive behaviors, and social interactions in different animal models.62,254,255 One of the plausible hypotheses about gut microbiota’s involvement in affecting neuronal disorders is described by stress-induced intestinal permeability, permitting endotoxins to enter the blood circulation, thereby triggering an immune response.256 This peripheral inflammation can also influence mental health by promoting the entry of neurotoxins into the brain and also by obstructing neurotransmitter systems.257 Although the direct mechanism of gut bacteria influencing neuropsychiatric disorders was clearly not studied, many studies believe that gut-induced stress has a vital role along with disrupted gut microbiome and various other factors in causing depression, anxiety, and other psychological disorders. Recently, Jiang et al. has demonstrated that fecal samples from patients with major depressive disorder have shown increased Bacteroidetes, Protobacteria and Actinobacteria along with less Firmicutes when compared with fecal samples from healthy controls.258 Decreased expression‎ of certain families such as Lachnospiraceae and Ruminococcaceae within the phylum Firmicutes was reported, and this is believed to be correlated with behavioral changes caused by stress. Some bacterial genera such as Roseburia, Blautia, Lachnospiraceae, and Ruminococcaceae are associated with synthesis of SCFA (responsible for barrier integrity) and anti-inflammatory properties. It was believed that there was an extensive correlation between diversity of gut microbiota and mood-related behaviors, especially depressive disorder.259

장내 미생물은 

장-뇌 축을 통해 신경 행동을 매개하는 데 중요한 역할을 하는 것으로 여겨집니다.253 

전임상 연구에 따르면 장내 미생물은 다양한 동물 모델에서 인지 능력, 반복 행동, 사회적 상호작용에 영향을 미치는 것으로 밝혀졌습니다.62,254,255 

신경 장애에 영향을 미치는 

장내 미생물의 관여에 대한 그럴듯한 가설 중 하나는 

스트레스에 의한 장 투과성으로 설명되며, 

장 내 독소가 혈액 순환으로 들어가 면역 반응을 유발합니다.256 

이러한 말초 염증은 

신경 독소의 뇌 유입을 촉진하고 

신경 전달 물질 시스템을 방해하여 정신 건강에도 영향을 미칠 수 있습니다.257 

장내 세균이 신경 정신 장애에 영향을 미치는 직접적인 메커니즘은 명확하게 연구되지 않았지만, 많은 연구에 따르면 장내 세균이 우울증, 불안 및 기타 심리적 장애를 유발하는 데 장내 미생물 생태계 및 다양한 다른 요인들과 함께 중요한 역할을 하는 것으로 알려져 있습니다. 최근 Jiang 등은 주요 우울 장애 환자의 분변 샘플에서 건강한 대조군의 분변 샘플과 비교했을 때 박테로이데테스, 프로토박테리아, 액티노박테리아는 증가하고 펌미쿠테스는 감소한 것으로 나타났습니다.258 펌미쿠테스 문 내 라크노스파이라과, 루미노코카테과와 같은 특정 과의 발현 감소가 보고되었으며 이는 스트레스로 인한 행동 변화와 관련이 있는 것으로 추정되고 있습니다. 로즈부리아, 블라우티아, 라크노스피라과, 루미노코카세아과와 같은 일부 박테리아 속은 SCFA(장벽 무결성 담당)의 합성 및 항염증 특성과 관련이 있습니다. 장내 미생물의 다양성과 기분 관련 행동, 특히 우울 장애 사이에는 광범위한 상관관계가 있는 것으로 여겨졌습니다.259

Both major brain disorders, depression and anxiety are indicated to be influenced by stress-regulated HPA axis pathway, which is believed to be strongly modulated by gut microbiota composition.257,260 An epigenetic study using GF mouse models had demonstrated that GF mice showed significant difference in gene expression‎ in the brain systems when compared with control mice, notably in the areas of cortex, cerebellum, striatum, and hippocampus.261 It is suggested that the gut-brain axis may be affected by regulation of stress hormones and the establishment of neuronal circuits. Based on this initial finding, many studies have investigated the substantial changes observed in GF mice compared with the wild-type controls. In GF rats, increased levels of neurotransmitters such as norepinephrine, dopamine, and serotonin were reported in the striatum, whereas dopaminergic turnover was found to be decreased in the frontal cortex, striatum, and hippocampus of GF rats.262 Few other study findings using GF mice models have demonstrated a reduction in brain-derived neurotropic factor and nerve growth factor-inducible protein A in several brain regions, and an increase in synaptophysin and post synaptic density (PSD-95) proteins in GF mice brain systems when compared with controls.261 When it comes to autism spectrum disorder (ASD), several pre-clinical studies have reported that gut dysbiosis induced significant neurodevelopmental changes in mouse models of ASD.263 Species like Clostridium and Ruminococcus was found to be different when compared between autism children and controls.264 Adams et al. demonstrated that symptoms of GI discomfort were correlated with severity of autism in children.265 A small pilot scale study conducted by Kang et al. using fecal transplantation of standardized gut microbiota to children diagnosed with autism spectrum disorder has enhanced GI function and decreased behavioral ASD scoring.266

주요 뇌 질환인 우울증과 불안증은 

모두 스트레스 조절 HPA 축 경로의 영향을 받는 것으로 나타났는데, 

이는 장내 미생물 구성에 의해 강하게 조절되는 것으로 여겨집니다.257,260 

GF 마우스 모델을 사용한 후성 유전학 연구에 따르면 GF 마우스는 대조 마우스와 비교할 때 뇌 시스템, 특히 피질, 소뇌, 선조체 및 해마 영역에서 유전자 발현에 상당한 차이를 보였습니다.261 장-뇌 축은 스트레스 호르몬의 조절과 신경 회로 확립의 영향을 받을 수 있다고 제안됩니다. 이 초기 발견을 바탕으로 많은 연구에서 야생형 대조군과 비교하여 GF 마우스에서 관찰된 상당한 변화를 조사했습니다. GF 쥐의 선조체에서 노르에피네프린, 도파민, 세로토닌과 같은 신경전달물질의 수치가 증가한 반면, GF 쥐의 전두피질, 선조체 및 해마에서는 도파민성 회전율이 감소하는 것으로 나타났습니다.262 GF 마우스 모델을 사용한 다른 연구 결과에서는 여러 뇌 영역에서 뇌 유래 신경영양인자 및 신경 성장 인자 유도 단백질 A가 감소하고 대조군과 비교했을 때 GF 마우스 뇌 시스템에서 시냅토피신 및 시냅스 후 밀도(PSD-95) 단백질이 증가한다는 사실이 입증되었습니다.261 

자폐 스펙트럼 장애(ASD)와 관련하여, 여러 전임상 연구에서 장내 미생물 이상증식이 ASD 마우스 모델에서 상당한 신경 발달 변화를 유도한다고 보고했습니다.263 클로스트리디움과 루미노코쿠스 같은 종은 자폐 아동과 대조군을 비교했을 때 다른 것으로 밝혀졌습니다.264 Adams 등은 소화기 불편 증상이 어린이의 자폐증 중증도와 상관관계가 있음을 입증했습니다.265 Kang 등이 자폐 스펙트럼 장애를 진단받은 어린이에게 표준화된 장내 미생물의 대변 이식을 사용하여 실시한 소규모 파일럿 규모 연구에서 소화기 기능이 향상되고 행동 ASD 점수가 감소했습니다.266

Neurodegenerative disorders

Lately, accumulating body of evidence from various studies are emphasizing the importance of gut microbiota in the progression of various neurological disorders such as Alzheimer’s disease (AD), cerebrovascular stroke (CVS), Parkinson’s disease (PD), and schizophrenia etc. It has been evident that gut microbes are involved with regulation of brain function via its effect on host innate immunity.267 The community composition is also found to be varied depending on the way of newborn delivery. Vaginally delivered newborns are colonized with microbiota from the maternal genital tract and is more heterogenous compared with newborns delivered by Cesarean section.268 Cesarean delivered newborns displayed less brain electrical activity, which is supported by in vivo studies using Cesarean-delivered rats, where these rats exhibited pre-pubertal alterations in the development of cortex and hippocampus.269

최근 다양한 연구를 통해 장내 미생물이 

알츠하이머병(AD), 뇌혈관 뇌졸중(CVS), 파킨슨병(PD), 정신분열증 등 

다양한 신경 질환의 진행에 중요하다는 증거가 축적되면서 

장내 미생물의 중요성이 강조되고 있습니다. 

장내 미생물이 숙주의 선천 면역에 영향을 미쳐 뇌 기능 조절에 관여한다는 사실이 밝혀졌습니다.267 

장내 미생물은 신생아 분만 방식에 따라 커뮤니티 구성도 달라지는 것으로 밝혀졌습니다. 질식으로 분만한 신생아는 산모의 생식기에서 나온 미생물로 군집화되어 있으며 제왕절개로 분만한 신생아에 비해 더 이질적입니다.268 제왕절개로 분만한 신생아는 뇌 전기 활동이 덜 나타났는데, 이는 제왕절개로 분만한 쥐를 사용한 생체 내 연구에서 피질과 해마 발달에서 사춘기 전 변화를 보인 쥐를 통해 뒷받침됩니다.269

During the presymptomatic stages of PD, α-synuclein-mediated Lewy body pathology was observed in the ENS and dorsal motor nucleus of the vagus nerve. A total of 38 human fecal samples were analyzed using 16s rRNA sequencing, displaying significant differences in bacterial composition such as decreased Blautia, Faecalibacterium and Ruminococcus and increased Escherichia-Shigella, Streptococcus, Proteus, and Enterococcus.270 Li et al. in a study conducted in China, has identified significant diversity in different taxa such as increases in Prevotella, Akkermansia and decreased abundance in Lactobacillus species in PD patients when compared with healthy controls.271 These species play a prominent role in affecting the harmony of gut homeostasis, for example, increased numbers of Akkermansia were shown to be responsible for increased intestinal permeability and facilitating pathogen entry.272 Increased level of certain Prevotella species is associated with mucin synthesis in the gut mucosal layer and production of SCFAs, which are shown to mediate neuroinflammation in mouse models of PD.67 However, another study has reported a decreased abundance of Prevotella in PD patients compared with healthy controls, which led to the need of additional studies or bigger sample size to understand the specific role of Prevotella and its family in progression of PD.273 Differences in genotype, diet, and lifestyles of the population subsets might be a potential reason for this disparity in reports. Pathological features of AD were characterized by the presence of amyloid-β plaques and intracellular tau based neurofibrillary tangles (NFT). Vogt et al. have reported significantly less microbiome diversity in AD patients compared with healthy controls. Particularly in this study, a decrease in phylum like Firmicutes, Actinobacteria (member of Bifidobacterium) and an increase in phylum of Bacteroidetes and Proteobacteria were observed in the AD group.274 Reduction in Firmicutes and Bifidobacterium has been well studied for their association with T2DM and inflammation, which are identified as major risk factors for AD.179 Inflammatory intestinal bacterial taxa are found to be associated with high level of inflammatory cytokines, including IL-6, TNF-α, CXCL2, NLRP3, and brain amyloidosis in a study conducted in older people suffering from cognitive disorders.275 In the same study, increased levels of pro-inflammatory cytokines were observed with increased numbers of Escherichia/Shigella. Colonization of certain pathogenic bacterial strains such as Toxoplasma and Chlamydiaceae pneumoniae has also been suggested for their roles in chronic neuroinflammation and NFT in AD.276

PD의 전증상 단계에서 미주신경의 ENS와 등쪽 운동핵에서 α-시누클레인 매개 루이체 병리가 관찰되었습니다. 총 38개의 인간 분변 샘플을 16s rRNA 시퀀싱을 사용하여 분석한 결과, 블라우티아, 페칼리박테리움, 루미노코쿠스는 감소하고 에스테리치아-시겔라, 스트렙토코커스, 프로테우스, 엔테로코쿠스는 증가하는 등 세균 구성에 상당한 차이가 나타났습니다.270 Li 등은 중국에서 실시한 연구에서 건강한 대조군과 비교했을 때 PD 환자에서 프레보텔라, 아커만시아의 증가와 락토바실러스 종의 풍부도 감소 등 다양한 분류군에서 상당한 다양성을 확인했습니다.271 이러한 종은 장 항상성의 조화에 영향을 미치는 중요한 역할을 하며, 예를 들어 아커만시아의 증가는 장 투과성을 증가시키고 병원체 유입을 촉진하는 것으로 나타났습니다.272 특정 프레보텔라 종의 증가는 장 점막층에서 뮤신 합성 및 SCFA의 생성과 관련이 있으며, 이는 PD 마우스 모델에서 신경 염증을 매개하는 것으로 나타났습니다.67 그러나 또 다른 연구에서는 건강한 대조군에 비해 PD 환자에서 프레보텔라의 농도가 감소한 것으로 보고되어, PD 진행에서 프레보텔라와 그 계열의 구체적인 역할을 이해하기 위해 추가 연구 또는 더 큰 표본 크기가 필요했습니다.273 인구 하위 집합의 유전자형, 식단 및 생활 방식의 차이가 이러한 보고 불균형의 잠재적 원인이 될 수 있습니다. AD의 병리학적인 특징은 아밀로이드-β 플라크와 세포 내 타우 기반 신경섬유 엉킴(NFT)의 존재로 특징지을 수 있습니다. Vogt 등은 건강한 대조군에 비해 AD 환자의 마이크로바이옴 다양성이 현저히 낮다고 보고했습니다. 특히 이 연구에서는 AD 그룹에서 펌미쿠테스, 액티노박테리아(비피도박테리움의 일원)와 같은 문이 감소하고 박테로이데테스 및 프로테오박테리아의 문이 증가하는 것이 관찰되었습니다.274 펌미쿠테스와 비피도박테리움의 감소는 AD의 주요 위험 요인으로 알려진 T2DM 및 염증과의 관련성에 대해 잘 연구되어 있습니다.179 염증성 장내 세균 분류군은 인지 장애를 앓고 있는 노인을 대상으로 실시한 연구에서 IL-6, TNF-α, CXCL2, NLRP3 및 뇌 아밀로이드증을 포함한 높은 수준의 염증성 사이토카인과 관련이 있는 것으로 밝혀졌습니다.275 같은 연구에서 대장균/시겔라의 수가 증가하면 염증성 사이토카인의 수준이 높아지는 것이 관찰되었습니다. 톡소플라즈마 및 클라미디아과 폐렴균과 같은 특정 병원성 박테리아 균주의 군집화도 만성 신경염증 및 알츠하이머성 치매에서 이들의 역할로 제안되었습니다.276

CVS is a major neurological condition associated with neurological defects and impairment in cognitive functions leading to disability and mortality. Acute middle cerebral artery occlusion-induced stroke mouse models have shown reduced species diversity and increased growth of Bacteroidetes in mice, while fecal transplantation of normal gut microbiota normalized brain lesion-induced dysbiosis and improved stroke outcomes.277 Another preclinical study using mice has reported a significant change in cecal microbiota, such as Prevotellaceae and Peptococcaceae, the former of which is a core part of microbiota in mice, although their functionality in humans is yet to be identified.278 Additionally, experiencing stress before stroke might increase the bacterial translocation from the intestine to the blood stream, triggering immune responses.279 Despite the number of studies done in strengthening the idea of gut microbiota involvement in orchestrating neuronal harmony, additional studies are required to identify the clinical benefits of targeting specific microbiota in treating these conditions.

Oral and respiratory microbiota in brain disorders

Oral microbiome is another key contributor to the development of neurological disorders, as improper maintenance of oral health can influence the growth of complex communities on the surface of teeth, tongue, or under the gum.280 Hicks et al. has reported that salivary microbiome analysis has shown wide differences between ASD, typically developing, and non-developmentally delayed groups of children.281 In a depression-related study, 1S rRNA gene-based next-generation sequencing was used to profile the bacterial composition of saliva in depressed patients compared with young adults; it has shown diversification but importantly, increased Prevotella nigrescens and Neisseria was observed in depressed individuals.282 Smoking and alcohol consumption are two major factors that induce dysbiosis in oral microbiota and promote growth of pathogenic bacteria.280 A meta-analysis study has revealed that drinking alcohol is associated with pathogenesis of AD and also with significantly decreased level in Firmicutes phyla and an increased level in Bacteroides phyla in these patients.283 In a cross-sectional case control design study on PD, around 16 bacterial families were found to be altered in early-stage PD patients.284 Among them, variation in families like Bifidobacteriaceae, Saccharomycetaceae and Lactobacillaceae were studied extensively for their role in progression of PD. A cohort study with 68 patients comprising of AD and control groups have reported differential abundance of two specific taxa Pasteurellaceae and Lautropia mirabilia, which were found to be associated with mild cognitive impairment.285 Additionally, another study conducted in 78 patients have revealed increased relative abundance of Moraxella, Leptotrichia and Sphaerochaeta and decreased Rothia in saliva of AD patients when compared with healthy controls.286 Unfortunately, not many studies have been reported about respiratory microbiota for its role in neurological disorders, and the research concerning respiratory microbiota is still at infancy stage. Although the affinity of microbial dysbiosis in many neurological disorders is being extensively studied, currently there is no gold standard to interlink the changes in microbial environment with the pathogenesis of these disorders. More preclinical and clinical studies targeting microbiome are required to understand the extent and complex nature of microbiome’s association with the development of several brain disorders.

구강 건강을 부적절하게 유지하면 치아 표면, 혀 또는 잇몸 아래에 있는 복잡한 커뮤니티의 성장에 영향을 미칠 수 있기 때문에 구강 마이크로바이옴은 신경 장애 발병의 또 다른 주요 원인입니다.280 Hicks 등은 타액 마이크로바이옴 분석에서 자폐증, 일반적으로 발달 지연 아동 그룹과 비발달 지연 아동 그룹 간에 큰 차이를 보인다고 보고했습니다.281 

우울증 관련 연구에서 1S rRNA 유전자 기반 차세대 시퀀싱을 사용하여 젊은 성인과 비교하여 우울증 환자의 타액의 박테리아 구성을 프로파일링한 결과, 다양성을 보였지만 중요한 것은 우울한 사람에서 Prevotella nigrescens와 Neisseria의 증가가 관찰되었다는 것입니다.282 흡연과 음주는 구강 미생물총의 이상균총을 유도하고 병원성 박테리아의 성장을 촉진하는 두 가지 주요 요인입니다.280 메타 분석 연구에 따르면 음주는 AD의 발병과 관련이 있으며 이러한 환자에서 Firmicutes 계통의 수준이 유의하게 감소하고 Bacteroides 계통의 수준이 증가하는 것으로 밝혀졌습니다.283 PD에 대한 단면 사례 관리 설계 연구에서 약 16개의 박테리아 과가 초기 PD 환자에서 변화된 것으로 밝혀졌습니다.284 그 중 비피더스균과, 사카로마이세스과 및 락토바실러스과와 같은 과의 변이가 PD 진행에 미치는 역할에 대해 광범위하게 연구되었습니다. 68명의 환자를 대상으로 한 코호트 연구에서 알츠하이머병 환자와 대조군으로 구성된 두 개의 특정 분류군인 파스튜렐라과와 라우트로피아 미라빌리아가 경도인지장애와 연관성이 있는 것으로 밝혀졌습니다.285 또한 78명의 환자를 대상으로 실시한 또 다른 연구에서는 건강한 대조군과 비교했을 때 알츠하이머병 환자의 타액에서 모락셀라, 렙토트리치아, 스페이로에차타의 상대적 풍부도가 증가하고 로티아는 감소한 것으로 나타났습니다.286 안타깝게도 호흡기 미생물이 신경 장애에 미치는 역할에 대한 연구는 아직 많이 보고되지 않았으며 호흡기 미생물에 관한 연구는 아직 초기 단계에 머물러 있습니다. 많은 신경계 질환에서 미생물 이상균총의 친화성이 광범위하게 연구되고 있지만, 현재 미생물 환경의 변화와 이러한 질환의 발병 기전을 연결할 수 있는 표준은 없습니다. 여러 뇌 질환의 발병과 마이크로바이옴의 연관성의 범위와 복잡한 특성을 이해하기 위해서는 마이크로바이옴을 대상으로 하는 더 많은 전임상 및 임상 연구가 필요합니다.

Chronic kidney diseases

Around 9% of the global population suffer from chronic kidney disease (CDK).287 Co-morbidities like diabetes, hypertension and heart disease are considered some of the major risk factors for CKD.288 CKD is physiologically identified as a decrease in glomerular filtration rate (GFR) < 60 ml/min per 1.73 m2 or by the existence of albuminuria for 3 or more months. Gradual loss of kidney function and irreversible renal structural changes are the main characteristics observed in CKD patients.

Gut-kidney axis communication and gut microbiota

Differences in microbial ecosystems were studied persistently for their involvement in the progression of CKD.289 Recently, oral microbiota were extensively studied for the role in mediating chronic systemic inflammatory dysregulation. It has been reported that conditions affecting oral microbiota like periodontitis indirectly affects CKD by augmenting systemic inflammation.290 Biomarker-based human studies have reported that elevated IgG levels due to the presence of elevated periodontal pathogen species like P. gingivalis, T. denticola, S. noxia, A. actinomycetemcomitans, and V. parvula are connected to detrimental kidney function.291 Bastos et al. has reported that higher frequency of Candida albicans, P. gingivalis, T. forsythia, and T. denticola was associated with the development of chronic periodontitis in CKD patients, thereby indicating a bidirectional relationship between changes in oral microbiota and CKD.292 A large 10-year cohort study with CKD patients suffering with periodontitis had demonstrated an increase in mortality rate from 32% to 41% in those patients.293 However, data is lacking to establish a solid confirmation on the role of oral microbiota in the pathogenesis of CKD.

The gut-kidney axis functionality is based on metabolic and immune pathways being interlinked with each other.288 The metabolic pathway is mostly focused on gut microbiota-produced metabolites that mediate host physiological functions, whereas the immune pathway depends on several other components like monocytes, lymphocytes, and cytokines, which facilitate the communication between the gut and kidney.294 Recently, involvement of dysbiosis in the gut microbial environment leading to CKD has garnered attention, as there are implications of cross functionality between the gut and renal system.295 Numerous studies have been conducted to link the qualitative and quantitative changes in intestinal microbiota with the pathogenesis of CKD and end-stage renal disease (ESRD).296,297 However, there is no solid evidence confirm‎ing the presence of altered gut microbiota in CKD patients.297 Factors such as increased protein absorption, reduced dietary fiber intake, slower intestinal transit, and frequent oral intake of iron supplements and antibiotics resulted in altered intestinal microbial environment, leading to systemic inflammation and accumulation of uremic toxins. Both inflammation and uremic toxins substantially contribute to the progression of CKD and CKD-associated complications.298 Vaziri et al. showed that continuous loss of kidney function augments intestinal dysbiosis in CKD and ESRD patients.299 A comparative study between fecal samples comparing healthy subjects with CKD patients have exhibited that CKD patients show reduced abundance of Actinobacteria phylum and Akkermansia genera, where the latter is correlated with regulating levels of IL-10, denoting its importance in systemic inflammation.300 Another clinical study conducted using 73 subjects have identified 31 phylotypic differences between CKD and control groups with phylotypes like Bacteroides, Parabacteroides, R. gnavus, R. torques, Flavonifractor, Weissella, Ruminiclostridium, Erysipelatoclostridium, Eggerthella, and Sellimonas being predominant in CKD patients.301 ESRD patients have shown an increase in Actinobacteria, Proteobacteria and Firmicutes and a decrease in Bifidobacteria and Lactobacilli compared with the control group.299 Another study has demonstrated that changes in gut microbiota is also shown to be an important factor in contributing to inflammation along with oxidative stress by increasing accumulation of gut-derived uremic toxins such as indoxyl sulfate, amines, ammonia, p-cresyl glucuronide (PCG), p-cresyl sulfate (PCS) and TMAO in CKD patients.302 Dietary intervention is also an additional variable that induced post-translational modification of uremic toxins, indirectly contributing to CKD progression.303 Fiber-rich diet is a main contributor to colonic bacterial fermentation, and CKD patients often have a low fiber intake diet to limit the potassium intake.304 A meta-analysis study has reported that one-third of CKD patients exhibit higher levels of pathogenic bacteria like E. coli and Enterobacter, and mild CKD patients have shown increasing presence of uremic toxin-producing bacteria.305 In vivo studies using collagen type 4α3 (Col4a3)–deficient mice demonstrated that uremia is associated with intestinal dysbiosis and intestinal barrier dysfunction, causing persistent systemic inflammation in CKD.306 Human studies conducted with CKD patients have shown higher levels of PCS and PCG in general with PCS reaching levels around 200-fold higher than PCG.307,308 Mutsaers et al. have demonstrated that PCS and PCG affect renal tubular function while simultaneously affecting the activity of MRP4 (PCS and PCG) and BCRP (PCG) transporters.309 In vivo studies have shown that PCS-administered rats at a dose of 50 mg/kg for 4 weeks induced renal tubular cell damage.310 Various in vitro studies have also shown that indoxyl sulfate is responsible for inducing inflammatory and profibrotic responses in tubular cells.311,312 Increased levels of TMAO are associated with increased risk prediction of CVD, systemic inflammation, and mortality in CKD patients.313 A trial study using samples obtained from CKD patients displayed higher plasma levels of TMAO in CKD vs non-CKD patients.314 Persistent low-grade inflammation is augmented due to translocation of bacteria and bacterial products from the gut lumen to blood via increase in intestinal permeability. Decreased levels of certain microbiota metabolites like butyrate and vitamin K, which are nephroprotective, were also observed.308 These studies show strong evidence for involvement of various disturbances in gut-renal system communication via dysbiosis in microbiota in the progression and pathogenesis of kidney diseases.

Chronic liver diseases

Liver diseases remain one of the leading causes of morbidity and mortality worldwide. Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and alcoholic liver disease (ALD) are the most common chronic liver diseases that often lead to liver cirrhosis and cancer.315 NAFLD comprises a wide span of liver damages from benign steatosis to steatohepatitis with hepatocellular inflammation and damage.315 ALD may take the form of chronic disease state (steatosis, steatohepatitis, fibrosis, or cirrhosis) or acute involvement (alcoholic hepatitis).316 Cirrhosis is the end stage of all chronic liver diseases, characterized by tissue fibrosis and the transformation of normal liver architecture to abnormal nodules. Recent studies have suggested the roles that oral and gut microbiota play in the pathogenesis of chronic liver diseases.

Gut microbiota in liver diseases

Mounting evidence supports the bidirectional gut-liver axis, due to the fact that liver secretes bile acids into the biliary tract and receives blood supply via the portal vein.317 Therefore, gut microbiota may contribute to liver diseases by delivering pathogens or metabolites into the liver through the portal vein. Currently, clinical data demonstrating the relationship between gut microbiota dysbiosis and liver diseases are still limited. Mouzaki et al. reported that patients with NASH have lower level of Bacteroidetes compared with healthy controls.318 Raman et al. suggested a compositional shift in the gut microbiota of obese NAFLD patients. Analysis of fecal microbiome showed an increased abundance of Lactobacillus and selected members of Firmicutes.319 Wong et al. reported an increased fecal abundance of Parabacteroides and Allisonella but decreased levels of Faecalibacterium and Anaerosporobacter.320 In liver cirrhosis patients, Chen et al. showed that abundance of Bacteroidetes was significantly reduced, while Proteobacteria and Fusobacteria were enriched compared with healthy controls.321 However, the investigation of gut microbiota with liver diseases is mainly conducted in preclinical studies. More evidence is required to conclude whether dysbiosis contributes to liver diseases or is a consequence of the disease state.

Researchers have postulated several mechanisms linking gut microbiota to liver diseases, including regulation of bile acid metabolism, intestinal permeability, chronic inflammation, and immune response. The gut microbiota plays an essential role in the metabolism of bile acids by converting primary bile acids into secondary bile acids. Deoxycholic acid, a major secondary bile acid, has been suggested to activate NF-κB stress response pathway by generating ROS.322 In addition, recent studies have established the crosstalk between ROS and NF-κB signaling pathway. While high ROS level usually results in cell damage, NF-κB pathway is known to promote cell proliferation.323 Therefore, it is likely that deoxycholic acid can induce cytotoxicity by promoting the generation of ROS, and simultaneously activates NF-κB pathway to allow damaged cells to resist apoptosis. Hence, microbiota dysbiosis may affect to bile acid homeostasis, leading to pathogenesis of chronic liver diseases such as NAFLD/NASH. Moreover, gut microbiota is involved in the metabolism of choline, and its deficiency usually leads to hepatic steatosis.324 There are multiple mechanisms established to explain choline deficiency and liver diseases, including 1) accumulation of DNA damage during choline depletion, 2) overproduction of free radicals in choline deficient hepatocytes, and 3) induction of inflammatory response due to death of hepatocytes.324 Spencer et al. showed that the abundance of Gammaproteobacteria and Erysipelotrichi were significantly associated with choline deficiency-induced fatty liver.325 Impaired intestinal permeability allows the translocation of gut bacteria and their component, which is associated with chronic liver diseases. For example, the Gram-negative bacteria structural element LPS was suggested to be elevated in portal vein in ALD and cirrhosis.326 Mechanistically, Seki et al. described that, upon LPS binding, TLR4 upregulates chemokine secretion and downregulates TGF-β pseudoreceptor Bambi to enhance TGF-β signaling pathway.327 The study also suggested that the effect of LPS is mediated by MyD88-NF-κB-dependent pathway, as MyD88-deficient mice had decreased hepatic fibrosis. Gut microbiota-mediated chronic inflammation and immune activation is central to the pathogenesis of multiple diseases. Recent studies also suggested such mechanisms in the development of NAFLD/NASH.328 In conclusion, current research highlights the potential role of gut microbiota in liver diseases, but further study is needed to confirm‎ their relationship.

Oral microbiota in liver diseases

As mentioned in other diseases, it has been demonstrated that oral microbes or their metabolites are able to invade other sites of the body. Although the correlation between periodontal and liver diseases is yet to be established, recent studies implicated that periodontal bacteria may be involved in the progression of NAFLD, NASH, and cirrhosis.329 Yoneda et al. reported that P. gingivalis (one of the most common periodontal pathogens) may influence the pathogenesis of NAFLD/NASH in a mouse model.330 In addition, they found that P. gingivalis infection was mostly observed in NAFLD patients compared with control subjects. Clinical data also support the notion that periodontitis may serve as a risk factor in the progression of NAFLD/NASH.331

Mechanistically, this process may be attributed to many factors including pro-inflammatory mediators, oxidative stress, and pathogen invasion. The migration of periodontal bacteria as well as their metabolites (LPS, peptidoglycans, etc.) into the systemic circulation is usually recognized by TLRs, which leads to the activation of T cells and the release of pro-inflammatory cytokines, chemokines, and ROS/RNS.332 This may indicate the oral-gut-liver axis in the inflammation pathway as suggested by Acharya et al.333 They proposed that the gut with impaired intestinal permeability may act as an intermediate between oral microbiota and the liver. Therefore, after the bacteria and metabolites enter the systemic circulation, they can reach the liver and bind to innate TLRs of hepatocytes and Kupffer cells, inducing inflammation and causing liver diseases.334 In addition, Silva Santos et al. observed that cirrhotic patients exhibited numerous oral diseases other than periodontitis, such as candidiasis, xerostomia, and petechiae.335 Moreover, dysbiosis of oral microbiota has been suggested to promote the pathogenesis of hepatitis B virus (HBV)-induced chronic liver disease. HBV-associated oral bacteria including Fusobacterium, Eubacterium, and Treponema may invade and contribute to the dysbiosis of gut microbiota as opportunistic pathogens, which subsequently participate in the formation of liver diseases.336

Microbiota and disease treatment

With the gradual understanding of microbiota, the potential of treating diseases through manipulating microbiota has attracted people’s attention. Because the human gut is involved in a wide range of physiologic functions, its modulation is expected to prevent or treat the corresponding diseases. Therefore, climbing number of clinical trials are ongoing to investigate this possibility (Fig. 5a). The majority of clinical trials focusing on efficacy of fecal microbiota transplantation (FMT) is various diseases. Since C.Difficile infection, cancer, and IBD has the highest number of trials, we also summarized the data from pubmed (Supplemental Table S1). As shown in Fig. 5b, c, FMT treatment in IBD and C.Difficile infection showed a significant response rate compared to placebo treatment. Similarly, probiotics treatment as an adjuvant therapy in cancer patients also demonstrated an optimal result (Fig. 5d). It should be noted that while the response rate is promising, the trials are mainly pilot studies with small sample size. In addition, the underlying mechanism for complete response required further investigation to optimize the experimental design and to personalize the treatment. Diet is considered the main short-term and long-term regulator of the gut microbiota,337 along with healthy lifestyle habits. As shown in Fig. 6, this section will present the latest clinical interventions targeting the gut microbiota, including microbiota modulations, FMT, and bacteria engineering. We will also discuss the pharmacological microbiota–drug interactions in clinical settings.

Fig. 5

Current number of microbiota-related clinical trials by regions and study phases. Data are updated until October 2021

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Fig. 6

Strategies to modify gut microbiota for disease treatment

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Microbiota modulationsProbiotics and prebiotics

Generally, probiotics and prebiotics are the most popular topic in microbiota modulation research. They are often used as a dietary supplement for clinical intervention by oral administration. Differences in dosage form and host are considered to be the main factors affecting the effectiveness of probiotics and prebiotics.338 Probiotic administration is suggested to restore microbial dysbiosis and maintain intestinal microbial balance by occupying host tissue and preventing colonization of pathogenic bacteria. Extensive research has indicated the potential mechanism of probiotics in disease treatments, including differences in various probiotic strains and mucosal immune system, regulation of host metabolism or altering intestinal neuromuscular function.339 However, clinical data is insufficient to support their role. Several clinical trials denied the benefits of probiotics in cancer treatment.340 Importantly, patients with damaged intestinal barrier and/or compromised immune systems might have a probiotic translocation. Some published case reports associate negative effects of probiotics with conditions such as bacteremia, fungemia, endocarditis, liver abscess and pneumonia,341 which compels us to ponder the actual effects of probiotics.

Prebiotic was recently redefined as “a substrate that is selectively utilized by host microorganisms conferring a health benefit” in 2017. Prebiotics were originally used to study the stimulating effect of probiotics. The most well-known prebiotics are inulin, fructo-oligosaccharides (FOS), lactulose, and galacto-oligosaccharides (GOS). Prebiotics are mainly used to modulate the strains of Bifidobacterium and Lactobacillus, which produce lactic acid and acetate, and to maintain the health of the host by fermenting prebiotics.342 Studies have confirmed that taking prebiotics can stimulate the selective enrichment of probiotics in the intestinal tract, thereby regulating immune response and preventing pathogens.70 Although some basic studies have confirmed that prebiotics can inhibit the colonization of pathogens by mimicking glycoconjugates of microvilli,343 and even directly act on the intestinal tract to regulate immunity,344 the applicability of prebiotics as a clinical intervention is still debatable. Belcheva et al. suggested that supplementation with prebiotic/butyrate could promote tumor progression due to genetic variation in individuals.345 Their findings suggest that butyrate functions as an oncometabolite, while a substantial of studies reported butyrate as tumor suppressive metabolite. Indeed, butyrate is known to exhibit differential effects toward normal and cancerous colonocytes. In colon cancer cells, butyrate is metabolized to a lesser extent compared to normal cells, thereby accumulating as HDAC inhibitor to inhibit cell proliferation and induce cell apoptosis.346 The difference observed in this study may lay between host genetic background, the age, and the presence of other bacterial metabolites. In addition, the study was performed in mice model, so the translation to human requires further investigations.

Sasaki et al. showed that transglucosidase, which generates prebiotics, can reduce high blood sugar levels in patients with T2DM and inhibit weight gain.347 Because probiotics and prebiotics are cheap and easy to handle, they are often used in the care of patients with AD. Long-term supplementation with milk enriched with Bifidobacteria and Lactobacillus fermentum improves learning and memory in AD patients.348 In CRC treatment, some probiotic strains could be beneficial as an adjuvant therapeutic agent, such as multigene and multistrain probiotics, including B. breve, B. infantis, B. longum, L. acidophilus.349,350 Recent studies in intestinal inflammatory disorders show that probiotics might have some efficacy in UC and pouchitis, but with insignificant effect in CD. Probiotic supplementation may significantly reduce rates of rotavirus diarrhea, although the curative effect of probiotics in NSAID enteropathy and IBS is controversial.351 This is because the study populations, types of probiotics and dosage and length of follow-up various greatly between the clinical studies. Similarly, the treatment with synbiotics and FMT demonstrated controversial results due to the limited data. In heart diseases, an in vivo study showed that rats treated with probiotics and prebiotics containing Lactobacillus plantarum 299 v could reduce infarct size and improve left ventricular function before coronary artery ligation.352 Gan et al. demonstrated similar cardioprotective results in a rat model of myocardial ischemia after supplementation with Lactobacillus rhamnosus GR-1.353 In addition, modulation of the gut microbiota through probiotics may present potential therapeutic strategies to protect against lung diseases.354 Moreover, probiotics is believed to have some positive effect on COVID-19 treatment. For example, Chen et al. suggested that probiotics could reduce hyperinflammation from COVID-19 through its anti-inflammatory effects.355 However, a systematic review by Bafeta et al., which investigated 384 RCTs, found that the report of side effects in published RCTs assessing probiotics, prebiotics, and symbiotic is often lacking or inadequate.356 Therefore, the safety of these interventions cannot be determined without enough safety data.

Antibiotic

Antibiotic administration is the most common approach to manipulate the composition of the gut microbiota. Researchers found that modulation of gut microbiota by antibiotics improves insulin signaling in high fat-fed mice.357 In a study of melanoma and lung cancer models, vancomycin can enhance the anti-tumor response induced by radiotherapy in mice by increasing CD8 + T cell infiltration and IFN-γ expression‎.358 Many studies have shown that antibiotics can prevent cancer development or attenuate tumor proliferation. For example, Bullman et al. showed that metronidazole treatment can eradicate the colonization of Fusobacterium and ameliorate the progression of CRC.359 The results showed that colonization of Fusobacterium with CRC tumor cells was maintained in distal metastasis, demonstrating a stable microbiome composition between primary and metastatic tumors. In addition, antibiotic treatment that reduced Fusobacterium load also inhibited cancer cell proliferation and tumor growth. Therefore, this finding suggests the potential of microbiota modulation, i.e., antibiotic intervention, for patients with microbial-associated cancer. However, we cannot exclude the possibility that broad spectrum antibiotics may have negative impact on the healthy intestinal microbiota, therefore the use of antimicrobial agent targeting to the specific bacteria is highly important. At the same time, antibiotics also showed potential as immunotherapy. In a metastatic mouse model, antibiotic consumption of the gut microbiota could inhibit tumor growth by triggering an anti-tumor immune response.360 The researchers studied the effect of antibiotics on tumor growth of pancreatic cancer, CRC, and melanoma. It is found that gut microbiota depletion by oral microbiota significantly reduced the tumor growth in all tumor models. Interestingly, the inhibition effect was not observed in Rag-1 KO mice, which lack mature B and T cells, suggesting the effect may be dependent on host immunity. Indeed, the mechanistic study showed that gut microbiota depletion resulted in a significant increase in IFγ producing T cells and the decrease in IL-17A/IL-10 producing T cells. In addition, gut microbiota depletion led to infiltration of effector-T cells into pancreatic tumors. Previous studies have shown that immune checkpoint inhibitors failed to antagonize pancreatic cancer due to low effector-T cell infiltration. Hence, the antibiotic treatment may be beneficial as an adjuvant therapy along with conventional immunotherapy. In patients with early gastric cancer, the eradication of H. pylori through the combination of amoxicillin and clarithromycin is associated with a lower incidence of metachronous gastric cancer and improvement of the degree of gastric gland atrophy.361

It remains controversial that, although antibiotics can effectively eradicate pathogens or harmful bacteria, their non-selective antibacterial effects may kill the symbiotic microbes, leading to another ecological disorder. It may also impair the efficacy of cancer immunotherapy and lead to treatment resistance. Vétizou et al. demonstrated that the efficacy of CTLA-4 blockade was associated with the T cell response for B. fragilis in mice and patients. Moreover, while GF mice were not responding to CTLA-4 blockade, introduction of B. fragilis was able to overcome this defect.362 Therefore, this study suggests a key role of microbiota in triggering the response to immunotherapy and it is meaningful to explore if other bacteria have the similar functions. Hernández et al. reported that compared with untreated individuals, subjects receiving antibiotics showed greater or unbalanced sugar anabolic capacity.363 Clinical studies have shown that antibiotics are closely related to the increased risk of CRC development,364,365 though this result may be affected by confounding indications.366 For example, compared with cancer patients, immunodeficient patients are more susceptible to bacterial infections that require antibiotic treatment.364 Despite the controversy surrounding the use of antibiotics, their potential for microbiota regulation should not be underestimated. With the development of modern sequencing methods, we can have a more comprehensive understanding of the impact of antibiotics on microbial communities, thereby bringing new vitality to the use of antibiotics.

Fecal microbiota transplantation

FMT refers to a method of introducing a solution of fecal matter from a donor into the intestinal tract of a recipient to cure disease. FMT treatment, which was first documented in China in the 4th century,367 will change the recipient’s microbial composition directly. The most prominent results in the use of fecal transplantation for disease treatment have been in the treatment of recurrent Clostridium difficile infection (rCDI), with reported cure rates near 90%.368 In 2013, FMT was approved by the FDA to treat rCDI. FMT methods include the use of a naso-intestinal tube, gastroscopy, and colonoscopy, all with different efficacies. A meta-analysis conducted by Laniro et al. showed that capsule FMT has an overall response rate of more than 90% and is minimally invasive.369

So far, more than 100 case reports and clinical trials of FMT for rCDI have been published; most reports have high resolution of diarrhea associated with rCDI. Several meta-analyses have confirmed that FMT is superior to standard antibiotic therapy. They also showed that FMT is a safe treatment method for patients with rCDI.370 Compared with the traditional therapy of vancomycin regimen which is only 31% effective, FMT therapy showed a cumulative effectiveness of 94%.371 The clinical remission rate of FMT therapy in the RCT study of UC is about 36–37%. FMT is also widely investigated in the treatment of cancer,372 diabetes,373 ASD,266 multiple sclerosis,374 atherosclerosis and hypertension,375 graft vs host disease,376 Parkinson’s disease,377 hepatic encephalopathy and NAFLD.378 Although these treatments showed promising results, they were investigated in preclinical models, or the sample sizes were too small. Therefore, extensive studies are required before drawing further conclusions.

Currently, there are several mechanisms proposed for FMT including the following: 1) FMT may stimulate decolonization of pathogenic microbes and enhance host resistance to pathogens by direct ecological competition;379 2) repopulating gut microbiota by FMT helps to restore immune function and reduce host damage induced by abnormal microbial colonization of the gastrointestinal tract; 3) FMT facilitates the restoration of essential metabolites used for host metabolism, including SCFAs, antimicrobial peptides, bacteriocins, and bile acids.380 FMT is safe to a large extent, and large studies report mainly minor, short-lived adverse reactions. The specific high-risk population is mainly immunocompromised patients.381 But this therapy still faces many challenges. For example, regarding the standardization of donor screening, eligible stool donors are often rare if considering the risk of infection. Starting from the selection of a donor to the route of administration and dynamic monitoring after FMT treatment, the entire FMT process requires the use of personalized methods to reach its full potential. Therefore, the future development direction of FMT may be in precision medicine.382

Engineering gut bacteria

Most bacteria that coexist with humans are nonpathogenic. Advances in modern DNA technology have made it possible to engineer bacteria for disease treatment. Based on traditional genetic engineering methods, engineered probiotics have been used in the treatment of colitis, diabetes, obesity, and a large number of pathogenic infections.383,384,385 Lactobacillus jannaschii (a conventional flora of the female vagina) has been modified to secrete HIV-resistant cyanovirin-N protein. This engineered bacteria has been proven to reduce HIV infection by 63% in rhesus monkeys.386 There are different types of engineered bacterial therapies for diseases, such as synthetic immune regulatory proteins, chemotactic response systems, and protein delivery systems.

“Smart probiotics” created using genetic engineering technology brings vitality to the application of probiotics. It has a better efficacy than natural probiotics. For example, Lactococcus lactis expressing human Trefoil Factor 1 (a cytopeptide involved in epithelial wound healing) has been formulated as a mouthwash for the treatment of oral mucositis.387 A combination therapy of engineered Lactococcus lactis has been used in a clinical trial of T1DM treatment.388 Moreover, an engineered Lactococcus lactis strain which secretes the anti-inflammatory cytokine IL-10 showed a clinical benefit in CD.389 Insulin production in epithelial cells can be induced by the gut hormone GLP.390 Duan et al. reported that an engineered GLP-1-secreting Lactobacillus gasseri strain can reprogram intestinal cells into insulin-secreting cells.391

Bacteria can bypass problems associated with poor selectivity and limited tumor penetrability of conventional cancer chemotherapies and can be finely engineered to sense and respond to the tumor microenvironment.392 One strategy is to utilize the native bacterial cytotoxicity to kill cancer cells. For example, Clostridium and Salmonella has exhibit anticancer effect in mice models. Accumulation of the bacteria in tumor tissues will induce neutrophil infiltration and antitumor immune response. Such response was also observed in phase 1 clinical trial that administrated a modified Salmonella strain to patients with metastatic melanoma.393 The second strategy is using engineered bacteria to directly express anticancer agents or transfer eukaryotic expression‎ vectors into cancer cells.394 With these approaches, the bacteria can 1) generate cytotoxic agents such as Cytolysin A to induce cancer cell apoptosis, 2) deliver cytokines such as IL-2, TNFSF14 that activate immune cells to eradicate cancer cells, and 3) sensitizing immune system against cancer cells by expressing tumor antigen. The third strategy is using bacteria to transfer genetic material to cancer cells. Therefore, it stimulates competition with the mechanisms that foster tumor formation, through the in-situ delivery of polypeptides with pro-apoptotic activity, anti-angiogenic factors, and cytokines. Bacteria have also been engineered to silence the expression‎ of important genes related to tumor development through RNA interference. For instance, Xiang et al. reported that E. coli can be engineered to transfect host cells with plasmids encoding short-hairpin RNAs (shRNAs) silencing catenin beta-1, whose overexpression‎ is involved in several types of cancer.395 This therapy has been granted orphan drug status by the FDA for the treatment of familial adenomatous polyposis and is currently under clinical trial investigation to analyze the safety and tolerability.

Gene-editing technology such as CRISPR has broadened the application of engineered bacteria in microbiota modulation. CRISPR is being utilized in the development of novel antimicrobial strategies. Hwang et al. showed that the exonuclease CRISPR-associated protein 3 (Cas3) can be engineered into a probiotic, which has the capacity to efficiently kill pathogenic bacteria.396 A bacterial protein secretion system (T3SS) can transfer proteins into the cytoplasm of infected cells. With this system, engineered bacteria can carry polypeptide vaccines or proteins into host cells and carry transcription factors into the cell. In addition, dysregulation of the microbiome can lead to cytokine storms, which may be associated with a decrease in angiotensin 2 (ACE2).397 Based on this, Verma et al. developed an expression‎ and delivery system (LP) using probiotic species Lactobacillus piracies as a live vector for oral delivery of human ACE2. It provides a new strategy for correcting the imbalance of the gut microbiota while increasing the serum ACE2 level.398 It is true that the way in which a given supplement or drug affects the microbiota-host interface is obviously not enough for the complex human environment. Awareness of the range of possible interactions between the intervention and the host’s diet, genome, immune system, and resident symbionts should be taken into consideration. Although the clinical application of new technologies, such as T3SS and CRISPR, still require more investigation, they provide more opportunities and possibilities for microbiota therapy in the future.

Gut microbiota and drug response

It is well established that drug response, mainly characterized by pharmacokinetic (PK) and pharmacodynamic (PD) properties, may differ among individuals due to factors such as gender, age, and genetic variations.399 However, it was only recently that researchers identified microbiota as a mediator of drug response, highlighting its role in medical therapy. We herein describe the role of gut microbiota on modulating drug effect as it is a current research focus.

It is known that the gut microbiota can metabolize a wide range of substances, which can have potential implications for affecting drug absorption. Particularly, the stability of orally administered drugs can be affected in the GI tract before entering the systemic circulation. Sousa et al. summarized that over thirty drugs are substrates of bacterial enzymes in the distal gut.400 Recently, it was suggested that small intestine microbiota may also have profound impact on host physiological functions.401 This finding highlighted the potential drug-microbiota interaction, since small intestine is a major site for drug absorption. Indeed, numerous studies have reported altered drug PK mediated by gut microbiota with clinical implications. For example, Sun et al. reported that a hypoxic environment can affect the composition of gut microbiota, which led to increased absorption of aspirin in rats.402 Matuskova et al. identified that concomitant orally administrated probiotic E. coli strain Nissle 1917 (EcN) affected the PK of the antiarrhythmic drug amiodarone in male rats.403 EcN increased the plasma level of amiodarone metabolites, probably due to increasing the drug absorption or the activity of CYP2C enzymes, which was not observed in the reference non-probiotic strain.

Wallace et al. suggested that β-glucuronidases from E. coli can metabolize irinotecan into the active metabolite SN-38 in intestinal lumen and damage the intestinal epithelium in a mouse model.404 Lindenbaum et al. reported that the most widely used cardiac glycoside digoxin can be converted to reduced derivatives produced by Eubacterium lentum, a common gut anaerobe.405 The same research group reported a follow-up study that showed that administration of antibiotics erythromycin or tetracycline was able to significantly reduce the levels of digoxin, reduced metabolites, and increase serum digoxin level to a maximum of 2-fold. Wu et al. established a pseudo-GF diabetic rat model to investigate the relationship between metformin and gut microbiota.406 They found that the antihyperglycemic effect of metformin was reduced by more than 40% in gut microbiota-depleted group. Moreover, the hepatoprotective effect of metformin was significantly reduced in the absence of gut microbiota. Recent studies in IBD revealed that gut microbiota may influence the metabolism of IBD drugs mesalazine, methotrexate, thioguanine, and glucocorticoids.407 In particular, thioguanine can be converted to its active form by gut bacteria without the requirement of host metabolism. Studies also suggested that microbiota can affect host metabolism by modulating cytochrome P450 enzymes and UDP-glucuronosyltransferase.408 Interestingly, a recent study by Klünemann et al. established multiple new bacteria-drug interactions, with more than half of them ascribed to bioaccumulation,409 phenomenon by which bacteria can store the drug without chemical modification, thereby altering host drug response. Particularly, the behavioral response of Caenorhabditis elegans to antidepressant duloxetine was attenuated by bioaccumulating bacteria such as S. salivarius.

A large number of data confirmed that the gut microbiota can have a major impact on drug PK and subsequently the drug response in clinical settings. A better understanding of such interaction is required to develop effective treatment strategies.

Conclusion

After decades of research, we have gradually established a new role of microbiota in health and disease. It is now confirmed that microbiota can affect almost all aspects of the host, while its dysbiosis is related to a wide spectrum of diseases. Thanks to advanced research technologies, we are able to closely examinate how microbiota maintain human health and contribute to pathogenesis. However, the study of microbiota is mainly focused on the bacterial component; the role of fungi, viruses, and other microbes in health and disease remain largely inconclusive. In addition, while microbiota dysbiosis is often observed in disease states, the causative role of microbiota is yet to be established. Hence, there are still a lot of questions to be answered in this field. The greater understanding of this host-microbiota relationship has allowed for the development of microbiota-based therapy such as FMT and bacteria modulation. These strategies are well on the way to achieving the optimal clinical effect in the treatment of C. difficile infection, diabetes, inflammatory bowel disease, etc. In summary, we are now in a better position to treat diseases and foster health via manipulation of the microbial symbionts.

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