장내 유해균에 의한 염증 기전.. 2023 리뷰논문

[문형철]

영향력지수 7점 논문..

Review

Immunological mechanisms of inflammatory diseases caused by gut microbiota dysbiosis: A review

Author links open overlay panelMin’an Zhao a b 1, Jiayi Chu b 1, Shiyao Feng b 1, Chuanhao Guo c 1, Baigong Xue d, Kan He e, Lisha Li a

Show more

Add to Mendeley

Share

Cite

https://doi.org/10.1016/j.biopha.2023.114985Get rights and content

Under a Creative Commons license

open access

Abstract

The gut microbiota is indispensable for maintaining host health by enhancing the host's digestive capacity, safeguarding the intestinal epithelial barrier, and preventing pathogen invasion. Additionally, the gut microbiota exhibits a bidirectional interaction with the host immune system and promotes the immune system of the host to mature. Dysbiosis of the gut microbiota, primarily caused by factors such as host genetic susceptibility, age, BMI, diet, and drug abuse, is a significant contributor to inflammatory diseases. However, the mechanisms underlying inflammatory diseases resulting from gut microbiota dysbiosis lack systematic categorization. In this study, we summarize the normal physiological functions of symbiotic microbiota in a healthy state and demonstrate that when dysbiosis occurs due to various external factors, the normal physiological functions of the gut microbiota are lost, leading to pathological damage to the intestinal lining, metabolic disorders, and intestinal barrier damage. This, in turn, triggers immune system disorders and eventually causes inflammatory diseases in various systems. These discoveries provide fresh perspectives on how to diagnose and treat inflammatory diseases. However, the unrecognized variables that might affect the link between inflammatory illnesses and gut microbiota, need further studies and extensive basic and clinical research will still be required to investigate this relationship in the future.

장내 미생물은 숙주의 소화 능력을 향상시키고 장 상피 장벽을 보호하며 병원균 침입을 방지하여 숙주의 건강을 유지하는 데 없어서는 안 될 필수 요소입니다. 또한 장내 미생물은 숙주 면역 체계와 양방향 상호작용을 하며 숙주의 면역 체계가 성숙하도록 촉진합니다. 숙주의 유전적 감수성, 나이, BMI, 식단, 약물 남용 등의 요인으로 인해 주로 발생하는 장내 미생물 군집의 불균형은 염증성 질환의 중요한 원인입니다. 그러나 장내 미생물 군집의 불균형으로 인한 염증성 질환의 근본적인 메커니즘은 체계적으로 분류되어 있지 않습니다. 본 연구에서는 건강한 상태에서의 공생 미생물의 정상적인 생리 기능을 정리하고, 다양한 외부 요인으로 인해 장내 미생물의 이상균총이 발생하면 장내 미생물의 정상적인 생리 기능이 상실되어 장 내벽의 병리적 손상, 대사 장애, 장 장벽 손상으로 이어진다는 것을 입증했습니다. 이는 결국 면역 체계 장애를 유발하고 다양한 시스템에 염증성 질환을 일으킵니다. 이러한 발견은 염증성 질환을 진단하고 치료하는 방법에 대한 새로운 관점을 제공합니다. 그러나 염증성 질환과 장내 미생물 사이의 연관성에 영향을 미칠 수 있는 미지의 변수에 대해서는 추가적인 연구가 필요하며, 향후에도 이러한 관계를 규명하기 위한 광범위한 기초 및 임상 연구가 필요할 것입니다.

Graphical Abstract

1. Download : Download high-res image (154KB)
2. Download : Download full-size image

• Previous article in issue
• Next article in issue

Keywords

Gut microbiota

Dysbiosis

Inflammatory diseases

Immune disorders

Microbiota-gut-brain axis

1. Introduction

The human microbiota is a dynamic and intricate micro-ecosystem comprising trillions of host-specific microorganisms, including bacteria, viruses, fungi, and other microbial and eukaryotic species. Bacteria dominate the diverse microbial ecosystem of the human gut, representing over 99% of the total composition. Research from MetaHit and the Human Microbiome Project reveals approximately 2,172 species of gut microbe [1]. The gut microbiota is predominantly composed of four key bacterial species—Firmicutes, Bacteroidetes, Proteobacteria, and Actinomycetes—accounting for more than 98% of the gut microbiota [2]. It profoundly influences multiple aspects of human physiology, including diet, metabolism, pathogen resistance, intestinal barrier protection, immune system maturation, and immune homeostasis, maintaining a balanced immune response.

It is essential to preserve a healthy and stable gut microbiota, which can recover and return to homeostasis following disruptions caused by an unhealthy diet, antibiotics, drugs, pathogens, and other factors. However, when the gut microbiota is unable to withstand these attacks, irreversible changes occur, leading to a potentially unhealthy condition known as dysbiosis [3]. Dysbiosis is characterized by variations in the gut microbiota, including an increase in pro-inflammatory species and a decrease in anti-inflammatory species [4]. Prolonged dysbiosis can push various bodily homeostasis to the brink of collapse, ultimately resulting in local and systemic inflammatory responses [5]. Extensive research has demonstrated that inflammatory diseases, such as asthma, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), rheumatoid arthritis (RA), and type II diabetes mellitus (T2DM), are triggered by dysbiosis of the gut microbiota.

Recent studies have focused on correcting disturbances in the gut microbiota as a means of treating inflammatory diseases. The gut microbiota offers a promising approach for addressing various inflammatory conditions, and the Mediterranean diet, probiotics, and fecal microbial transplantation have shown significant potential in clinical applications. This review aims to establish a logical framework for understanding how the gut microbiota triggers inflammatory diseases. We synthesize current data on the connection between inflammatory diseases and microbiota dysbiosis, summarize the crucial functions of gut microbiota in regulating body metabolism, colonizing resistance, and modulating innate and adaptive immune responses. Additionally, we highlightpotential immune mechanisms through which the gut microbiota influences the pathogenesis of inflammatory diseases and discusse prospective strategies for implementing microbial therapies in the treatment of inflammatory diseases.

2. Methodology for literature search

The literature search was primarily conducted on the PubMed, Web of Science, and Scopus databases, encompassing a broad range of medical and disease-related literature. The search utilized keywords such as "gut microbiota," "dysbiosis," and "inflammatory disease." The search was filtered to include "reviews," "randomized clinical trials (RCTs)," "clinical studies," and "case series reports" published in the past 10 years, written in English. The obtained literature was thoroughly examined and screened for relevant references of interest. Additionally, a narrative review was performed on various topics related to the gut microbiota, including its role in nutrition, metabolism, colonization resistance, immune system modulation, intestinal barrier function, factors influencing gut microbial disorders, perspectives, neurodegenerative diseases, and obesity. Only English-language literature was considered in this section, without any publication year constraints.

We retrieved publications from the Web of Science Core Collection database from its inception until May 6th, 2023, using the search terms "gut microbiota" AND "inflammatory diseases," resulting in 17,528 publications. By analyzing the search results using the analysis function of Web of Science, we observed a progressive increase in the number of publications over the years (Fig. 1), indicating a growing research focus on inflammatory diseases associated with the gut microbiota. The research in this area predominantly falls within the domains of gastroenterology hepatology, immunology, biochemistry molecular biology, nutrition dietetics, pathology, infectious diseases, and other related fields.

1. Download : Download high-res image (209KB)
2. Download : Download full-size image

Fig. 1. Analysis of the results of searches on the Web of Science. Retrieved on the Web of Science Core Collection under the topics of "gut microbiota" and "inflammatory issues", with a deadline of May 6, 2023. Apply the "Analyze Results" function of WoS to analyze the search results of 17528 obtaied literature. (A) The bar chart of all literature publication years. (B) The treemap chart of research areas for the retrieved literature.

To gain insights into the current hotspots and research frontiers, we employed CiteSpace to visualize and analyze highly cited literature within the core database. We specifically examined publications matching the search strategy "gut microbiota" AND "inflammatory diseases" in the Science Citation Index Expanded from 2012 to 2022. This yielded 585 papers, which were exported as plain text in a file named "download_GM&IDs.txt" and imported into CiteSpace 6.2. R2 for co-occurrence clustering analysis of keywords. The results are presented in Fig. 2. The analysis highlights fecal microbial transplantation as the most frequently occurring keyword, indicating a research focus on its application and investigation of the underlying mechanisms in gut microbial therapy for inflammatory diseases. CiteSpace's analysis of hotspots and research frontiers concerning the influence of gut microbiota on inflammatory diseases enhances our understanding and guides the direction of the review.

1. Download : Download high-res image (310KB)
2. Download : Download full-size image

Fig. 2. Keywords co-occurrence clustering analysis of literature. The text in the upper left corner of the figure shows the relevant data, in which “N” indicates the node and a total of 372 keywords of the literature were included in the analysis. The larger the node, the more frequently the keywords appear in the same article. “E” denotes the linkages, and the thicker the linkage between nodes indicates the greater the frequency of keywords appearing in the same article. In the figure, the Modularity Q = 0.6859 > 0.3, indicating that the clustering structure is significant. And the weighted mean silhouette = 0.8319 > 0.7, indicating that the change of clustering structure is convincing. Each color block in the figure represents a cluster label, and the cluster label serial number, from largest to smallest, represents the number of keywords contained.

3. The role of gut microbiota3.1. Metabolic benefit

The gut microbiota serves as the host's "external metabolic organ," supplying the host with absorbable nutrients, utilizable energy, and metabolites with distinct functions. Based on the taxonomy proposed by Yang et al. [6], the supplementary metabolic activities of gut microbes are categorized into three groups: the breakdown of dietary components to generate metabolites, the modification of host metabolites, and the de novo synthesis of metabolites.

The gut microbiota breaks down dietary components to generate metabolites that supply energy and raw materials for protein synthesis. Indigestible dietary fiber can be converted into short-chain fatty acids (SCFAs) by the gut microbiota. Carbohydrate-active enzymes encoded by the microbiota provide cellular energy while modulating intestinal hormone secretion to achieve a balance between food intake and energy production/utilization [7], [8]. For instance, Akkermansia muciniphila is recognized as a key bacterium for producing propionate and butyrate, contributing to mucus degradation [9]. Moreover, both Gram-positive and Gram-negative bacteria express numerous enzymes capable of converting tryptophan into molecules that support indole signaling [10]. Clostridium sporogenes have been shown to convert tryptophan to indole propionic acid and inhibit tryptophan biosynthesis in Mycobacterium tuberculosis [11].

The gut symbiotic microbiota also participates in bile metabolism, aiding in the digestion, transport, and absorption of nutrients. Bacteria in the cecal colon, such as Clostridium in Firmicutes, produce enzymes that convert primary bile acids to secondary bile acids [12]. Sclerotinia members of the phylum have demonstrated 7-dehydroxylation activity, facilitating the metabolism of deoxycholic acid and lithocholic acid from primary to secondary bile acids [13]. Furthermore, gut microbes reduce the inhibition of the nuclear receptor farnesoid X receptor (FXR) in the small intestine, thereby enhancing bile acid synthesis [14].

In addition to its metabolic functions, the gut microbiota synthesizes SCFAs, polyamines, and vitamins. Indigestible carbohydrates are fermented by the gut microbiota to produce butyrate, the primary fuel for colon wall cells, known for its anti-cancer and anti-inflammatory properties [15]. Gut microbiota also synthesizes polyamines through the decarboxylation of ornithine, arginine, and lysine, which promote cell proliferation, differentiation, and intestinal mucosal integrity [6]. Magnusdottir et al. extensively investigated the biosynthetic pathways of eight B vitamins (biotin, cobalamin, folic acid, niacin, pantothenate, pyridoxine, riboflavin, and thiamine), emphasizing the complementary relationship between intestinal microbes and vitamin synthesis [16].

3.2. Colonization resistance

The gut microbiota establishes symbiotic relationships with the host, effectively preventing and inhibiting the invasion and proliferation of pathogens, a phenomenon referred to as gut microbiota colonization resistance. Successful replication and disease-causing ability of foreign pathogens rely on their ability to outcompete the indigenous microbiota for favorable positions. Based on the relevant literature, we summarize three mechanisms explaining the role of the gut microbiota in colonization resistance (Fig. 3).

1. Download : Download high-res image (318KB)
2. Download : Download full-size image

Fig. 3. Mechanisms of gut microbiota colonization resistance. The gut microbiota can release inhibitory metabolites and bacteriocins to kill pathogens or inhibit their proliferation. Bacteriocins exert antibacterial effects by perforating target cells, inhibiting bacterial peptidoglycan synthesis, inhibiting protein synthesis by interacting with ribosomes or tRNAs, or directly degrading target cell DNA. SCFAs can regulate pH, affect bacterial metabolism and inhibit the expression‎ of virulence genes in pathogens. Then, gut microbiota competes with pathogens for nutritional niches and physical niches to inhibit the growth and proliferation of pathogens. In addition, the host’s immune system can be stimulated by gut microbiota to produce antimicrobial peptides and anti-inflammatory factors to enhance immune barrier function and clear pathogens. The image was created with BioRender.

Firstly, the gut microbiota can release inhibitory metabolites and bacteriocins that possess antibacterial properties, including perforating target cells, inhibiting peptidoglycan formation, disrupting protein synthesis, and disassembling target cell DNA [17], [18], [19]. Bacteriocins like Microcins C7, Colicins 1b, and E1, produced by E. coli H22, effectively inhibit the proliferation of pathogenic enteric microorganisms such as Klebsiella pneumonia and Salmonella species in laboratory conditions [20]. However, they lack efficacy against the normal human microbiota members, such as Phytophthora and Bifidobacterium spp. [21] Bacteriocins increase levels of anti-inflammatory substances and decrease levels of cytokines that promote inflammation via multiple signaling pathways including MAPKs and Toll-like receptors. Bacteriocin CC34 demonstrates anti-inflammatory properties through the inhibition of IKKβ, IκBα, and NF-κB p65 phosphorylation. In LPS-treated mice, CC34 effectively down-regulates the release of inflammatory cytokines TNF-α, IL-1β, and IL-6 in jejunal tissue and serum, while also reducing myeloperoxidase (MPO) levels and mitigating pathological damage [22]. Nisin has demonstrated efficacy in treating pneumonia, meningitis, and sepsis caused by Streptococcus pneumoniae [23]. SCFAs produced by the symbiotic microbiota regulate gut pH, impact the metabolic functions of invasive pathogens, and inhibit their growth and reproduction [24]. Furthermore, SCFAs can also suppress the expression‎ of virulence genes in pathogens. The ydiQRSTD operon, absent in Salmonella Typhimurium, enables S. Typhi to utilize butyrate derived from the microbiota during gastrointestinal disease, which reduces S. Typhi's invasion of epithelial cells and intestinal inflammation through genetic ablation [25].

Secondly, the normal gut microbiota competes with pathogens for nutritional and physical niches, inhibiting their growth and reproduction. Bacterial strains of the same species typically require similar nutrients for optimal growth and reproduction. The "trophic niche" hypothesis proposed by Freter et al. suggests that native gut microbiota populations are governed by one or more nutrient substrates that a particular strain can utilize most efficiently under specific conditions [26]. Numerous studies have highlighted the significance of nutrient load in shaping the gut microbiota composition and human metabolic function [27], [28]. Furthermore, competition for physical space, including adhesion sites on glycan structures and direct contact with intestinal epithelial cells, is a crucial factor in the gut microbiota's ability to hinder pathogen colonization [29], [30].

Various factors in the gut, such as pH, specific amino acids, and dietary vitamins, influence the competition between symbiotic microorganisms and invasive pathogens. For instance, propionate produced by the symbiotic microbiota Bacteroides lowers intestinal pH, minimizing damage caused by Salmonella species to intestinal homeostasis [31]. Amino acids, such as methionine and cysteine, can promote the metabolism of the symbiotic gut microbiota to produce H2S [32], which effectively prevents the expansion of intestinal pathogens [33], [34]. Additionally, vitamins B2 and B6 obtained from the diet have been shown to limit the colonization of foreign pathogens. Experimental evidence suggests that vitamins accelerate the clearance of Salmonella spp. and prevent their multiplication [35].

Thirdly, the gut microbiota contributes to colonization resistance by stimulating the host's immune defense system. This function primarily involves strengthening the gut epithelial barrier, which triggers the production of antimicrobial peptides and anti-inflammatory factors by the host immune system. Surface antigens of commensal gut microbiota activate MyD88 signaling in Paneth cells and MyD88-dependent toll-like receptors (TLRs) in epithelial cells [36], [37], leading to the secretion of antimicrobial peptides and activation of the host's innate immune system [38].

Moreover, recognition of specific commensal microorganisms by TLRs induces innate antimicrobial activity that can limit the colonization and systemic invasion of Salmonella enterica [36], [39]. The surface antigens of commensal microorganisms also stimulate innate immune cells to produce anti-inflammatory factors like IL-10, IL-17, and IL-22, which play a crucial role in maintaining intestinal mucosal barrier integrity. IL-17, by recruiting neutrophils and inducing antimicrobial peptide production, rapidly responds to infectious agents such as Salmonella typhimurium and Candida albicans [40]. Symbiotic bacteria regulate the abundance and activation status of intraepithelial lymphocytes (IELs), with the T-cell population of IELs being a significant source of innate IL-17 production [41], [42]. Additionally, IL-22 effectively protects the host against pathogens like Klebsiella pneumoniae [43], vancomycin-resistant Enterococci [44], and Plasmodium parasites [45].

3.3. Intestinal barrier protection

The intestinal epithelial barrier (IEB), comprised of mechanical, chemical, immune, and biological barriers [46], functions to prevent the escape of pathogens and toxins from the intestinal lumen [47]. Additionally, the gut microbiota plays a pivotal role in maintaining homeostatic balance within the body, safeguarding the IEB, and modulating normal gastrointestinal functions[48], [49].

The gut microbiota exerts significant influence on the permeability and integrity of the IEB by repairing and sustaining tight junctions (TJs) in the mucosal epithelium, thereby mitigating damage to intestinal epithelial cells (IECs) caused by pathogenic bacteria. It can express genes involved in TJs signaling, influence apoptosis or proliferation of IECs, and facilitate the repair of the compromised gut barrier [50]. For instance, Lactobacillus royi LR1 has been shown to ameliorate damage inflicted by enterotoxigenic bacteria (E. coli) on the membrane barrier by preserving the appropriate localization of ZO1 and preventing its destruction [51]. Furthermore, Lactobacillus royi enhances the expression‎ of TJs, thereby enhancing the intestinal barrier [52].

The gut microbiota also plays a critical role in maintaining the functionality and integrity of the mucus layer [53], [54]. It promotes the activation of methylase beta, which catalyzes mucus formation in the small intestine [55]. The production of SCFAs by the Akkermansia genus elevates levels of endocannabinoid compounds 2-AG and 2-OG in the intestines, leading to improved integrity of the intestinal barrier and reduced metabolic endotoxemia [56]. Therefore, the gut microbiota not only contributes to the constitution and protection of the intestinal barrier but also participates in its repair.

3.4. Immune function regulation3.4.1. Promotes the development and maturation of the immune system

The gut microbiota interacts with the human immune system, stimulating immune cell maturation and function [57]. It achieves this through three main mechanisms: stimulating mucin secretion by intestinal goblet cells to maintain the structural integrity of the mucus layer and act as a barrier; inducing the development of intestinal mucosa-associated lymphoid tissue; and promoting the differentiation and maturation of immune cells, primarily through microbiota-driven refinements that stimulate isolated lymphoid follicle (ILF) development for innate defense and activation of naive T and B cells [58].

Studies have shown that SCFA-producing Bifidobacterium dentium colonizes germ-free mice, enhancing intestinal mucous layer and function through increased mucin production [59]. Moreover, Bouskra et al. demonstrated that germ-free mice exhibited immature intestinal lymphoid tissues, including crypt nodes and ILFs, along with decreased serum immunoglobulin levels [60]. However, colonization of germ-free mice's intestines with the gut microbiota led to an increase in lymphocyte numbers and proliferation of immunoglobulin germinal centers in the small cysts and lamina propria, resulting in elevated serum immunoglobulin levels [61]. These findings emphasize the vital role of the gut microbiota in promoting immune system maturation. Furthermore, the synthesis of folic acid by Lactobacillus and Bifidobacterium has been shown to increase DNA methylation and mRNA N6-methyladenosine (m6A) in intestinal cells. Additionally, butyrate-modified histone acylation is induced by anaerobic bacteria, Clostridial clusters, and eubacteria. Through epigenetic modifications of intestinal tissues, gut microbes have the potential to promote gut development and immune homeostasis [62].

3.4.2. Regulation of immune homeostasis

The gut microbiota plays a vital role in promoting the maturation of the human immune system and maintaining immune system balance in the intestine and beyond. Enteroendocrine cells (EECs) are known to express TLRs and initiate NF-κB-mediated responses when exposed to microbial-associated molecular patterns (MAMPs) [63]. This response leads to the secretion of pro-inflammatory cytokines and enteroendocrine peptides (EEPs) [64]. In response to these microbes, transcription of genes encoding antimicrobial peptides (AMPs), Tachykinin (Tk), and DH31 appears upregulated. These transcriptional changes are mediated by IMD pathway signaling in EECs that express Tachykinin in the anterior midgut [64]. The gut microbiota also influences adaptive immune responses, particularly the development and differentiation of CD4+ and CD8+ T cells. Lactobacillus induces and activates T regulatory cells (Tregs), while Clostridium perfringens G+ promotes the proliferation and differentiation of Tregs and Th17 cells, leading to IL-17 production by intestinal Th17 cells [65]. Bifidobacterium stimulates B cells to synthesize and release secretory immunoglobulin A (sIgA). Moreover, the gut microbiota can impact other immune cells and immunoglobulins by stimulating regulatory B cells (Breg) to produce suppressive cytokines such as IL-10 and TGF-β, thereby suppressing inflammation [66].

Additionally, the gut microbiota produces substances that indirectly regulate immune function. SCFAs, which can be metabolized by intestinal epithelial cells and enter the circulatory system, modulate the host immune response by inhibiting histone deacetylase, exerting anti-inflammatory effects [67]. For instance, butyric acid, a bacterial strain-specific compound, functions as an inhibitor of histone deacetylase and as a ligand for G protein-coupled receptors. It serves as a critical signaling molecule that influences the host's immune response [68]. The maintenance of intestinal immune homeostasis relies on both direct activation of adaptive and innate immunity by the gut microbiota and the indirect influence of microbiota-derived metabolites on the immune response (Table 1).

Table 1. The role of the gut symbiotic microbiota.

RoleEffectsRelated gut microbiotaReferenceMetabolic benefitColonization resistanceIntestinal barrier protectionImmune function regulation

Provide energy and raw materials for protein synthesis	Akkermansia muciniphila	[9]
Facilitate the digestion, transport, and absorption of nutrients	Sclerotinia (Clostridium, Fungi)	[12], [13]
Synthesize SCFAs, polyamines, and vitamins	Bacteroides, Clostridium IV, XIV, Bifidobacterium spp., and Lactobacillus	[16], [69], [70]
Kill pathogens and inhibit pathogen proliferation	E. coli H22	[20]
Hinder the spread of invading pathogens and inhibit the expression‎ of virulence-related genes	Gut microbiota that produces SCFAs (Akkermansia muciniphila, Bacteroides, Clostridium, etc.)	[9], [69]
Inhibit the pathogens' growth and reproduction	Bacteroides	[31]
Enhance the gut epithelium barrier and provoke the host immune system	Symbiotic gut microbiota	[36], [37]
Intestinal epithelial biological barrier, maintain the permeability and integrity of IEB	Lactobacillus royi LR1	[51]
Safeguard the normal function and integrity of the mucus layer	Akkermansia muciniphila	[56]
Promote the development and maturation of the immune system, increase mucin production to enhance the intestinal mucous layer and function	Bifidobacterium	[59]
Regulate immune homeostasis	Lactobacillus, Clostridium perfringens G+, and Bifidobacterium	[65], [66]
SCFAs regulate immune function indirectly	Akkermansia muciniphila and Bifidobacterium	[67], [71]

4. Factors affecting the gut microbiota dysbiosis

Diet significantly influences the gut microbiota's structure throughout an individual's lifespan, with dietary components like fiber, lipids, proteins, amino acids, micronutrients, vitamins, and minerals playing a profound role. Recent research underscores the personalized nature of diet-microbe interactions, suggesting that effective nutritional interventions may require adjustments based on an individual's baseline microbiota [72].

Through extensive research on the macronutrients that shape the gastrointestinal microbiome, we found that the composition of the gut microbiota is also substantially affected by dietary fat. At the same time, different dietary patterns can affect the gut microbiota differently. In addition, drug abuse can result in gut microbiota dysbiosis [73]. The microbiome is influenced by a high-fat diet, resulting in modified production of bacterial metabolites that increase the host's susceptibility to inflammation. This interaction between the microbiome and diet causes modifications in histone modifications of reactive enhancers, which are enriched with binding sites of signal-responsive transcription factors. These changes in histone methylation and acetylation are linked to signaling pathways that play a crucial role in the development of colon cancer [74]. Previous research has discovered that antibiotics, chemotherapy-related drugs, and morphine alter the quantity and composition of the gut microbiome. Individual differences, such as gender and age, are also important factors influencing gut microbiota abundance and the risk of potential disorders. The specific changes in gut microbial dysbiosis due to various factors are detailed in Table 2.

Table 2. Factors affecting gut microbiota dysbiosis changes.

FactorsGut microbiota changesReferenceDietDrugsIndividual differences

Resistant starch	Bifidobacterium, Enterobacter faecium, and Eubacterium↑ Rumen cocci↓	[75]
Polyunsaturated fatty acids ω-3	Lactobacillus, Lactobacillus, Roseobacter, and Bifidobacterium↑	[76]
Medium-chain fatty acids	Bifidobacterium, Bacillus, and Prevotella↑ Helicobacter pylori and Clostridium histolyticum↓	[77]
High-fat diet	Firmicutes, Bacteroidetes, and Desulfovibrio spp.↑ The α-diversity of the gut microbiota↓	[78], [79]
High-protein diet	Actinobacteria↑ Saccharobacteria↓	[79]
Low-protein, high-carbohydrate diet	Akkermansia and Bacteroides↑ Blautia, Oscillibacter, Oscillospira, and Desulfovibrionaceae↓	[80]
High-fiber diet	Bifidobacterium, Akkermansia, and Lactobacillus↑ Enterobacteriaceae↓	[81], [82], [83]
Clindamycin	Bacteroidetes and obligate anaerobic Firmicutes species↓ E. coli, Enterococcus, and Anaplasma spp.↑	[84]
Vancomycin and metronidazole	Clostridium difficile↑	[85]
Morphine	Bile acid metabolism disorder and gut microbial dysbiosis↑	[86], [87]
Cyclophosphamide	Pathogenic microorganisms↑	[88]
Fluoxetine	Pathogens (E. coli and Shigella)↑ Conditional pathogens (Enterococcus, Verticillium, and Aerococcus)↑	[89]
APOA5 gene variant rs651821	Lactobacillus, Sartorius, and Methanobrevibacter↑	[90]
Aging	Chronic systemic low-level inflammation↑ Digestion, nutrient absorption, and immune activity↓	[91]
Female	Firmicutes, Bacteroides caccae, and Bilophila↑	[92], [93]
Male	Bacteroides plebeius and Coprococcus catus ↑	[92], [93]

5. The correlation between the gut microbiota dysbiosis and inflammation

A healthy adult's gut microbiota primarily comprises Firmicutes, Bacteroidetes, and Actinobacteria, with trace amounts of Proteobacteria, Verrucomimicrobia, Euryarchaeota, and Fusobacteria detected in fecal samples [94]. Dysbiosis of the gut microbiota is characterized by reduced abundance and diversity of the gut microbiota, a decline in beneficial bacterial species, and an increase in harmful bacteria. In patients with Crohn's disease, the case report indicates a reduction in protective intestinal microbiota and bacterial diversity, particularly bacteria like Faecalibacterium, Roseburia, Oscillibacter, and Coprococcus in the phylum Firmicutes that produce butyrate. This imbalance in the gut microbiota is associated with the occurrence of inflammatory bowel disease [95].

The gut microbiota plays a regulatory role in systemic chronic inflammation in various diseases. Microbial factors such as virulence factors and pathogen-associated molecular patterns (PAMPs) are primarily responsible for inducing inflammation [96]. The flagellin of segmented filamentous bacteria (SFB) plays a crucial role in differentiating classical mucosal CD4 + Th17 cells and regulating the transcription of genes involved in the IL-17 signaling pathway [97]. Yao Dong et al. demonstrated a correlation between the inflammatory chemokines TNF-α, IL-6, and IL-17 and different species of gut microbiota, with beneficial bacteria such as Lactobacillus and Bifidobacterium being negatively correlated and opportunistic pathogenic bacteria such as Escherichia and Shigella being positively correlated [98]. Additionally, studies on mice with colitis revealed that probiotics promote the differentiation of Th0 cells into Treg cells and upregulate IL-10 secretion [99], [100]. The decline in beneficial bacteria and the increase in pathogenic bacteria during dysbiosis can shift the immune system towards inflammation.

6. Mechanisms of the gut microbiota dysbiosis contributing to inflammatory diseases

Dysbiosis of the gut microbiota can influence the physiological functions of the body through a variety of immune mechanisms leading to the development of inflammatory diseases. These mechanisms include metabolic dysfunction, intestinal barrier damage, and immune system disorders (Fig. 4). Notable associations between gut microbiota impairment, inflammatory diseases, and alterations in inflammatory factors are summarized in Table 3.

1. Download : Download high-res image (399KB)
2. Download : Download full-size image

Fig. 4. Mechanisms of the gut microbiota leading to inflammatory diseases. The symbiotic gut microbiota maintains the body in a healthy state through multiple pathways. They become part of the intestinal barrier, produce bacteriocins as well as beneficial metabolites such as SCFAs and bile acids that prevent pathogens from colonizing the intestinal epithelium, aid the body's digestive metabolism, and promote the development and balance of the body‘s immune system. However, a chronic dysbiosis of the gut microbiota disturbs the balance of immune function under the interference of internal and external factors. With a compromised intestinal barrier, pathogens invade the intestine and trigger the release of multiple pro-inflammatory factors, and the long-term bias of the immune system toward pro-inflammatory responses eventually leads to the development of inflammatory diseases. In addition, damage to the intestinal barrier allows gut microbiota, toxins as well as pro-inflammatory factors to enter the circulatory system, where they are transported to various parts of the body and cause inflammatory diseases in multiple sites. The image was created with BioRender.

Table 3. The gut microbiota changes and inflammatory factors in inflammatory diseases associated with gut microbiota dysbiosis.

DiseaseGut microbiota changesInflammatory factorsReferenceAsthmaCrohn's diseaseUlcerative colitisNonalcoholic fatty liver diseaseObesityAlzheimer's diseaseAnkylosing spondylitisRheumatoid Arthritishypertensionhepatitis and liver cirrhosis

Escherichia coli, Helicobacter pylori, Streptococcus, and Staphylococcus↑ Bifidobacterium and Lactobacillus↓	CRP, TNF-α, and IL-6↑	[101]
Escherichia coli and Enterococcus spp.↑ Bifidobacteria and Bacillus lactic acid↓	IL-1, IL-17, IL-22, and IL-33↑	[102]
Bacteroides fragilis and Escherichia coli↑ Bifidobacterium and Lactobacillus↓	p-ERK/ERK, IL-1β, IL-6, TNF-α, and MPO↑	[103]
Streptococcus, Escherichia–Shigella, and Oscillibacter↑ Lactobacillus and Alistipes↓	IL-17A, IL-6, and CRP↑	[104]
Escherichia, Enterococcus and Prevotella↑ Butyricicoccus, Clostridium, Lactobacillus, Bifidobacterium, Lachnospiraceae, and Rikenellaceae↓	IL-6, TNF-α, IL-17, IL-23, IL-1β, and IFN-γ↑ IL-13, IL-10, and IL-4↓	[105]
Enterobacteriaceae and Enterococcus↑ Bifidobacterium and Lactobacillus↓	IL-10 and IL-17↑	[106]
Firmicutes↑ Fusobacteria, Proteobacteria, and Bacteroidetes↓	IL-1β and TMAO↑ IL-10↓	[107]
Escherichia and Enterococcus↑ Lactobacillus, Bifidobacterium, and Ruminococcus ↓	TNF-α and IL-6↑	[108]
Cyanobacteria, Deinococcota, Patescibacteria, Actinobacteriota, and Synergistota↑ Acidobacteriota, Bdellovibrionota, Campylobacterota, Chloroflexi, Gemmatimonadota, Myxococcota, Nitrospirota Proteobacteria, and Verrucomicrobiota↓	IFN-γ, IL-17, and IL-23 ↑ TNF-α and IL-1 ↓	[109]
Verrucomicrobia, Lactobacillus, Streptococcus, Akkermansia and Proteobacteria ↑ p_Bacteroidetes, Bacteroides, and Faecalibacterium ↓	TNF-α, IL-6, IL-10, IL-4 and IL-2↑	[110], [111]
Firmicutes and Bacteroidetes↑ Their abundance became higher with the increased severity of the disease.	IL-2, IL-4, TNF-α, and IL-1β↑	[112]
Enterobacteriaceae, Enterococcus, Staphylococcus aureus, and Saccharomyces↑ Lactobacillus, Bacteroides, Bifidobacterium, and Clostridium ↓	IL-17A↑ Serum vitamin D, 25-(OH)-D, and 1, 25-(OH)2-D3↓	[113]

6.1. Metabolic dysfunctions

Dysbiosis of the gut microbiota disrupts host metabolic function, leading to inflammatory diseases. Mechanisms involved include disturbances in short-chain fatty acid (SCFA) synthesis, biosynthesis of amino acids and nucleotides, abnormal catabolism of dietary components, sulfur amino acid metabolism, redox balance, mucin degradation, secretory systems, adhesion, and gene enrichment for intrusion [114]. These mechanisms contribute to inflammatory diseases resulting from impaired digestive function, bile acid metabolism, and increased hydrogen sulfide production under dysbiosis of the gut microbiota. Dysbiosis affects the breakdown of dietary components, particularly SCFA synthesis, which is impaired by reduced levels of Bacteroides, Clostridium IV, XIV, and Bifidobacterium spp [69]. Bacteroides possess genes for carbohydrate metabolism, enabling the breakdown of indigestible plant and host sugars [115]. Consequently, dysbiosis disrupts the digestive function of the host intestine, leading to difficulties in metabolizing and utilizing dietary components, resulting in symptoms like indigestion, malnutrition, and an increased risk of inflammatory diseases.

Impaired bile acid metabolism weakens the body's ability to combat inflammation and induces inflammatory diseases. Bile salt metabolism, initiated by the gut microbiota, involves bile salt hydrolysis, which produces primary free bile acids and amino acids catalyzed by the bacterial enzyme bile salt hydrolase (BSH) [116]. BSH-expressing bacteria, primarily Firmicutes, Bacteroidetes, and Actinobacteria, play a crucial role in this process [117]. Dysbiosis characterized by a decrease in these representative genera significantly impairs bile acid metabolism. Bile acids are vital for digestion, facilitating cholesterol and fat-soluble vitamin absorption, as well as maintaining triglyceride homeostasis and certain endocrine functions [118]. For instance, bile acids are crucial signaling regulatory molecules, as they activate the nuclear FXR, the pregnane X receptor (PXR), the vitamin D receptor (VDR), and the G protein-coupled bile acid receptor 1 [119], enabling them to activate genes implicated in intestinal conservation, bacterial proliferation suppression, and mucosal barrier injury, including inducible NO synthase, the inflammation-causing cytokine IL18, and carbonic anhydrase12 [116]. Bile acids have been shown to have antibacterial activity [120], [121]. In the meantime, bile acids regulate glucose and lipid utilization, expenditure of energy, and triglyceride homeostasis by activating several nuclear receptors and cellular signaling pathways [122], [123], [124]. For example, FXR regulates lipoprotein lipase activity by inducing coactivators Apoc II and inhibiting inhibitors Apoc III [124]. The FXR, NF-κB, and Wnt/β-catenin signaling pathways are interconnected. Studies have demonstrated that FXR deficiency in mice leads to early mortality and promotes Wnt signaling, which induces the production of neutrophils, macrophages, and TNF-α, thereby contributing to intestinal inflammatory disease [125]. The underlying mechanism involves dysregulated intestinal microbiota producing LPS, which activate NF-κB, leading to the recruitment of inflammatory cells and elevated levels of inflammatory factors. Notably, the overexpression‎ of NF-κB subunits p50 and p65 directly inhibits FXR activity, resulting in reduced FXR-mediated suppression of intestinal inflammation and the subsequent development of chronic intestinal inflammation [126]. In summary, the dysbiosis of the gut microbiota can impact the host organism in ways that affect bile acid metabolism.

Obesity is a chronic metabolic disease and a systemic chronic low-inflammatory condition. A growing array of studies suggests that gut microbiota, a key environmental factor, may help towards the development and progression of obesity [127], [128]. In obese populations, the composition and abundance of the gut microbiota differ from healthy populations. Gut microbiota diversity is lower in obese than healthy individuals [129]. Several studies involving rodents and humans have demonstrated an increase in Firmicutes and a decrease in Bacteroidetes in obese individuals [130], [131]. Gut microbiota dysbiosis may mediate obesity through mechanisms that regulate energy absorption, eating behavior, and chronic inflammatory responses [132]. Gut microbes regulate energy absorption mainly through the metabolite SCFAs, which stop rodents and overweight humans from gaining weight. SCFAs act on G protein-coupled receptors (GPR), promote the expression‎ of GPR43 and GPR41, and upregulate the expression‎ of mitochondrial biogenesis genes PGC-1a, NRF-1, Tfam, β-F1-ATPase, COX IV and cyt-c. In addition, it increases beige lipogenesis, which ultimately leads to increased TG hydrolysis and FFA oxidation in adipose tissue and suppresses chronic inflammation[133]. Therefore, when dysbiosis produces fewer SCFAs, the risk of obesity will increase. And studies have shown that excess SCFAs are equally important in promoting obesity and metabolic abnormalities. Propionate increases plasma concentrations of glucagon, norepinephrine, and fatty acid binding protein 4 (FABP4) to stimulate glycogenolysis and hyperglycemia, resulting in insulin resistance and compensatory hyperinsulinemia [134]. Activation of GPR41 and GPR43 receptors by propionate induces secretion of peptide tyrosine-tyrosine, which reduces host appetite by stimulating the central nervous system (CNS) via the brain-gut-microbe axis [135]. LPS produced by dysbiosis can stimulate pro-inflammatory pathways by activating the receptors TLR4 and NF-κB upregulation on adipocytes, activating pro-inflammatory cascades and discharging inflammatory factors, which in turn promote insulin resistance [136]. Reduced SCFAs inhibit LPS or TNF-α-induced inflammatory responses through mechanisms related to the regulation of NF-κB and MAPK signaling pathways and are key signaling molecules in the regulation of intestinal mucosal immunity [137]. Therefore, the development of obesity is closely associated with the gut microbiota and its metabolites.

6.2. Intestinal barrier damage

The biological barrier of the intestine is crucial for the maintenance of normal function. Its integrity depends on the stability and performance of the mechanical, chemical, and immunological barriers as well as the gut microbiota and the SCFAs it produces [138]. Related experimental research has demonstrated that following gut microbiota dysbiosis and decreased flora abundance, intestinal epithelial cell damage is more severe, cup cells are significantly increased, sIgA secretion, which has a protective effect on the mucosa, is reduced, TJs levels are reduced, activating inflammatory vesicles and inducing an intestinal mucosal immune response and intestinal permeability [139], leads to the migration of intestinal pathogens and causes local or systemic inflammatory reactions [140], [141]. Immune-induced intestinal barrier dysfunction is believed to perform a crucial function in the susceptibility to and amplification of a variety of autoimmune and inflammatory diseases, such as IBD, dietary allergies, celiac disease, and diabetes [142].

Dysbiosis usually causes damage or structural changes to epithelial cells and intercellular junctions in the mechanical barrier, which directly affects intestinal permeability, and bacteria, as well as harmful substances such as endotoxins, are prone to enter the bloodstream through the intestinal mucosa, which is one of the mechanisms of inflammation. Oral administration of high doses of vancomycin to mice results in a model of dysbiosis with a reduction in Gram-positive microorganisms (mainly from the thick-walled species) and a supplementary increment in Gram-negative bacteria (mainly from the species Proteobacteria) [143]. Intestinal alkaline phosphatase (IAP) can contribute to barriers in the intestine's homeostasis by way of regulation and cellular localization of protein TJ [144]. When high levels of ATP cause a disturbance in the homeostasis of gut microbiota, many anaerobic archaea take advantage of the phosphorylation process [145], [146]. It was found that dysregulated microbial products lipopolysaccharide and ATP together induce NLRP3 inflammatory vesicle activation and activated NLRP3 inflammatory vesicles decrease trans-epithelial resistance, also decreasing occludin, ZO-1, and claudin-1 expression‎ and leading to relocalization of ZO-1 and occludin in Caco-2 cells [147], disrupting tight junctions in the mechanical barrier and increasing intestinal permeability [148]. In addition, dysbiosis of the gut microbiota, pathogenic bacteria, and the products can activate the immune system of the intestinal mucosa to release IFN-γ and TNF-α. IFN-γ and TNF-α are primary mediators of intestinal inflammatory diseases, such as IBD. These cytokines can modulate the activity of myosin light chain kinase, resulting in phosphorylation and downregulation of myosin., and redistribution of TJ or other appendicular junction proteins, thus upregulation of paracellular permeability and transcellular permeability of IEB [149]. Increased permeability causes infiltration of different pro-inflammatory factors into the submucosa, resulting in an inflammatory chain reaction and IEB destruction and long-term elevation of TNF-α and IFN-γ in the intestinal mucosa, resulting in chronic mucosal inflammation [150].

The mucus layer generally serves a defensive function in chemical obstacles. The immune substances in mucus trap bacteria and prevent their transfer to tissues. When the mucus layer is thin or incomplete, pathogens are more likely to attack IEC, causing a long-term inflammatory response in the body and inducing IBD [151]. In sensitive hosts, the commensal B. thetaiotaomicron causes colitis utilizing required sulfatase activity for bacterial outer membrane vesicles penetrating the mucus and inducing inflammation [152]. When pathogens escape the safeguarding influence of mucus and invade the epithelial cells of the intestinal wall, the intestinal immune system is activated. The first system to be activated is the senGC guarding cell that triggers mucus secretion to wash bacteria away at the crypt opening [153]. In addition, antimicrobial peptides produced by Paneth cells can work together with secreted IgA to limit the survival environment of microorganisms in the tiny intestines [154].

6.3. Immune disorders

Th17 cell/Treg imbalance, resulting from dysbiosis of the intestinal flora, plays a crucial role in the pathogenesis and progression of inflammatory diseases. Th17 cell differentiation is initiated by STAT3 and retinoic acid-related orphan nuclear receptor γt (RORγt), leading to the secretion of pro-inflammatory cytokines [155]. IL-17 triggers a cascade response by activating the MAPK pathway and NF-kB pathway, mediating neutrophil mobilization and amplifying inflammation [156]. IL-22 enhances IL-17-induced protective functions by promoting antimicrobial peptide production and neutrophil recruitment, and contributing to various inflammatory processes [157]. Treg cells express CD25 and forkhead box protein 3 (Foxp3) transcription factors, maintaining immune tolerance, suppressing inflammation, and releasing anti-inflammatory cytokines such as TGF-β and IL-10 [158], [159]. During inflammation, IL-6 plays a crucial role in converting Treg cells into pathogenic Th17 cells at the early stage of TGFβ-induced Treg differentiation [160]. Increased Th17 cell/Treg ratios have been observed in inflammatory diseases such as IBD [161], [162], RA [163], [164], and SLE [165], [166], highlighting dysbiosis as a significant contributor to Th17/Treg imbalance and consequent inflammation.

The gut microbiota influences the Th17/Treg ratio through metabolite and cytokine production. For instance, E. faecalis promotes butyrate production and inhibits the IL-6/Stat3/IL-17 pathway, thereby declining the differentiation of CD4T cells into Th17 cells [167]. SCFAs can strengthen Foxp3-motivated promoter and the acetylation of histone H3 in conserved non-coding regions, or bind to free fatty acid receptors, regulate the colonic Treg pool size in non-hematopoietic cells to promote Treg cell proliferation and differentiation [168]. TGF-β expression‎ significantly increased in H. pylori colonized colitis mice, which inhibits expression‎ of IL-23R, promotes expression‎ of Foxp3, inhibits RORt functions and Th17 differentiation, and has a protective effect against chronic colitis [169]. Further studies found that SFB induced serum amyloid A (SAA) production in the terminal ileum and that SAA action on LP dendritic cells (DCs) promoted IL-22 secretion, increased IL-6 and IL-22 secretion through innate lymphocyte channels, promoted differentiation of RORγt+ T cells and Th17 and increased IL-17A production [170]. Gut microbiota disorders may regulate the secretion of inflammatory mediators by inducing Th17/Treg immune imbalance in the organism and thus participate in the formation of inflammatory diseases.

Gut microbiota dysbiosis plays a significant role in the initiation, progression, and regression of various immunoinflammatory diseases by influencing macrophage polarization. The macrophages contain two subpopulations [171]. M1-type macrophages exhibit high phagocytic activity, swiftly eliminate invading pathogens, and induce tissue injury by triggering the secretion of inflammatory factors such as IFN-β, IL-12, and TNF-α [172], [173]. On the other hand, M2 macrophages contribute to immunomodulation, clearance of apoptotic cells, tissue repair, wound healing, and attenuation of inflammatory responses [174]. Gut microbiota dysbiosis and immune abnormalities result in abnormal and persistent activation of M1 macrophages, contributing to the pathogenesis and progression of numerous chronic inflammatory and autoimmune diseases [175]. LPS acts through TLR4 on the surface of M1 macrophages to activate MyD88 and MaL/TirapM2-dependent signal transduction pathways and then promotes the release of inflammatory factors such as TNF-α, IFN-β, IL-12, IL-1β, and IL-6, followed by promoting abnormal immune responses in Th1 lymphocytes [176]. Butyrate could inhibit LPS-mediated M1 macrophage polarization by declining pro-inflammatory mediators such as NO and IL-6 production [177]. In addition, butyrate is a novel STAT6-mediated transcriptional activator that drives M2 macrophage polarization through H3K9 acetylation, which in turn can induce IBD [178]. Intestinal dysbiosis is mainly due to the reduction of the number or proportion of normal flora, the diminishing of secreted anti-inflammatory metabolites, and the weakening of resistance to pathogenic flora, which predisposes macrophages to polarization in the M1 direction and then triggers inflammation.

The intestine is among the most important immunocyte locations for development, and intestinal microecology can influence intestinal and extraintestinal immunity. Activated lymphocytes can reach multiple mucosa-associated lymphoid tissues, such as the respiratory tract and kidney mucosa, and exert immune responses against the same antigen, which of the following is an important contributor to the development of extraintestinal inflammatory diseases [179]. Through the mucosal immune system, changes in the microbiota's composition in the digestive tract can influence the microbiota composition at other locations. Due to intestinal dysbiosis, mucosal barrier dysfunction, particularly disruption of TJs, frequently results in incremental intestinal permeability; this pathological condition is referred to as leaky bowel syndrome (LGS) [180]. Dysregulated autophagy mediated by intestinal dysbiosis impacts the integrity of the intestinal barrier, increases intestinal permeability, and permits the transport of gastrointestinal microbes, microbial-derived metabolites, and MAMPs to mesenteric lymphoid tissue [181], they can reach other tissues outside the intestine via circulatory trafficking, causing systemic inflammation and disturbing immune homeostasis. Narges et al. demonstrated that intestinal barrier function disruption occurs before the inflammatory phase begins in autoimmune mouse and human RA, identifying it as a transitional checkpoint from autoimmunity to inflammation [182]. Patients with primary sclerosing cholangitis have multiple bacteria with barrier-disrupting properties [183]. SCFAs can act as signaling molecules of antigen-presenting cells in the lung and are involved in regulating pulmonary inflammation and allergic reactions [184]. Therefore, intestinal dysbiosis can induce other extraintestinal tissues or even systemic inflammation through the standard mucosal immune system or intestinal barrier with increased permeability, causing immune system dysregulation in the body.

6.4. Microbiota-gut-brain axis

The microbiota-gut-brain axis is a bidirectional signal-regulating system for communication between the nervous and gastrointestinal systems. This system is comprised of the autonomic nervous system (ANS), the CNS, the hypothalamic-pituitary-adrenal axis (HPA), the sympathetic adrenal axis, and intestinal microorganisms. It regulates fundamental intestinal functions and shares neurotransmitters and signaling molecules with the brain [185]. Disturbances in the composition of the gut microbiome can alter the function of the CNS and the enteric nervous system [186]. In the enteric nervous system (ENS), the gut microbiota releases various signaling molecules. Information from the gastrointestinal tract reaches the central nervous system, stimulates relevant brain regions to issue commands, and acts on the gastrointestinal tract and surrounding organs via sympathetic and parasympathetic nerves to regulate motility, secretion, and blood flow in the gastrointestinal tract by means of feedback regulation [187]. Intestinal signals are transmitted to the brain predominantly by vagal afferent nerves, and the CNS physiologically innervates the gastrointestinal tract via the HPA axis, coordinating stress responses and anti-inflammatory effects [188]. In particular, alterations in the gut microbiota have the potential to stimulate neurogenic and inflammatory responses in both the gut and peripheral regions, ultimately resulting in neuroinflammation and neurodegeneration within the CNS. The NLRP3 inflammatory vesicles serve as a crucial mediator in regulating host physiology and influencing immune and inflammatory responses in both the peripheral and central regions of the CNS, by means of processing and releasing IL-1β and IL-18 [189]. The mechanisms by which the gut microbiota exerts its influence directly or indirectly on the CNS are shown in Fig. 5.

1. Download : Download high-res image (464KB)
2. Download : Download full-size image

Fig. 5. Mechanisms of the Gut Microbiota-Gut-Brain Axis in the Pathogenesis of Neurodegenerative Diseases. The microbiota-gut-brain axis is a bidirectional signaling system between the nervous and gastrointestinal systems. It regulates intestinal functions, shares neurotransmitters, and influences peripheral organs through the autonomic nervous system. Gut microbiota releases signaling molecules, which integrate in the brain, affecting gastrointestinal motility and blood flow. Vagal afferent nerves transmit intestinal signals to the brain, while the CNS innervates the gut through the HPA axis.

Alterations in the composition of the gut microbiota play a crucial role in the development of neurodegenerative diseases through the microbiota-gut-brain axis [190]. Alzheimer's disease (AD) and Parkinson's disease (PD) are both neurodegenerative diseases with persistent neuronal loss. AD leads to a progressive decline in memory, thinking, and the ability to perform daily activities [191]. PD leads to the impairment of various neurological functions, including motor, planning, cognitive, and executive functions [192]. Intestinal microbiota regulates several physiological processes in the CNS, affecting brain biological processes such as neurogenesis, development, and behaviors such as anxiety, learning, and memory, and contributing to the maintenance of cerebral homeostasis.

When the gut microbiota is disrupted by diet, aging, and diseases, it can utilize its production of LPS, amyloid proteins, and low-level inflammatory reactions to participate in the occurrence and development of AD. An important pathological feature of AD is the deposition of amyloid β (Aβ) plaques in the CNS [193]. Aβ1–42 oligomers were injected into the gastric wall of mice; one year later, Aβ migrated from the intestine to the brain via the vagus nerve, and the mice exhibited cognitive deficits on the Y-maze spontaneous change test and the new object recognition test [194]. Aβ deposition may result from variations in the number of microbiota strains. The detection of gastrointestinal organisms in mice transgenic for the Aβ precursor protein (APP) revealed a decrease in Firmicutes and an increase in Bacteroides. While germ-free APP transgenic mice show a decrease in brain Aβ pathology [195]. Enteric pathogens such as Escherichia coli, and Staphylococcus aureus can directly produce Aβ, which reaches the brain for deposition via the gastrointestinal mucosa and blood-brain barrier, thereby fostering the development of AD [196]. Meanwhile, Aβ produced by bacteria can mediate microglia activation via TLR2 pathway [197]. At the same time, Aβ produced by bacteria can mediate microglia activation through the TLR2 pathway, causing an increase in the levels of cellular inflammatory factors IL-17A and IL-22, triggering NF-κB signaling and COX-2 activation, inducing inflammatory response and cytophagy, and aggravating brain injury [198].

Parkinson's disease is also thought to be associated with the microbiota-gut-brain axis. Several studies have shown that the gut microbiota can influence CNS function via intestinal TLRs and microbial metabolites, such as SCFA, bile acid metabolites, neuroactive substances such as GABA, trypsinogen precursors and metabolites, and 5-HT [199]. Gut microbiota dysbiosis in PD patients enhances α-syn inflammatory response and leads to α-syn misfolding by initiating the natural immune response and activation of TLRs [200]. When gut microbial metabolites and α-syn-mediated TLRs act superimposed, local inflammation is exacerbated and clearance of α-syn deposition is dysfunctional, both synergistically exacerbate the development of neurodegenerative lesions in PD [201]. One study reported that fecal transplantation of PD patients in germ-free mice resulted in more severe organismal damage compared to fecal transplantation with a healthy control population, suggesting that PD patients may have altered intestinal flora composition and a severe inflammatory response in the intestine[202]. Through neuromodulation, immune response, and stimulation of intestinal inflammation, the gut microbiota and its metabolites may play a role in the pathogenesis of PD.

7. Treatments of inflammatory diseases by regulating gut microbiota dysbiosis7.1. Diet improvement

Numerous studies have demonstrated that dietary changes substantially alter the microbial abundance and fermentation products [203], [204]. Chitosan, obtained by deproteinization and deacetylation of chitin extracted from shrimp and crab in an alkaline environment, exhibits multiple biological activities [205]. It was found that chitosan can ameliorate lipid metabolism disorders, increase the number of beneficial microbes, and prevent the development of metabolic disorders [206]. The gut microbiota plays a critical role in diminishing the fat deposition and metabolic disturbances caused by HFD. Fubrick tea aqueous extracts have beneficial effects on HFD-induced obesity, and the underlying mechanism is partly related to the reprogramming of the gut microbiota, which can increase the relative abundance of Bacteroides, Adlercreutzia, and Alistipes and decrease the relative abundance of Staphylococcus to modulate gut microbiota dysbiosis [207].

The Mediterranean diet (MD), comprised of fruits, vegetables, whole cereals, olive oil, red wine, and yogurt, may have beneficial effects on IBD. There is evidence that following the MD reduces the incidence of IBD and inflammation [208]. MD facilitates the survival of anti-inflammatory bacterial species and prevents the development of dysbiosis in the intestinal microbiota [209]. By modulating the gut microbiota, which modifies the gut microbial composition, increases SCFAs levels, and decreases urinary TMAO levels, MD can be a potential therapeutic intervention for AD [210]. In addition, greater adherence to the MD delays the progression of AD and offers 1.5–3.5 years of protection against AD [211]. John R. et al. discovered that diet-induced alterations in the composition of the gastrointestinal microbiome may increase levels of pro-IL-1 that can be converted by caspases 1 and 8, thereby promoting auto-inflammatory diseases in susceptible individuals [212].

7.2. Fecal microbiota transplantation

Fecal microbiota transplantation (FMT) is a new approach to restore and re-establish intestinal micro-ecological balance and diversity by reconstructing the intestinal microbiota and delivering feces from healthy donors to the patient's gastrointestinal tract [213]. FMT substantially restored the intestinal microbial community, decreased intestinal inflammation and barrier disruption, and reduced systemic inflammation. A pilot randomized controlled study showed the efficacy of FMT in maintaining remission of Crohn's disease, as evidenced by decreased endoscopic severity indices and lower C-reactive protein levels in FMT group compared with the sham-transplant group [214]. FMT can also reduce hepatic fat accumulation by improving the dysbiosis of the intestinal microbiota, thus decreasing NAFLD. Notably, FMT appears to have greater clinical efficacy in slender individuals with NAFLD compared with those who are overweigh [215]. A systematic review of the role of FMT in the treatment of Alzheimer's disease indicates that FMT can restore SCFAs and a healthy microbiome to disrupt Aβ oligomers in AD patients, thereby diminishing the pathogenesis of AD [216]. Further mechanistic investigations revealed that FMT decreased LPS levels in the colon, serum, and SN, inhibited the TLR4/MyD88/NF-κB signaling pathway, normalized gut microbiota and SCFAs, increased synaptophysin I expression‎, and ameliorated cognitive deficits and Aβ deposition in mouse modeld of AD [217], [218].

7.3. Probiotics and prebiotics

Probiotics and prebiotics have been found to reduce and ameliorate the progression of digestive disorders, as well as be used as adjuvants in the treatment of metabolic disorders [219]. Lactobacillus and Bifidobacterium are the two main phyla that constitute probiotics that can inhibit the adhesion of pathogens to the mucosal surface by increasing the adhesion of healthy probiotics, competitively eliminate pathogenic microorganisms, produce antimicrobial substances, modulate immune function, protect intestinal mucosa and re-establish intestinal symbiosis [220]. The use of probiotics as dietary supplements induced an anti-inflammatory response that substantially decreased IL-1, TNF-α, and IL-8 levels, restored intestinal homeostasis, and alleviated IBD symptoms [221]. In addition, probiotics, prebiotics, and phenolic compounds that stimulate favorable strains of microbiota can support the regulation of microbiota patterns over time and the attenuation of indirect causes that determine ecological dysbiosis [222].

In the treatment of NAFLD, it was discovered that compound probiotics decreased fat mass, as well as liver TC and TG levels and serum TG, FFA, ALT, LPS, IL-1, and IL-18 in rats with NAFLD, and improved chronic metabolic inflammation and gut microbiota ecological dysbiosis in NAFLD rats [223]. Probiotics modulated the rat bile acid receptor FXR/FGF15 signaling pathway by altering intestinal microbiota disorder to alleviate NAFLD in HFD rats and significantly reduced lipid and TBA levels [224]. Multiple probiotic "Symbiter", concentrated biomass of 14 probiotics of the genera Bifidobacterium, Lactococcus, and Lactobacillus, reduced liver lipid, transaminase activity, TNF-α, and IL-6 levels in patients with NAFLD, according to a randomized clinical trial [225].

Metabolic syndromes (MetS) can be treated with probiotics and prebiotics. Probiotics such as lactobacillus salivarius and Bifidobacterium can inhibit the rate of weight gain in obese rats and prevent the rise of non-esterified fatty acids (NEFAs) and ketone bodies, which may have been mediated by their negative regulation of energy metabolism [226]. Some experimental studies have shown that Lactobacillus in apple juice is effective in preventing obesity. It prevents weight gain and fat accumulation, maintains normal blood lipid levels, and enhances the Sobs, Ace, and Chao indices of the intestinal microbiota by decreasing the ratio of Firmicutes/Bacteroidetes [227]. It has been reported that when probiotic compounds are used in patients with MetS, clinical symptoms of MetS can be alleviated and inflammatory biomarkers such as TNF-α are effectively reduced [228]. The use of prebiotics and/or probiotics (especially Akkermansia spp) in MetS has many benefits in improving metabolic parameters such as BMI, insulin resistance, and inflammatory parameters [229]. In T2DM patients, the administration of probiotics and synbiotics improved lipid profile, anthropometric indices, and blood pressure [230]. A meta-analysis demonstrates that probiotics can decrease inflammation and oxidative stress in patients with diabetic nephropathy [231].

Utilizing intestinal microorganisms effectively inhibits neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). Probiotics may be a potent tool for altering the microbiota associated with PD and improving gastrointestinal function, thereby reducing leaky gut, bacterial translocation, and neuroinflammation in ENS [232]. Bonfili in his experiments demonstrated that administration of a mouse SLAB51 mixture (including Streptococcus thermophilus, Bifidobacterium, and Lactobacillus preparations), was effective in inhibiting cortical atrophy in mice [233]. Lactobacillus and Bifidobacterium probiotics decreased inflammatory biomarkers such as WBC, TNF-α, and IL-6 and enhanced the oxidative/nitrosative profile in RA patients [234] (Table 4).

Table 4. Treatments of inflammatory diseases through regulation of dysbiosis.

DiseasesTreatmentsRelated gut microbiotaResultReferencedisorders of lipid metabolismAD/PDCrohn’s diseaseNAFLDMetabolic syndromes

Chitosan	Bacteroides, Lachnospiraceae, Lactobacillus, Oscillospira, and Akkermansia↑ Desulfovibrio genera↓	Serum lipid and liver lipids accumulation↓ Glucose tolerance↑	[206], [235]
Fubrick tea aqueous extracts	Bacteroides, Adlercreutzia, and Alistipes↑, Staphylococcus↓	LPS and BCAAs↓	[207]
MD	Bacteroides and Clostridium↑, Proteobacteria and Bacillaceae↓	SCFAs and urinary TMAO↑	[208], [236]
FMT	Bacteroidetes↑ Akkermansia↓	a)Restore SCFAs, healthy microbiome, and disrupt Aβ oligomers b)LPS in the colon, serum, and SN↓ Inhibit the TLR4/MyD88/NF-B signaling pathway	[216], [218]
MD	Lacnospira and Ruminococcus↑	SCFAs induce anti-inflammatory regulatory T cells↑	[209]
FMT	Actinobacteria and Proteobacteria↑	C-reactive protein↓	[214]
FMT	Bacteroidetes and Bacteroidetes-to-Firmicutes (B/F)↑	Intestinal permeability↓	[215], [237]
Probiotics and prebiotics	Lactobacillus and Bifidobacterium↑	a)Fat mass, live TC/TG, and Serum TG/FFA/ ALT/ LPS/ IL-1/IL-18↓ b)Modulate the bile acid receptor FXR/FGF15 signaling pathway	[223], [224], [226]
Probiotics and prebiotics	Lactobacillus, Bifidobacterium and Bacteroidetes-to-Firmicutes (B/F)↑	IL-1, TNF-α, and IL-8↓, restored intestinal homeostasis	[221]

8. Discussion8.1. Limitations

This review focuses on the three main mechanisms by which gut microbiota dysbiosis contributes to inflammatory diseases. Given the enormous quantity and complex structure of microbiota, the relationship between gastrointestinal microbiota and inflammatory diseases may be influenced by additional factors that have yet to be identified. Therefore, extensive basic and clinical research is still required in the future to explore this relationship. The study of human gut microbiota still poses significant challenges, including pronounced inter-individual differences, clinical status changes during different disease stages, and other confounding factors inherent in cross-sectional human studies. Additionally, because the composition of gut microbiota varies along different segments of the digestive tract and the fecal colon transit time is relatively lengthy, further investigation is needed to determine whether fecal sample analysis can adequately represent the composition of the gut microbiota.

8.2. Challenges

Even though numerous studies have established a link between intestinal microbiota and inflammatory diseases, several obstacles persist. Most existing research relies on feces samples for gastrointestinal microbiome studies. However, the presence of microbial impurities in feces can impact the quality of DNA generated during the extraction process, potentially influencing the interpretation of α-diversity and compromising the study results. Secondly, research is needed to determine how to screen for microbiota and metabolites associated with specific inflammatory diseases, as well as the range of metabolite levels. In addition, many studies have been limited to the analysis of microbiota abundance and the investigation of a few cytokine levels to infer the possible pathogenic mechanisms of the gut microbiota. The inflammatory marker factors related to specific bacterial taxa in certain phenotypic populations have not been thoroughly identified, and their concrete mechanisms and the involved signaling pathways have not been fully elucidated. Finally, probiotics, FMT, and other methods of regulating the gut microbiiota provide new ideas for the adjuvant treatment of patients with inflammatory diseases, but there is no clear evidence-based basis for their dosing, treatment duration, and long-term prognosis, which needs further in-depth research; the mass production technology of probiotics, prebiotics, and postbiotics lacks unified standards and processes, and the safety and regulatory issues still need to be solved, and the supervisory standards need to be unified.

8.3. Prospects

With the advent of high-throughput sequencing and metagenomics, the structure and function of the intestinal microbiota are progressively becoming clearer. One of the ultimate goals of human microbiome research is to improve health and treat diseases by manipulating symbiotic microbiota. Approaches to rebuilding the gut microbiota are emerging as potential therapeutics for inflammatory diseases. The current research results are inconsistent due to differences in research population, sequencing methods, treatment doses, and course of treatment. The current research results are inconsistent due to differences in research populations, sequencing methods, treatment doses, and regimens. Nonetheless, the available evidence suggests that gut microbiota research holds promise in elucidating the pathogenesis of inflammatory diseases, analyzing the heterogeneity of clinical manifestations, and identifying potential drug targets. responses, and developing new therapeutic approaches. For example, postbiotics, as derivatives of intestinal microbiota, exert a wide range of effects in the intestinal tract and throughout the body to treat or prevent a variety of diseases. In the current body of research, the anti-inflammatory, anti-infectious, metabolic, and anti-tumor effects of postbiotics have been largely confirmed, and their clinical application to prevent or treat inflammatory diseases is anticipated or has already underway [200].

As the understanding of the liver-gut axis, brain-gut axis, and the interaction between gut microbes and the immune system deepens, preclinical research related to next-generation probiotics and biotherapeutic products spread across various fields such as digestion, metabolism, oncology, neuropsychiatric system, and immune system. In the future, methodologies such as machine learning could achieve patient stratification, disease progression prediction, and treatment response to fine-tune treatment regimens with a positive impact on cost, health, and safety [238]. Establishing personalized microbiota fingerprints and prediction tools through machine learning is expected to form predictive models and personalized gut microbiota intervention plans that guide clinical practice[239]. A new generation of probiotics and biol-derivatives developed for specific health issues will be developed to "customize" probiotics for patients, ultimately achieving the goal of precise and personalized healthcare.

9. Conclusion

In a nutshell, we have reviewed the literature on gut microbiota and inflammatory diseases to clarify the potential mechanisms by which gut microbial disorders contribute to the development of inflammatory diseases. The symbiotic relationship between gut microbiota and host's immunity system play a crucial role in maintaining intestinal homeostasis and suppressing inflammation. Disruption of this delicate balance can result in a cascade of events, including metabolic dysfunction, damage to the intestinal barrier, and immune dysregulation, leading to an excessive release of pro-inflammatory factors. Consequently, the disruption of the normal immune homeostasis of the intestine and the activation of abnormal immune responses lead to the development of various inflammatory diseases. In light of these findings, therapeutic interventions aimed at restoring gut microbiota dysbiosis, such as dietary modifications, FMT, and the administration of probiotics and prebiotics, hold promise as effective approaches for managing chronic inflammatory diseases.

Ethical approval

Not applicable as we utilized publicly available data.

CRediT authorship contribution statement

Min’an Zhao: Visualization, Writing – original draft, Writing – review & editing. Jiayi Chu: Writing – original draft, Writing – review & editing. Shiyao Feng: Writing – original draft, Writing – review & editing. Chuanhao Guo: Visualization, Writing – review & editing. Baigong Xue: Conceptualization, Project administration. Kan He: Conceptualization, Writing – review & editing. Lisha Li: Conceptualization, Writing – review & editing, Funding acquisition.

Declaration of Competing Interest

The authors declare that they have no conflict of interest and consent for publication. This study was funded by Jilin Provincial Department of Science and Technology, China (Grant No. 20230101163JC). The authors confirm‎ independence from the sponsors; the content of the article has not been influenced by the sponsors.

Data availability

No data was used for the research described in the article.

References

1. [1]

   P. Hugon, J.C. Dufour, P. Colson, P.E. Fournier, K. Sallah, D. Raoult

   A comprehensive repertoire of prokaryotic species identified in human beings

   Lancet Infect. Dis., 15 (10) (2015), pp. 1211-1219, 10.1016/S1473-3099(15)00293-5

   View PDFView articleView in ScopusGoogle Scholar

2. [2]

   X. Guo, E.S. Okpara, W. Hu, C. Yan, Y. Wang, Q. Liang, J.Y.L. Chiang, S. Han

   Interactive relationships between intestinal flora and bile acids

   Int. J. Mol. Sci., 23 (15) (2022), 10.3390/ijms23158343

   View article 

   Google Scholar

3. [3]

   F. Cristofori, V.N. Dargenio, C. Dargenio, V.L. Miniello, M. Barone, R. Francavilla

   Anti-inflammatory and immunomodulatory effects of probiotics in gut inflammation: a door to the body

   Front Immunol., 12 (2021), Article 578386, 10.3389/fimmu.2021.578386

   View article 

   View in ScopusGoogle Scholar

4. [4]

   T.G. Dinan, J.F. Cryan

   The microbiome-gut-brain axis in health and disease

   Gastroenterol. Clin. North Am., 46 (1) (2017), pp. 77-89, 10.1016/j.gtc.2016.09.007

   View PDFView articleView in ScopusGoogle Scholar

5. [5]

   E. Stachowska, M. Wisniewska, A. Dziezyc, A. Bohatyrewicz

   Could the use of butyric acid have a positive effect on microbiota and treatment of type 2 diabetes?

   Eur. Rev. Med. Pharm. Sci., 25 (13) (2021), pp. 4570-4578, 10.26355/eurrev_202107_26250

   View article 

   View in ScopusGoogle Scholar

6. [6]

   J. Noack, B. Kleessen, J. Proll, G. Dongowski, M. Blaut

   Dietary guar gum and pectin stimulate intestinal microbial polyamine synthesis in rats

   J. Nutr., 128 (8) (1998), pp. 1385-1391, 10.1093/jn/128.8.1385

   View PDFView articleView in ScopusGoogle Scholar

7. [7]

   J.H. Cummings, E.W. Pomare, W.J. Branch, C.P. Naylor, G.T. Macfarlane

   Short chain fatty acids in human large intestine, portal, hepatic and venous blood

   Gut, 28 (10) (1987), pp. 1221-1227, 10.1136/gut.28.10.1221

   View article 

   View in ScopusGoogle Scholar

8. [8]

   W. Yang, Y. Cong

   Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases

   Cell Mol. Immunol., 18 (4) (2021), pp. 866-877, 10.1038/s41423-021-00661-4

   View article 

   Google Scholar

9. [9]

   M. Akhtar, Y. Chen, Z. Ma, X. Zhang, D. Shi, J.A. Khan, H. Liu

   Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation

   Anim. Nutr., 8 (2022), pp. 350-360, 10.1016/j.aninu.2021.11.005

   View PDFView articleView in ScopusGoogle Scholar

10. [10]

    A.M. Madella, J. Van Bergenhenegouwen, J. Garssen, R. Masereeuw, S.A. Overbeek

    Microbial-derived tryptophan catabolites, kidney disease and gut inflammation

    Toxins (Basel), 14 (9) (2022), 10.3390/toxins14090645

    View article 

    Google Scholar

11. [11]

    D.A. Negatu, Y. Yamada, Y. Xi, M.L. Go, M. Zimmerman, U. Ganapathy, V. Dartois, M. Gengenbacher, T. Dick

    Gut microbiota metabolite indole propionic acid targets tryptophan biosynthesis in Mycobacterium tuberculosis

    mBio, 10 (2) (2019), 10.1128/mBio.02781-18

     View PDF 

    This article is free to access.

    Google Scholar

12. [12]

    Y. Kiriyama, H. Nochi

    Physiological role of bile acids modified by the gut microbiome

    Microorganisms, 10 (1) (2021), 10.3390/microorganisms10010068

    View article 

    Google Scholar

13. [13]

    J.M. Ridlon, D.J. Kang, P.B. Hylemon

    Bile salt biotransformations by human intestinal bacteria

    J. Lipid Res., 47 (2) (2006), pp. 241-259, 10.1194/jlr.R500013-JLR200

    View PDFView articleView in ScopusGoogle Scholar

14. [14]

    L. Mancin, G.D. Wu, A. Paoli

    Gut microbiota-bile acid-skeletal muscle axis

    Trends Microbiol. (2022), 10.1016/j.tim.2022.10.003

     View PDF 

    This article is free to access.

    Google Scholar

15. [15]

    E.C. Soto-Martin, I. Warnke, F.M. Farquharson, M. Christodoulou, G. Horgan, M. Derrien, J.M. Faurie, H.J. Flint, S.H. Duncan, P. Louis

    Vitamin biosynthesis by human gut butyrate-producing bacteria and cross-feeding in synthetic microbial communities

    mBio, 11 (4) (2020), 10.1128/mBio.00886-20

     View PDF 

    This article is free to access.

    Google Scholar

16. [16]

    S. Magnusdottir, D. Ravcheev, V. de Crecy-Lagard, I. Thiele

    Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes

    Front Genet, 6 (2015), p. 148, 10.3389/fgene.2015.00148

    View article 

    View in ScopusGoogle Scholar

17. [17]

    P.D. Cotter, R.P. Ross, C. Hill

    Bacteriocins - a viable alternative to antibiotics?

    Nat. Rev. Microbiol., 11 (2) (2013), pp. 95-105, 10.1038/nrmicro2937

    View article 

    View in ScopusGoogle Scholar

18. [18]

    D. Destoumieux-Garzon, J. Peduzzi, X. Thomas, C. Djediat, S. Rebuffat

    Parasitism of iron-siderophore receptors of Escherichia coli by the siderophore-peptide microcin E492m and its unmodified counterpart

    Biometals, 19 (2) (2006), pp. 181-191, 10.1007/s10534-005-4452-9

    View article 

    View in ScopusGoogle Scholar

19. [19]

    S. Telhig, L. Ben Said, S. Zirah, I. Fliss, S. Rebuffat

    Bacteriocins to thwart bacterial resistance in gram negative bacteria

    Front Microbiol, 11 (2020), Article 586433, 10.3389/fmicb.2020.586433

    View article 

    View in ScopusGoogle Scholar

20. [20]

    L. Cursino, D. Smajs, J. Smarda, R.M. Nardi, J.R. Nicoli, E. Chartone-Souza, A.M. Nascimento

    Exoproducts of the Escherichia coli strain H22 inhibiting some enteric pathogens both in vitro and in vivo

    J. Appl. Microbiol., 100 (4) (2006), pp. 821-829, 10.1111/j.1365-2672.2006.02834.x

    View article 

    View in ScopusGoogle Scholar

21. [21]

    K.G. Markovic, M.Z. Grujovic, M.G. Koracevic, D.D. Nikodijevic, M.G. Milutinovic, T. Semedo-Lemsaddek, M.D. Djilas

    Colicins and microcins produced by enterobacteriaceae: characterization, mode of action, and putative applications

    Int. J. Environ. Res Public Health, 19 (18) (2022), 10.3390/ijerph191811825

    View article 

    Google Scholar

22. [22]

    L. Dong, H. Yang, Z. Wang, N. Jiang, A. Zhang

    Antimicrobial peptide CC34 attenuates intestinal inflammation via downregulation of the NF-kappaB signaling pathway

    3 Biotech, 11 (9) (2021), p. 397, 10.1007/s13205-021-02948-9

    View article 

    View in ScopusGoogle Scholar

23. [23]

    S.K.Tiwari Anjana

    Bacteriocin-producing probiotic lactic acid bacteria in controlling dysbiosis of the gut microbiota

    Front Cell Infect. Microbiol, 12 (2022), Article 851140, 10.3389/fcimb.2022.851140

    View article 

    View in ScopusGoogle Scholar

24. [24]

    Q.R. Ducarmon, R.D. Zwittink, B.V.H. Hornung, W. van Schaik, V.B. Young, E.J. Kuijper

    Gut microbiota and colonization resistance against bacterial enteric infection

    Microbiol. Mol. Biol. Rev., 83 (3) (2019), 10.1128/MMBR.00007-19

     View PDF 

    This article is free to access.

    Google Scholar

25. [25]

    D.N. Bronner, F. Faber, E.E. Olsan, M.X. Byndloss, N.A. Sayed, G. Xu, W. Yoo, D. Kim, S. Ryu, C.B. Lebrilla, A.J. Baumler

    Genetic ablation of butyrate utilization attenuates gastrointestinal salmonella disease

    Cell Host Microbe, 23 (2) (2018), pp. 266-273 e4, 10.1016/j.chom.2018.01.004

    View PDFView articleView in ScopusGoogle Scholar

26. [26]

    R. Freter, H. Brickner, M. Botney, D. Cleven, A. Aranki

    Mechanisms that control bacterial populations in continuous-flow culture models of mouse large intestinal flora

    Infect. Immun., 39 (2) (1983), pp. 676-685, 10.1128/iai.39.2.676-685.1983

     View PDF 

    This article is free to access.

    View in ScopusGoogle Scholar

27. [27]

    Y. Minnebo, K. De Paepe, J. Raes, T.V. de Wiele

    Nutrient load acts as a driver of gut microbiota load, community composition and metabolic functionality in the simulator of the human intestinal microbial ecosystem

    FEMS Microbiol Ecol., 97 (9) (2021), 10.1093/femsec/fiab111

     View PDF 

    This article is free to access.

    Google Scholar

28. [28]

    E. Deriu, J.Z. Liu, M. Pezeshki, R.A. Edwards, R.J. Ochoa, H. Contreras, S.J. Libby, F.C. Fang, M. Raffatellu

    Probiotic bacteria reduce salmonella typhimurium intestinal colonization by competing for iron

    Cell Host Microbe, 14 (1) (2013), pp. 26-37, 10.1016/j.chom.2013.06.007

    View PDFView articleView in ScopusGoogle Scholar

29. [29]

    L.Z. Jin, R.R. Marquardt, X. Zhao

    A strain of Enterococcus faecium (18C23) inhibits adhesion of enterotoxigenic Escherichia coli K88 to porcine small intestine mucus

    Appl. Environ. Microbiol., 66 (10) (2000), pp. 4200-4204, 10.1128/AEM.66.10.4200-4204.2000

     View PDF 

    This article is free to access.

    View in ScopusGoogle Scholar

30. [30]

    I. Khan, Y. Bai, L. Zha, N. Ullah, H. Ullah, S.R.H. Shah, H. Sun, C. Zhang

    Mechanism of the gut microbiota colonization resistance and enteric pathogen infection

    Front Cell Infect. Microbiol, 11 (2021), Article 716299, 10.3389/fcimb.2021.716299

    View article 

    View in ScopusGoogle Scholar

31. [31]

    A. Jacobson, L. Lam, M. Rajendram, F. Tamburini, J. Honeycutt, T. Pham, W. Van Treuren, K. Pruss, S.R. Stabler, K. Lugo, D.M. Bouley, J.G. Vilches-Moure, M. Smith, J.L. Sonnenburg, A.S. Bhatt, K.C. Huang, D. Monack

    A gut commensal-produced metabolite mediates colonization resistance to salmonella infection

    Cell Host Microbe, 24 (2) (2018), pp. 296-307 e7, 10.1016/j.chom.2018.07.002

    View PDFView articleView in ScopusGoogle Scholar

32. [32]

    J.L. Wallace, J.P. Motta, A.G. Buret

    Hydrogen sulfide: an agent of stability at the microbiome-mucosa interface

    Am. J. Physiol. Gastrointest. Liver Physiol., 314 (2) (2018), pp. G143-G149, 10.1152/ajpgi.00249.2017

     View PDF 

    This article is free to access.

    View in ScopusGoogle Scholar

33. [33]

    F. Blachier, M. Andriamihaja, P. Larraufie, E. Ahn, A. Lan, E. Kim

    Production of hydrogen sulfide by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa

    Am. J. Physiol. Gastrointest. Liver Physiol., 320 (2) (2021), pp. G125-G135, 10.1152/ajpgi.00261.2020

     View PDF 

    This article is free to access.

    View in ScopusGoogle Scholar

34. [34]

    A. Stacy, V. Andrade-Oliveira, J.A. McCulloch, B. Hild, J.H. Oh, P.J. Perez-Chaparro, C.K. Sim, A.I. Lim, V.M. Link, M. Enamorado, G. Trinchieri, J.A. Segre, B. Rehermann, Y. Belkaid

    Infection trains the host for microbiota-enhanced resistance to pathogens

    Cell, 184 (3) (2021), pp. 615-627 e17, 10.1016/j.cell.2020.12.011

    View PDFView articleView in ScopusGoogle Scholar

35. [35]

    T. Miki, R. Goto, M. Fujimoto, N. Okada, W.D. Hardt

    The bactericidal lectin regiiibeta prolongs gut colonization and enteropathy in the streptomycin mouse model for salmonella diarrhea

    Cell Host Microbe, 21 (2) (2017), pp. 195-207, 10.1016/j.chom.2016.12.008

    View PDFView articleView in ScopusGoogle Scholar

36. [36]

    S. Vaishnava, C.L. Behrendt, A.S. Ismail, L. Eckmann, L.V. Hooper

    Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface

    Proc. Natl. Acad. Sci. USA, 105 (52) (2008), pp. 20858-20863, 10.1073/pnas.0808723105

    View article 

    View in ScopusGoogle Scholar

37. [37]

    A. Menendez, B.P. Willing, M. Montero, M. Wlodarska, C.C. So, G. Bhinder, B.A. Vallance, B.B. Finlay

    Bacterial stimulation of the TLR-MyD88 pathway modulates the homeostatic expression‎ of ileal Paneth cell alpha-defensins

    J. Innate Immun., 5 (1) (2013), pp. 39-49, 10.1159/000341630

     View PDF 

    This article is free to access.

    View in ScopusGoogle Scholar

38. [38]

    D. Kim, M.Y. Zeng, G. Nunez

    The interplay between host immune cells and gut microbiota in chronic inflammatory diseases

    Exp. Mol. Med., 49 (5) (2017), Article e339, 10.1038/emm.2017.24

     View PDF 

    This article is free to access.

    View in ScopusGoogle Scholar

39. [39]

    M. Cieslik, N. Baginska, A. Gorski, E. Jonczyk-Matysiak

    Human beta-defensin 2 and its postulated role in modulation of the immune response

    Cells, 10 (11) (2021), 10.3390/cells10112991

    View article 

    Google Scholar

40. [40]

    F.E.Y. Aggor, T.J. Break, G. Trevejo-Nunez, N. Whibley, B.M. Coleman, R.D. Bailey, D.H. Kaplan, J.R. Naglik, W. Shan, A.C. Shetty, C. McCracken, S.K. Durum, P.S. Biswas, V.M. Bruno, J.K. Kolls, M.S. Lionakis, S.L. Gaffen

    Oral epithelial IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral mucosal candidiasis

    Sci. Immunol., 5 (48) (2020), 10.1126/sciimmunol.aba0570

     View PDF 

    This article is free to access.

    Google Scholar

41. [41]

    M.M. Nielsen, D.A. Witherden, W.L. Havran

    gammadelta T cells in homeostasis and host defence of epithelial barrier tissues

    Nat. Rev. Immunol., 17 (12) (2017), pp. 733-745, 10.1038/nri.2017.101

    View article 

    View in ScopusGoogle Scholar

42. [42]

    S. Krishnan, I.E. Prise, K. Wemyss, L.P. Schenck, H.M. Bridgeman, F.A. McClure, T. Zangerle-Murray, C. O'Boyle, T.A. Barbera, F. Mahmood, D.M.E. Bowdish, D.M.W. Zaiss, J.R. Grainger, J.E. Konkel

    Amphiregulin-producing gammadelta T cells are vital for safeguarding oral barrier immune homeostasis

    Proc. Natl. Acad. Sci. USA, 115 (42) (2018), pp. 10738-10743, 10.1073/pnas.1802320115

    View article 

    View in ScopusGoogle Scholar

43. [43]

    N. Iwanaga, I. Sandquist, A. Wanek, J. McCombs, K. Song, J.K. Kolls

    Host immunology and rational immunotherapy for carbapenem-resistant Klebsiella pneumoniae infection

    JCI Insight, 5 (8) (2020), 10.1172/jci.insight.135591

    View article 

    Google Scholar