스크랩 건선 질환 .. 피부 세균, 장내 세균과의 관계..

[물치사랑!!]

피부에는 

수백만 개의 박테리아, 바이러스, 곰팡이가 서식하며, 

이를 통칭하여 피부 미생물총

Psoriasis (Auckl). 2023; 13: 71–78.

Published online 2023 Oct 26. doi: 10.2147/PTT.S328439

PMCID: PMC10614657

PMID: 37908308

The Skin Microbiome and Its Role in Psoriasis: A Review

Valentina Celoria,#1,* Francois Rosset,#1,* Valentina Pala,1 Paolo Dapavo,1 Simone Ribero,1 Pietro Quaglino,1 and Luca Mastorino1

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Abstract

The skin microbiome is made of various microorganisms, most of which have the function of protecting individuals from harmful pathogens, and they are involved in innate and adaptive immune responses. The skin acts as a physical and immunological barrier against external stimuli, including pathogens and physical damage. Changes in the composition of the skin microbiome can trigger inflammatory processes leading to inflammatory skin diseases in susceptible individuals. Psoriasis (PsO) is a chronic inflammatory disease with a multifactorial etiology, where breakdown of immune tolerance to cutaneous microorganisms is implicated in its pathogenesis. Dysregulation of the microbiome due to genetic and environmental factors plays a significant role in the development of psoriatic disease. Dermatologic conditions such as atopic dermatitis, acne, psoriasis, and rosacea have been associated with intestinal dysbiosis. The skin microbiota composition is crucial for the development of appropriate immune responses, and alterations in the skin microbiome can contribute to changes in physiology and susceptibility to skin diseases or inflammatory conditions. Understanding the microbial settlement of the skin and the network of interactions that occur throughout life is essential for comprehending the pathogenesis of skin diseases and developing innovative treatments. With this article we tried to explore the relationship between the human microbiome and psoriatic disease, shedding light on the functions of the microbiome and the inflammatory disease processes to identify additional therapeutic targets. This review aims to highlight the relationship between skin and gut microbiome functions and inflammatory processes in skin psoriasis and psoriatic arthritis (PsA). The goal is to facilitate future studies on the skin microbiome to identify potential novel therapies for patients with psoriatic disease.

피부 미생물은 

다양한 미생물로 구성되어 있으며, 

대부분은 유해한 병원체로부터 개인을 보호하는 기능을 가지고 있으며 

선천성 및 후천성 면역 반응에 관여합니다. 

피부는 

병원균과 물리적 손상을 포함한 외부 자극에 대한 

물리적, 면역학적 장벽 역할을 합니다. 

피부 마이크로바이옴 구성의 변화는 

염증 과정을 유발하여 취약한 개인에게 

염증성 피부 질환을 일으킬 수 있습니다. 

건선(PsO)은 

다인성 병인을 가진 만성 염증성 질환으로, 

피부 미생물에 대한 면역 내성의 붕괴가 그 발병 기전과 관련이 있습니다. 

breakdown of immune tolerance to cutaneous microorganisms

유전적 및 환경적 요인으로 인한 

마이크로바이옴의 조절 장애는 

건선 질환의 발병에 중요한 역할을 합니다. 

아토피 피부염, 여드름, 건선, 주사비와 같은 

피부과 질환은 

장내 미생물 이상증과 관련이 있습니다. 

피부 미생물 구성은 

적절한 면역 반응의 발달에 매우 중요하며, 

피부 미생물 군집의 변화는

 피부 질환이나 염증 상태에 대한 생리학 및 감수성의 변화에 기여할 수 있습니다. 

피부의 미생물 정착과 

일생 동안 발생하는 상호 작용 네트워크를 이해하는 것은 

피부 질환의 발병 기전을 이해하고 

혁신적인 치료법을 개발하는 데 필수적입니다. 

이 글에서는 

인간 마이크로바이옴과 

건선 질환의 관계를 살펴보고, 

마이크로바이옴의 기능과 염증성 질환 과정을 조명하여 

추가적인 치료 표적을 확인하고자 합니다. 

이 리뷰는 

피부 건선 및 건선성 관절염(PsA)의 

피부 및 장내 미생물군집 기능과 

염증 과정 사이의 관계를 조명하는 것을 목표로 합니다. 

건선 질환 환자를 위한 잠재적인 새로운 치료법을 찾기 위한 

피부 마이크로바이옴에 대한 향후 연구를 촉진하는 것이 목표입니다.

Keywords: psoriasis, skin microbiome, new therapies, gut microbiome, molecular precision medicines, next generation treatments

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Background

The skin microbiome is composed of various microorganisms, most of which have the function of protecting individuals from harmful pathogens, and they are involved in innate and adaptive immune responses.1,2 The skin acts as a physical and immunological barrier against external stimuli, including pathogens and physical damage. Changes in the composition of the skin microbiome can trigger inflammatory processes in the epithelial microenvironment, leading to inflammatory skin diseases in susceptible individuals. Psoriasis, a chronic inflammatory skin disease, is caused by the interaction between multiple genetic and environmental risk factors. While the exact mechanisms are not yet clear, both the cutaneous and intestinal microbial populations contribute to the pathogenesis of psoriatic disease, as their alteration can lead to pro-inflammatory processes in the intestine, skin, and joints.3

Psoriasis (PsO) is a chronic inflammatory disease with a multifactorial etiology, where breakdown of immune tolerance to cutaneous microorganisms is implicated in its pathogenesis. Dysregulation of the microbiome due to genetic and environmental factors plays a significant role in the development of psoriatic disease. Dysbiosis, or an alteration in the composition of the microbiome, can lead to downstream proinflammatory effects in the gut, skin, and joints. Both the cutaneous and intestinal microbial populations are implicated in the pathogenesis of psoriatic disease, although the exact mechanisms are still unclear. This review aims to explore the relationship between the human microbiome and psoriatic disease, shedding light on the functions of the microbiome and the inflammatory disease processes to identify additional therapeutic targets. Furthermore, cutaneous dysbiosis has been observed not only in cutaneous psoriasis but also in Psoriatic arthritis (PsA).4

피부 마이크로바이옴은 

다양한 미생물로 구성되어 있으며, 

대부분 유해한 병원체로부터 개체를 보호하는 기능을 하며 

선천성 및 후천성 면역 반응에 관여합니다.1,2 

피부는 병원체와 물리적 손상 등 

외부 자극에 대한 물리적, 면역학적 장벽으로 작용합니다. 

피부 마이크로바이옴 구성의 변화는 

상피 미세환경에서 

염증 과정을 유발하여 취약한 개인에게 

염증성 피부 질환을 일으킬 수 있습니다. 

만성 염증성 피부 질환인 건선은 

여러 유전적 및 환경적 위험 요인의 상호작용으로 인해 발생합니다. 

정확한 메커니즘은 아직 명확하지 않지만, 

피부와 장내 미생물 집단 모두 

건선 질환의 발병에 기여하며, 

이들의 변화는 장, 피부, 관절의 염증 과정을 유발할 수 있습니다.3

건선(PsO)은 

다인성 병인을 가진 만성 염증성 질환으로, 

피부 미생물에 대한 면역 내성의 붕괴가 발병 기전과 관련이 있습니다. 

유전적 및 환경적 요인으로 인한 

마이크로바이옴의 조절 장애는 

건선 질환의 발병에 중요한 역할을 합니다. 

미생물 군집의 구성에 변화가 생기면 

장, 피부, 관절에 염증 반응을 일으킬 수 있습니다. 

피부와 장내 미생물 집단 모두 

건선 질환의 발병과 관련이 있지만, 

정확한 메커니즘은 아직 명확하지 않습니다. 

이 리뷰는 

인간 마이크로바이옴과 건선 질환 사이의 관계를 탐구하여 

마이크로바이옴의 기능과 

염증성 질환 과정을 조명하여 

추가적인 치료 표적을 식별하는 것을 목표로 합니다. 

또한, 피부 건선뿐만 아니라 

건선성 관절염(PsA)에서도 

피부 미생물 군집 이상증식이 관찰되고 있습니다.4

Materials and Methods

This review aims to highlight the relationship between skin and gut microbiome functions and inflammatory processes in skin psoriasis and psoriatic arthritis (PsA). The goal is to facilitate future studies on the skin microbiome to identify potential novel therapies for patients with psoriatic disease.5

이 리뷰는 

피부 건선과 건선성 관절염(PsA)에서 

피부 및 장내 미생물군집 기능과 염증 과정 사이의 관계를 강조하는 것을 목표로 합니다. 

건선 질환 환자를 위한 잠재적인 새로운 치료법을 확인하기 위해 

피부 마이크로바이옴에 대한 향후 연구를 촉진하는 것이 목표입니다.5

The Skin Microbiome

In addition to the epithelial barrier, the gut microbiome also impacts the immune-regulatory properties of the gut. Certain intestinal microbes have the ability to produce or enhance the expression‎ of immune-modulating molecules, including retinoic acid, polysaccharide A, and short-chain fatty acids (SCFAs), which play a role in maintaining the balance between effector and regulatory T cells. However, the specific microbes responsible for these mechanisms in PsO are not yet well understood.

The skin, the largest organ in the human body, serves as a barrier to prevent the invasion of pathogens. It harbors millions of bacteria, viruses, and fungi, collectively known as the skin microbiota, with bacterial density reaching cells per square centimeter. These bacteria play crucial roles in combating pathogens and contributing to the immune system.6,7 The colonization of the skin microbiome undergoes changes during the first year of life, particularly in the initial weeks after birth. This colonization process may impact long-term microbiome stability and skin function. For instance, the presence of the commensal bacterium Staphylococcus epidermidis during early life can reduce exposure to the pathogen S. aureus, thereby preventing inflammatory diseases.8 Bidirectional microbial transmission between mother and child is crucial in this process, while the role of paternal microbiota inheritance is yet to be elucidated. Moreover, the skin microbiome undergoes marked shifts during puberty, with a change in predominant bacterial groups and the overproduction of sebum associated with the overcolonization of Cutibacterium acnes.9 Over time, the skin microbiome undergoes age-related physiological changes, including alterations in sebum and sweat secretion, as well as changes in the immune response of the cutaneous barrier.10

When the skin barrier or the balance between commensal and pathogenic microorganisms is disrupted, various skin diseases or even systemic diseases can occur. Studying the microbiota composition at different skin sites is crucial to understanding the etiology of common skin disorders, which often manifest in specific areas of the skin.5 Advances in sequencing technology have enabled the analysis of the skin microbiota composition. Studies conducted on healthy adults have demonstrated associations between microbial communities and specific microenvironments. For example, lipophilic Propionibacterium species predominantly colonize sebaceous skin sites, while Staphylococcus and Corynebacterium are dominant in various areas, including the elbows and foot folds.11 Different skin sites exhibit considerable variation in bacterial diversity, with high diversity observed in the forearm, palm of the hand, index finger, back of the knee, and sole of the foot.11 Longitudinal studies have shown that the stability of the skin microbiome varies depending on the site, with less variability observed in the external auditory canal, inguinal crease, and wing crease, while more variability is seen in the popliteal fossa, forearm, and buttock.12 The microbial communities found on the hands are more similar to those on the forearm than those on the forehead or the inside of the elbow.13 Differences in the hand surface microbiome have been observed between men and women, and these differences become more evident as time since handwashing increases.13 Further studies are needed to elucidate the underlying factors contributing to these differences, including cutaneous pH, sweat or sebum production, use of creams, skin thickness, and hormonal variations.13

Temporal stability of the skin microbiome has been demonstrated in healthy individuals for up to 2 years, with the most abundant species contributing to the long-term stability of microbial communities, thus defining a unique microbial signature for each individual.14 Similar findings have been reported regarding the stability of the facial skin microbiome over a 2-year period, with substantial changes associated with alterations in stratum corneum barrier function and follicular porphyrins.15

장 마이크로바이옴은 

상피 장벽 외에도 

장의 면역 조절 특성에도 영향을 미칩니다. 

특정 장내 미생물은 

레티노산, 다당류 A, 단쇄 지방산(SCFA) 등 

면역 조절 분자를 생성하거나 발현을 강화하는 능력이 있으며, 

이는 이펙터와 조절 T 세포 사이의 균형을 유지하는 데 중요한 역할을 합니다. 

그러나 

PsO에서 

이러한 메커니즘을 담당하는 특정 미생물은 아직 잘 알려져 있지 않습니다.

인체에서 가장 큰 기관인 피부는 

병원균의 침입을 막는 장벽 역할을 합니다. 

피부에는 

수백만 개의 박테리아, 바이러스, 곰팡이가 서식하며, 

이를 통칭하여 피부 미생물총이라고 하며 

박테리아 밀도는 평방 센티미터당 세포 수에 이릅니다. 

이러한 박테리아는 

병원균과 싸우고 면역 체계에 기여하는 중요한 역할을 합니다.6,7 

피부 미생물 군집은 

생후 첫해, 특히 출생 후 첫 몇 주 동안 변화를 겪습니다. 

이러한 군집화 과정은 

장기적인 마이크로바이옴 안정성과 

피부 기능에 영향을 미칠 수 있습니다. 

예를 들어, 

생후 초기에 공생 세균인 

황색포도상구균 표피상구균이 존재하면 

병원균인 황색포도상구균에 대한 노출을 줄여 

염증성 질환을 예방할 수 있습니다.8 

이 과정에서 

엄마와 아이 사이의 양방향 미생물 전파가 중요하지만 

부계 미생물 유전의 역할은 아직 명확히 밝혀지지 않은 상태입니다. 

또한, 피부 미생물군은 

사춘기 동안 우세한 박테리아 그룹의 변화와 

큐티박테리움 아크네스의 과잉 군집화와 관련된 피지 과다 생산과 함께 

뚜렷한 변화를 겪습니다.9 

시간이 지나면서 피부 미생물군은 

피지 및 땀 분비의 변화와 

피부 장벽의 면역 반응 변화를 포함하여 연령과 관련된 생리적 변화를 겪게 됩니다.10

피부 장벽이나 

공생 미생물과 병원성 미생물 간의 균형이 깨지면 

다양한 피부 질환이나 전신 질환이 발생할 수 있습니다. 

피부의 특정 부위에 나타나는 일반적인 피부 질환의 원인을 이해하려면 피부 부위별 미생물 구성에 대한 연구가 중요합니다.5 시퀀싱 기술의 발전으로 피부 미생물 구성에 대한 분석이 가능해졌습니다. 건강한 성인을 대상으로 실시한 연구에서 미생물 군집과 특정 미생물 환경 사이의 연관성이 입증되었습니다. 

예를 들어, 

친유성 프로피오니박테리움 종은 

피지 피부 부위에 주로 서식하는 반면, 

팔꿈치와 발 주름을 포함한 다양한 부위에서는 

포도상구균과 코리네박테리움이 우세합니다.11 

피부 부위별로 세균 다양성에 상당한 차이가 있으며 

팔뚝, 손바닥, 검지, 무릎 뒤, 발바닥에서 높은 다양성이 관찰됩니다.11 

종단 연구에 따르면 

피부 마이크로바이옴의 안정성은 부위에 따라 달라지는데 외이도, 

사타구니 주름, 날개 주름에서는 변동성이 적은 반면 

슬와, 팔뚝, 엉덩이에서는 변동성이 더 큰 것으로 나타났습니다.12 

손에서 발견되는 미생물 군집은 

이마나 팔꿈치 안쪽보다 팔뚝에서 더 유사합니다.13 

손 표면 미생물 군집은 

남성과 여성 간에 차이가 관찰되었으며, 

이러한 차이는 손씻기 이후 시간이 늘어날수록 더욱 분명해집니다.13 

피부 pH, 

땀 또는 피지 생성, 

크림 사용, 

피부 두께 및 호르몬 변화를 포함하여 

이러한 차이에 기여하는 근본 요인을 밝히기 위해서는 추가 연구가 필요합니다.13

피부 마이크로바이옴의 시간적 안정성은 

건강한 개인에서 최대 2년 동안 입증되었으며, 

가장 풍부한 종은 미생물 군집의 장기 안정성에 기여하여 

각 개인의 고유한 미생물 시그니처를 정의합니다.14 

2년 동안 얼굴 피부 마이크로바이옴의 안정성과 관련하여 유사한 결과가 보고되었으며, 각질층 장벽 기능 및 모낭 포르피린의 변화와 관련된 상당한 변화가 나타났습니다.15

Skin Microbiome and Skin Disorders

Using techniques described in seminal publications, researchers have gained new insights into the complexity of individual cutaneous microbiomes. Not only is the cutaneous microbiome highly diverse and individualized, but it is also tightly regulated within and between different skin regions, and stable over time. This stability has allowed for the identification of individual microbial signatures or “fingerprints” which have been the focus of research in forensic medicine, enabling the identification of individuals based on microbial information retrieved from surfaces they have touched.9

In literature, there are descriptions about the skin microbiome of injured and diseased skin, including psoriasis, and its substantial differences from healthy skin.9 Psoriasis is a multifactorial inflammatory disease with a complex pathogenesis, which in most cases manifests as well-circumscribed erythematous papules and plaques covered with silvery scales. The etiology of psoriasis is not entirely clear; it is hypothesized that an environmental trigger evokes a T-cell-mediated inflammatory response and subsequent hyper-proliferation of keratinocytes. Well-identified triggers include trauma in Koebner’s phenomenon, sunburns, HIV infection, Streptococcal infection in psoriasis guttata, medications such as beta-blockers or ACE inhibitors, emotional stresses, alcohol consumption, smoking, and obesity.16

Studies in the literature suggest that bacteria, including Staphylococcus aureus and Streptococcus pyogenes, can trigger and sustain psoriatic disease, and group A Streptococcus antigens and superantigens (GAS) have been implicated in the pathogenesis of psoriasis in individuals with genetic predisposition.17,18 In addition, the wounds on the skin caused by the severe itching of psoriatic lesions can promote the establishment of epidermal bacteria in the deep dermis and, in severe cases, into the bloodstream, where the encounter with immune system cells can promote an inflammatory environment and dysbiosis of the skin microbiota.19

These data, therefore, suggest the importance of the study of the skin microbiota of patients with psoriasis to improve the treatment of the disease.20

Gao and colleagues analyzed the microbiome of skin with psoriatic lesions, uninvolved skin, and skin from healthy people.21 The microbial population covering the lesions was more abundant and varied than the healthy skin samples, which were found to be relatively homogeneous. In addition, the lesions had a decrease in Actinobacteria, Proteobacteria, and Propionibacterium and its main human species P. acnes and an increase in Firmicutes, the three main phyla that populate healthy skin.22

Based on sequencing of the 16S rRNA V1-V3 variable region of 28 psoriasis patients and 26 healthy subjects, Chang et al showed that the relative abundance of the Staphylococcus species across all samples is associated with different disease states. They also confirmed that microbial communities in psoriatic lesions display higher heterogeneity but lower stability than healthy skin, associated with an increase of Proteobacteria, Pseudomonas genera, Staphylococcus aureus, and Staphylococcus pettenkoferi, and a reduction of Actinobacteria, Cutibacterium, Ethanoligenens, and Macrococcus genera, Cutibacterium acnes, Cutibacterium granulosum, and Staphylococcus epidermidis.23

On the other hand, Alekseyenko et al, comparing swabs of 54 patients with psoriasis and 37 healthy controls, demonstrated that the microbiome of psoriatic lesions is characterized by taxonomic diversity reduction and an increase of Firmicutes and Actinobacteria.24

Although there are several studies in the literature that have determined the composition of the microbiome of psoriatic skin compared with healthy skin, the results obtained are conflicting, particularly in relation to the variation in the abundances of Firmicutes, Actinobacteria, and Proteobacteria.25

Therefore, further studies are needed to better characterize the microbiome of psoriatic lesions and to establish standardized protocols that take into account hygiene regimen, climate, and cosmetic use, larger sample size, and standardize the amplification region and sampling method.26

연구자들은 중요한 논문에서 설명한 기술을 사용하여 개별 피부 미생물 군집의 복잡성에 대한 새로운 통찰력을 얻었습니다. 

피부 마이크로바이옴은 

매우 다양하고 개별화되어 있을 뿐만 아니라 

피부 부위 내부와 부위 간에도 엄격하게 조절되며 

시간이 지나도 안정적입니다. 

이러한 안정성으로 인해 법의학 연구의 초점이 되어온 개별 미생물 서명 또는 '지문'을 식별할 수 있게 되었으며, 접촉한 표면에서 검색된 미생물 정보를 기반으로 개인을 식별할 수 있게 되었습니다.9

문헌에는 

건선을 포함하여 

손상되거나 병든 피부의 피부 마이크로바이옴과 

건강한 피부와의 상당한 차이에 대한 설명이 있습니다.9 

건선은 

복잡한 병인을 가진 다인자 염증성 질환으로, 

대부분의 경우 은빛 비늘로 덮인 

홍반성 구진과 플라크가 잘 윤곽이 잡힌 형태로 나타납니다. 

건선의 원인은 완전히 명확하지 않으며, 

환경적 유발 요인이 

T세포 매개 염증 반응과 

그에 따른 각질 세포의 과증식을 유발한다는 가설이 있습니다. 

잘 알려진 유발 요인으로는 

쾨브너 현상의 외상, 

일광 화상, 

HIV 감염, 

구진성 건선의 연쇄상구균 감염, 

베타 차단제 또는 ACE 억제제와 같은 약물, 

정서적 스트레스, 

알코올 섭취, 

흡연, 

비만 등이 있습니다.16

https://academic.oup.com/bjd/article-abstract/149/3/530/6635449?redirectedFrom=fulltext

https://journals.lww.com/ijru/fulltext/2019/14001/drug_induced_psoriasis.6.aspx

Drug-Induced Psoriasis : Indian Journal of Rheumatology

문헌 연구에 따르면 

황색 포도상 구균 및 연쇄상 구균을 포함한 

박테리아가 건선 질환을 유발하고 유지할 수 있으며, 

그룹 A 연쇄상 구균 항원 및 슈퍼 항원(GAS)이 

유전적 소인을 가진 개인의 건선 발병에 관여하는 것으로 나타났습니다.17,18 

Staphylococcus aureus and Streptococcus pyogenes

또한 

건선 병변의 심한 가려움증으로 인한 피부 상처는 

표피 박테리아가 진피 깊숙이, 

심한 경우 혈류로 침투하여 

면역계 세포와의 만남이 염증 환경과 피

부 미생물 군집의 이상균총을 촉진할 수 있습니다.19

따라서 

이러한 데이터는 

건선 환자의 피부 미생물총 연구가 

질병 치료를 개선하는 데 중요하다는 것을 시사합니다.20

가오와 동료들은 

건선 병변이 있는 피부, 

건선이 없는 피부, 건

강한 사람의 피부의 미생물군을 분석했습니다.21 

병변을 덮고 있는 미생물군은 

건강한 피부 샘플보다 더 풍부하고 다양했으며 

비교적 동질적인 것으로 밝혀졌습니다. 

또한 

병변에서는 건강한 피부를 구성하는 세 가지 주요 문(門)인 

액티노박테리아, 

프로테오박테리아, 

프로피오니박테리움과 

그 주요 인간 종인 P. acnes가 감소하고 

staphylococcus aureus, 피르미쿠테스(Firmicutes)가 증가한 것으로 나타났습니다.22

Chang 등은 건선 환자 28명과 건강한 피험자 26명의 16S rRNA V1-V3 가변 영역 염기서열 분석을 통해 모든 샘플에서 포도상구균 종의 상대적 풍부도가 다른 질병 상태와 관련이 있음을 보여주었습니다. 또한 건선 병변의 미생물 군집은 건강한 피부보다 이질성은 높지만 안정성은 낮으며, 프로테오박테리아, 슈도모나스 속, 황색포도상구균, 포도상구균 페텐코페리의 증가와 액티노박테리아, 큐티박테리움, 에탄올리게넨, 마크로코커스 속, 큐티박테리움 아세네스, 큐티박테리움 그라눌로섬, 표피포도구균의 감소와 관련이 있음을 확인했습니다.23

한편, 건선 환자 54명과 건강한 대조군 37명의 면봉을 비교한 알렉세이엔코 등은 건선 병변의 마이크로바이옴이 분류학적 다양성이 감소하고 피르미쿠테스와 액티노박테리아가 증가하는 특징이 있다는 것을 입증했습니다.24

건선 피부의 마이크로바이옴 구성을 건강한 피부와 비교한 여러 연구가 있지만, 특히 피르미쿠테스, 액티노박테리아 및 프로테오박테리아의 풍부도 변화와 관련하여 얻은 결과는 상충됩니다.25

따라서 건선 병변의 마이크로바이옴을 더 잘 특성화하고 위생 요법, 기후 및 화장품 사용, 더 큰 샘플 크기, 증폭 영역 및 샘플링 방법을 표준화하는 표준화된 프로토콜을 확립하기 위한 추가 연구가 필요합니다.26

Tobacco Smoke and Cutaneous Microbiome: Their Role in Psoriasis

Environmental factors are extremely important to consider in microbiome analysis. For example, smoking is known to promote the onset and maintenance of psoriasis and to reduce the response to treatment.27

In addition, patients with psoriasis have been known to be four times more likely to smoke. There are currently no specific studies in the literature on the effect of smoking on the skin microbiome and psoriasis.28 However, tobacco smoke is known to alter the lung and gastrointestinal microbiome, leading to a decrease in diversity in composition and favoring the presence of specific bacterial genera such as Bacteroides, Prevotella, Enterobacteria, and Clostridium. Since there is a potential interaction between the gastrointestinal and skin microbiomes, it is conceivable that tobacco smoke may directly and/or indirectly affect the skin microbiome, thereby contributing to the development of psoriasis. This possibility is supported by studies that have shown the presence of impaired gastrointestinal microbiomes in patients with inflammatory dermatoses.29

환경적 요인은 마이크로바이옴 분석에서 고려해야 할 매우 중요한 요소입니다. 

예를 들어, 

흡연은 건

선의 발병과 유지를 촉진하고 

치료에 대한 반응을 감소시키는 것으로 알려져 있습니다.27

또한 건선 환자는 흡연할 가능성이 4배 더 높은 것으로 알려져 있습니다. 흡연이 피부 미생물 군집과 건선에 미치는 영향에 대한 구체적인 연구 결과는 아직 없습니다.28 그러나 담배 연기는 폐와 위장 미생물 군집을 변화시켜 구성의 다양성을 감소시키고 박테로이데스, 프레보텔라, 장내 세균 및 클로스트리디움과 같은 특정 세균 속의 존재에 유리하게 작용하는 것으로 알려져 있습니다. 위장 미생물과 피부 미생물 사이에는 잠재적인 상호 작용이 있기 때문에 담배 연기가 피부 미생물에 직간접적으로 영향을 미쳐 건선 발병에 기여할 수 있다고 생각할 수 있습니다. 이러한 가능성은 염증성 피부질환 환자의 장내 미생물군집이 손상되었다는 연구 결과에 의해 뒷받침됩니다.29

Skin and Gut Microbiome Crosstalk (Figure 1)

Figure 1

Relationship between skin and gut microbiome. Diet and gastrointestinal diseases have an impact on the skin functions. Intestinal dysbiosis increases intestinal permeability and promotes the migration of bacteria, toxins and metabolites into the bloodstream, reaching skin and joints. Skin dyshomeostasis can induce inflammatory skin disease including psoriasis. Probiotics integration may improve skin condition by reducing inflammation, improving the barrier function, modulating immune activation, and hindering the colonization of harmful bacteria.

피부와 장내 미생물 군집의 관계. 

식습관과 위장 질환은 

피부 기능에 영향을 미칩니다. 

장내 미생물 이상증은 

장 투과성을 증가시키고 

박테리아, 독소 및 대사 산물이 혈류로 이동하여 

피부와 관절에 도달하는 것을 촉진합니다. 

피부 항상성 장애는 

건선을 비롯한 염증성 피부 질환을 유발할 수 있습니다. 

프로바이오틱스 통합은 

염증을 줄이고 장벽 기능을 개선하며 

면역 활성화를 조절하고 

유해 박테리아의 군집을 방해하여 피부 상태를 개선할 수 있습니다.

The skin and gut are complex immune and neuroendocrine organs that play a crucial role in maintaining the overall homeostasis and survival of the body.30 The composition of a healthy intestinal microbiome remains relatively stable from a young age and is characterized by the presence of Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, with Firmicutes and Bacteroidetes representing the majority. Gastrointestinal diseases and diet have been shown to have an impact on skin pathologies, as many dermatoses are strongly associated with gastrointestinal diseases.30 However, the precise mechanisms by which the gut microbiome affects skin health are still not fully understood.

Studies in mice have provided insights into the possible mechanisms involved in the relationship between the skin and gut microbiome. Administration of probiotics to mice has been shown to improve integumentary health, increase serum levels of IL-10 (an anti-inflammatory cytokine), and reduce IL-17 levels. Moreover, mice lacking IL-10 did not exhibit any modification of the integumentary system following probiotic administration, further supporting the involvement of IL-10 in the interaction between the skin and gut microbiome, possibly through the modulation of regulatory T cells (Tregs).30 Numerous studies in the literature support the hypothesis of skin-gut crosstalk mediated by the modulation of the immune environment through the microbiota. It has also been demonstrated that the intestinal microbiome can directly influence skin physiology and immune responses by the migration of microbiota and its metabolites to the skin.30

In recent years, there has been a significant increase in metagenomic data due to advances in sequencing technology, particularly in the field of skin microbiome research. The introduction of next-generation sequencing has revolutionized our understanding of the skin microbiome, allowing for a more comprehensive characterization of the diverse range of bacteria that colonize human skin 46. Specifically, the use of 16S rRNA sequencing has greatly expanded our understanding beyond what was previously possible with traditional culture techniques, which only identified about 1% of the cutaneous microbiome. Through 16S rRNA sequencing, a large international effort was able to chart the human microbiome by sampling diverse body habitats.

In cases where the intestinal barrier is compromised, the intestinal microbiota can enter the bloodstream and accumulate in the skin, leading to alterations. This hypothesis was supported by the detection of intestinal bacterial DNA in the plasma of patients with psoriasis.31

Literature studies have assessed the association between gut microbiome alterations and psoriasis. Chen et al observed an increase in Firmicutes and a decrease in Bacteroidetes in the intestines of psoriatic patients compared to control patients.32 Similar findings were reported by Huang et al, who found increased abundance of Firmicutes, Proteobacteria, and Actinobacteria, along with a decrease in Bacteroidetes in the gut microbiome of psoriatic patients.33 Scher et al eval‎uated gut microbiota alterations in patients with psoriatic arthritis and psoriasis and found a reduction in microbiota biodiversity and specific bacterial genera, such as Akkermansia, Ruminococcus, and Pseudobutyrivibrio, compared to healthy controls. The dysbiosis observed in these patients was associated with higher levels of secretory immunoglobulin A (sIgA) and a reduction in RANKL levels in the gut lumen of psoriatic arthritis patients.34 The authors speculated that the reduction of RANKL in PsA patients may be a response to the specific composition of the intestinal bacterial community.

Yu and colleagues investigated the causal relationship between gut microbiota and psoriasis and PsA using genome-wide association study (GWAS) data. Mendelian randomization analysis revealed that certain types of intestinal flora, including Lactococcus, Ruminiclostridium 5 and E. fissicatena are risk factors for psoriasis, while Odoribacter has shown a protective effect. The authors highlight a distinct set of risk and protective factors for PsA, despite it being a complication of psoriasis. In fact, Lactococcus, Verrucomicrobiales, Akkermansia, Coprococcus 1 and Verrucomicrobiaceae were found to be risk factors, while Odoribacter and Rikenellaceae have protective action against the development of PsA.35

Moreover, Zang and colleagues conducted two-sample Mendelian randomization study and observed that Bacteroidete and Prevotella 9 and Bacteroidia, Bacteroidales, and Ruminococcaceae UCG002 have protective action in psoriasis and PsA, respectively. The phylum Bacteroidetes is capable of producing short-chain fatty acids (SCFAs) that have anti-inflammatory activity and are reduced in psoriasis and PsA. On the other hand, Pasteurellales, Pasteurellaceae, Blautia, Methanobrevibacter, and Eubacterium fissicatena are risk factors for PsA, while E. fissicatena results as a risk factor for psoriasis after FDR correction.36

피부와 장은 

신체의 전반적인 항상성과 생존을 유지하는 데 중요한 역할을 하는 

복잡한 면역 및 신경 내분비 기관입니다.30 

건강한 장내 미생물의 구성은 

어릴 때부터 비교적 안정적으로 유지되며 

펌리쿠테스, 박테로이드테스, 액티노박테리아, 프로테오박테리아, 푸소박테리아 및 베루코마이크로바이러스가 존재하며 

펌리쿠테스와 박테로이드테스가 

대부분을 차지하는 것이 특징입니다. 

많은 피부병이 위장 질환과 밀접한 관련이 있기 때문에 

위장 질환과 식단이 피부 병리에 영향을 미치는 것으로 나타났습니다.30 

그러나 

장내 미생물이 피부 건강에 영향을 미치는 정확한 메커니즘은 아직 완전히 이해되지 않았습니다.

생쥐를 대상으로 한 연구를 통해 피부와 장내 미생물군집 사이의 관계에 관여하는 가능한 메커니즘에 대한 통찰력을 얻었습니다. 생쥐에게 프로바이오틱스를 투여하면 외피 건강이 개선되고, IL-10(항염증 사이토카인)의 혈청 수치가 증가하며, IL-17 수치가 감소하는 것으로 나타났습니다. 또한, IL-10이 결핍된 생쥐는 프로바이오틱스 투여 후 외피 시스템에 어떠한 변화도 보이지 않았으며, 이는 아마도 조절 T 세포(Treg)의 조절을 통해 피부와 장내 미생물군집 간의 상호작용에 IL-10이 관여하는 것을 뒷받침합니다.30 수많은 문헌 연구에서 미생물군을 통한 면역 환경의 조절이 매개하는 피부-장내 교차 가설을 뒷받침하고 있습니다. 또한 장내 미생물이 피부로 이동하여 미생물과 그 대사산물이 피부 생리와 면역 반응에 직접적인 영향을 미칠 수 있음이 입증되었습니다.30

최근에는 특히 피부 마이크로바이옴 연구 분야에서 시퀀싱 기술의 발전으로 메타게놈 데이터가 크게 증가하고 있습니다. 차세대 시퀀싱의 도입으로 피부 미생물 군집에 대한 이해가 혁신적으로 발전하여 인간의 피부에 서식하는 다양한 박테리아를 보다 포괄적으로 특성화할 수 있게 되었습니다46. 특히 16S rRNA 시퀀싱의 사용은 피부 미생물의 약 1%만 식별할 수 있었던 기존 배양 기술로는 불가능했던 이해의 폭을 크게 넓혔습니다. 16S rRNA 시퀀싱을 통해 다양한 신체 서식지를 샘플링하여 인간 마이크로바이옴을 도표화할 수 있는 대규모 국제적 노력이 이루어졌습니다.

장 장벽이 손상된 경우 장내 미생물이 혈류로 유입되어 피부에 축적되어 변화를 일으킬 수 있습니다. 이 가설은 건선 환자의 혈장에서 장내 박테리아 DNA가 검출됨으로써 뒷받침되었습니다.31

문헌 연구에서는 장내 미생물군집 변화와 건선 사이의 연관성을 평가했습니다. Chen 등은 건선 환자의 장내에서 대조군 환자에 비해 피르미쿠테스균이 증가하고 박테로이데테스균이 감소하는 것을 관찰했습니다.32 Huang 등은 건선 환자의 장내 미생물에서 피르미쿠테스균, 프로테오박테리아, 액티노박테리아의 풍부도가 증가하고 박테로이데테스균은 감소한다는 유사한 결과를 보고한 바 있습니다.33 Scher 등은 건선성 관절염과 건선 환자의 장내 미생물총 변화를 평가한 결과 건강한 대조군에 비해 미생물총 생물 다양성과 아커만시아, 루미노코커스, 슈도부티리비브리오 같은 특정 세균 속이 감소한 것을 발견했습니다. 이러한 환자에서 관찰된 이상균총은 건선성 관절염 환자의 장 내강에서 더 높은 수준의 분비성 면역글로불린 A(sIgA) 및 RANKL 수치 감소와 관련이 있었습니다.34 저자는 건선성 관절염 환자의 RANKL 감소가 장내 세균 군집의 특정 구성에 대한 반응일 수 있다고 추측했습니다.

Yu와 동료들은 게놈 전체 연관성 연구(GWAS) 데이터를 사용하여 장내 미생물과 건선 및 PsA 사이의 인과 관계를 조사했습니다. 멘델 무작위 배정 분석 결과 락토코커스, 루미클로스트리디움 5, E. 피시카테나 등 특정 유형의 장내 세균총이 건선의 위험 요인인 반면, 오도리박터는 보호 효과가 있는 것으로 나타났습니다. 저자는 건선의 합병증임에도 불구하고 건선에는 뚜렷한 위험 및 보호 요인이 있다고 강조합니다. 실제로 락토코커스, 베루코마이크로바이알레스, 아커만시아, 코프로코커스 1, 베루코마이크로바이아과가 위험 요인으로 밝혀진 반면, 오도리박터와 리케넬라과가 PsA 발병에 대한 보호 작용을 하는 것으로 나타났습니다.35

또한, 장과 동료들은 두 개의 샘플 멘델 무작위 배정 연구를 수행하여 박테로이데테와 프레보텔라 9, 박테로이디아, 박테로이데아과, 루미노코카세과 UCG002가 각각 건선과 PsA에서 보호 작용을 하는 것을 관찰했습니다. 박테로이데테스 문은 항염증 작용을 하는 단쇄 지방산(SCFA)을 생산할 수 있으며 건선 및 건선성 건선(PsA)에서 감소합니다. 반면, 파스튜렐라균, 파스튜렐라과, 블라우티아균, 메타노브레비박터균, 유박테리움 피시카테나는 건선의 위험 인자이며, E. 피시카테나는 FDR 보정 후 건선의 위험 인자로 작용합니다.36

Probiotics and Effects on Skin

Several studies have demonstrated that probiotic intake can improve skin barrier integrity and reduce signs of reactive skin inflammation in mice.37 For instance, supplementation with Lactobacillus johnsonii protected glabrous mice from UV-induced contact hypersensitivity by reducing epidermal Langerhans cells and increasing systemic levels of IL-10.38 Similar protective effects were observed in a clinical trial with healthy volunteers after UV exposure, where intake of Lactobacillus johnsonii La1 normalized epidermal CD1A expression‎ and maintained skin immune homeostasis.38

There are few clinical trials exploring the use of probiotics for the prevention and treatment of dermatological diseases, with the exception of atopic dermatitis. Most studies investigating probiotic interventions are oral, and of those that use topical probiotics, few include skin commensals. Generally, available clinical trials show positive results with improvements in skin conditions following probiotic intervention.

Oral and topical probiotics show promise in the treatment of specific inflammatory skin conditions and may have a beneficial effect on wound healing and skin cancer. Nevertheless, further research is required to verify these findings.

Although studies investigating the role of probiotics in psoriasis are lacking, there is some evidence that probiotics may have beneficial immunoregulatory effects by reducing inflammation. For example, in one study, oral administration of Bifidobacterium infantis for 8 weeks led to significantly decreased levels of inflammatory C-reactive protein and tumor necrosis factor-A in patients with psoriasis. However, it remains unclear whether this was accompanied by clinical improvements. In a mouse model of psoriasis, oral administration of Lactobacillus pentosus GMNL-77 reduced tumor necrosis factor-A and IL23-IL-17 axis cytokines, which was associated with decreased erythematous scaling lesions. Further research exploring the role of the microbiome and its modulation as a therapy in psoriasis would be a valuable complement to the many ongoing immunological treatment studies.

Fecal microbiota transplantation (FMT) has gained popularity in the past decade. Although FMT has mainly been used to treat gastrointestinal diseases, a few studies have explored its potential therapeutic benefits in psoriasis as well.39 One study reported significant improvement in severe plaque psoriasis and irritable bowel syndrome in a patient treated with FMT.40 Another study transplanted fecal microbiota from psoriatic patients and healthy individuals into mouse models of psoriasis and observed delayed recovery of psoriatic dermatitis and higher levels of IL-17A in mice receiving psoriatic microbiota.41 These findings suggest that FMT may hold promise as a therapeutic option for psoriasis, but further research is needed.42

Molecular studies in psoriatic patients have revealed biomarkers of an altered intestinal barrier, including higher levels of claudin-3 and intestinal fatty acid-binding protein.42 Integration of probiotics has shown improvements in psoriasis by increasing TNF-α expression‎, enhancing barrier function, and regulating the NF-kβ pathway involved in psoriasis pathogenesis.43,44

여러 연구에 따르면 

프로바이오틱스 섭취가 

피부 장벽을 개선하고 

생쥐의 반응성 피부 염증의 징후를 줄일 수 있다는 사실이 입증되었습니다.37 

예를 들어, 

락토바실러스 존소니를 보충하면 

표피 랑게르한스 세포가 감소하고 

전신 IL-10 수치가 증가하여 자외선에 의한 접촉 과민증으로부터 피부가 벗겨진 마우스를 보호했습니다.38 

건강한 지원자를 대상으로 한 임상 시험에서 

자외선 노출 후 락토바실러스 존소니 La1을 섭취한 경우 표피 CD1A 발현이 정상화되고 피부 면역 항상성이 유지되는 유사한 보호 효과가 관찰되었습니다.38

아토피성 피부염을 제외하고 

피부과 질환의 예방 및 치료에 프로바이오틱스를 사용하는 

임상시험은 거의 없습니다. 

프로바이오틱스 개입을 조사하는 대부분의 연구는 경구용이며, 국소용 프로바이오틱스를 사용하는 연구 중 피부용을 포함하는 연구는 거의 없습니다. 일반적으로 이용 가능한 임상 시험은 프로바이오틱스 개입 후 피부 상태가 개선되는 긍정적인 결과를 보여줍니다.

경구용 및 국소용 프로바이오틱스는 특정 염증성 피부 질환의 치료에 유망하며 상처 치유와 피부암에 유익한 효과를 나타낼 수 있습니다. 하지만 이러한 결과를 검증하기 위해서는 추가 연구가 필요합니다.

건선에서 프로바이오틱스의 역할을 조사한 연구는 부족하지만, 

프로바이오틱스가 염증을 감소시켜 

유익한 면역 조절 효과를 가질 수 있다는 증거가 일부 있습니다. 

예를 들어, 한 연구에서 8주 동안 비피도박테리움 인판티스를 경구 투여한 결과 건선 환자의 염증성 C반응성 단백질과 종양 괴사인자-A 수치가 유의하게 감소한 것으로 나타났습니다. 그러나 이것이 임상적 개선을 동반했는지는 아직 명확하지 않습니다. 건선 마우스 모델에서 락토바실러스 펜토서스 GMNL-77의 경구 투여는 종양괴사인자-A와 IL23-IL-17 축 사이토카인을 감소시켰으며, 이는 홍반성 비늘 병변 감소와 관련이 있는 것으로 나타났습니다. 건선 치료제로서 마이크로바이옴의 역할과 그 조절을 탐구하는 추가 연구는 현재 진행 중인 많은 면역학적 치료 연구를 보완할 수 있는 귀중한 자료가 될 것입니다.

분변 미생물군 이식(FMT)은 

지난 10년 동안 인기를 얻었습니다. 

FMT는 

주로 위장 질환 치료에 사용되어 왔지만, 

몇몇 연구에서 건선에서도 잠재적인 치료 효과를 탐색했습니다.39 

한 연구에서는 

FMT로 치료받은 환자의 중증 판상 건선과 

과민성 대장 증후군이 크게 개선되었다고 보고했습니다.40 

또 다른 연구에서는 

건선 환자와 건강한 사람의 대변 미생물을 건선 마우스 모델에 이식한 결과 건선 미생물을 이식한 마우스에서 건선 피부염의 회복이 지연되고 IL-17A 수치가 높아지는 것을 관찰했습니다.41 이러한 결과는 FMT가 건선 치료 옵션으로서 가능성이 있음을 시사하지만 추가 연구가 필요합니다.42

건선 환자를 대상으로 한 분자 연구에서 

클라우딘-3 및 장 지방산 결합 단백질 수치가 높아지는 등 

장 장벽의 변화된 바이오마커가 밝혀졌습니다.42 

프로바이오틱스의 통합은 

TNF-α 발현을 증가시키고 

장벽 기능을 강화하며 

건선 발병에 관여하는 NF-kβ 경로를 조절하여 

건선을 개선하는 것으로 나타났습니다.43,44

Conclusions

Dermatologic conditions such as atopic dermatitis, acne, psoriasis, and rosacea have been associated with intestinal dysbiosis. The skin microbiota composition is crucial for the development of appropriate immune responses, and alterations in the skin microbiome can contribute to changes in physiology and susceptibility to skin diseases or inflammatory conditions. Understanding the microbial settlement of the skin and the network of interactions that occur throughout life is essential for comprehending the pathogenesis of skin diseases and developing innovative treatments. Collecting data on the skin microbiome can aid in monitoring skin conditions, predicting disease onset, and selecting appropriate therapeutic approaches.

The role of the microbiota and its metabolic activity in psoriasis is gaining importance and may lead to the identification of crucial psoriatic biomarkers and the development of new therapeutic approaches. However, larger clinical studies with standardized methodologies are necessary to fully understand the role of the cutaneous microbiota and microbial pathways in psoriasis.

Probiotics have demonstrated an important role in promoting a healthy microbiome by reducing inflammation, modulating immune activation, and inhibiting the colonization of harmful bacteria. However, long-term safety data on probiotic use are limited, and caution is warranted, particularly in immunocompromised individuals who may be at risk of infections and serious side effects. Combination therapies involving phage or antibiotics may hold promise for microbiome replacement strategies and should be further explored.

In conclusion, there is a need for further research to fully understand the role of the microbiome in the development and treatment of diseases. Basic research and epidemiological studies are needed to identify the specific microbiota associated with disease and their mechanisms of action. Clinical trials with larger samples and greater power are necessary to establish the safety and efficacy of probiotic interventions, including identifying optimal species combinations, doses, and treatment durations. Additionally, exploring combination therapy with phages or antibiotics may provide promising results for microbiome replacement strategies. Overall, continued research in this field may lead to the development of new diagnostic and therapeutic opportunities for a range of diseases.

아토피 피부염, 여드름, 건선, 주사비와 같은 

피부과 질환은 

장내 미생물 이상증과 관련이 있습니다. 

피부 미생물 구성은 

적절한 

면역 반응의 발달에 매우 중요하며, 

피부 미생물 군집의 변화는 

피부 질환이나 염증 상태에 대한 생리학 및 감수성의 변화에 기여할 수 있습니다. 

피부의 미생물 정착과 일생 동안 발생하는 상호 작용 네트워크를 이해하는 것은 피부 질환의 발병 기전을 이해하고 혁신적인 치료법을 개발하는 데 필수적입니다. 피부 미생물군에 대한 데이터를 수집하면 피부 상태를 모니터링하고 질병 발병을 예측하며 적절한 치료법을 선택하는 데 도움이 될 수 있습니다.

건선에서 미생물의 역할과 그 대사 활동은 점점 더 중요해지고 있으며, 중요한 건선 바이오마커의 확인과 새로운 치료 접근법의 개발로 이어질 수 있습니다. 그러나 건선에서 피부 미생물총과 미생물 경로의 역할을 완전히 이해하려면 표준화된 방법론을 사용한 대규모 임상 연구가 필요합니다.

프로바이오틱스는 

염증을 줄이고 

면역 활성화를 조절하며 

해로운 박테리아의 군집을 억제하여 

건강한 미생물 군집을 촉진하는 데 중요한 역할을 하는 것으로 입증되었습니다. 

그러나 

프로바이오틱스 사용에 대한 장기 안전성 데이터는 제한적이며, 

특히 감염 및 심각한 부작용의 위험이 있는 

면역력이 저하된 사람의 경우 주의가 필요합니다. 

파지 또는 항생제를 포함하는 병용 요법은 마이크로바이옴 대체 전략에 대한 가능성을 제시할 수 있으며, 이에 대한 추가 연구가 필요합니다.

결론적으로, 

질병의 발병과 치료에서 

마이크로바이옴의 역할을 완전히 이해하기 위한 

추가 연구가 필요합니다. 

질병과 관련된 특정 마이크로바이옴과 

그 작용 메커니즘을 파악하기 위해서는 

기초 연구와 역학 연구가 필요합니다. 

최적의 종 조합, 용량 및 치료 기간을 확인하는 등 프로바이오틱스 개입의 안전성과 효능을 입증하기 위해서는 더 많은 샘플과 더 큰 규모의 임상시험이 필요합니다. 또한, 파지 또는 항생제와의 병용 요법을 탐색하면 마이크로바이옴 대체 전략에 대한 유망한 결과를 얻을 수 있습니다. 전반적으로 이 분야에 대한 지속적인 연구는 다양한 질병에 대한 새로운 진단 및 치료법의 개발로 이어질 수 있습니다.

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Disclosure

The authors report no conflicts of interest in this work.

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