【樂的次元】

找腸漏症文獻的時候，發現 Gut - Brain - Skin Axis的話題

但是大部分資料都在講Gut Brain, Gut-skin的卻很少...

最近終於找到這篇專門說Gut-Skin的，整合很多資訊，也有提到很多益生箘種類的測試結果

特意貼在這邊給大家參考，原文是英文，連結點標題就有

訊息很長，還有很多表格跟輔助圖我沒貼過來，良心建議自己去原網站爬文

我只是逐段用谷歌翻譯，併貼在ㄧ起方便閱讀

因為實在信息量有點大，有些英文專有名詞我也得看中文才能有直接反應:P

最近發現我濕疹文點閱率總是有細微增長，真是頗欣慰

不愧我花這麼多時間整理資料，還是能幫助到ㄧ些人

希望能讓越來越多人重視腸道健康，也能讓有濕疹困擾的人能對症下藥～

補充：Atopic Dermatitis(AD)就是濕疹Eczema嚕～

記得要去原文連結，有很多紀錄各種益生箘的研究測試結果

Gut-Skin Axis （中英翻譯）

The Gut Microbiome as a Major Regulator of the Gut-Skin Axis 

（圖表都在原文連結喔！請點上面進去看）

Abstract

The adult intestine hosts a myriad of diverse bacterial species that reside mostly in the lower gut maintaining a symbiosis with the human habitat. In the current review, we describe the neoteric advancement in our comprehension of how the gut microbiota communicates with the skin as one of the main regulators in the gut-skin axis. We attempted to explore how this potential link affects skin differentiation and keratinization, its influence on modulating the cutaneous immune response in various diseases, and finally how to take advantage of this communication in the control of different skin conditions.

抽象

成年腸道內有無數種多樣的細菌，它們大多位於下消化道中，與人類的棲息地保持共生。在當前的綜述中，我們描述了腸道菌群如何與皮膚作為腸道皮膚軸主要調節因子之一進行交流的最新進展。我們試圖探索這種潛在的聯繫如何影響皮膚分化和角質化，其對調節各種疾病中皮膚免疫反應的影響，以及最終如何在控制不同皮膚狀況時利用這種交流。

Keywords: gut microbiome, skin homeostasis, acne vulgaris, atopic dermatitis, psoriasis, probiotics

關鍵詞：腸道微生物組，皮膚穩態，尋常痤瘡，特應性皮炎，牛皮癬，益生菌

Introduction

The gut and skin, densely vascularized and richly innervated organs with crucial immune and neuroendocrine roles, are uniquely related in purpose and function (O’Neill et al., 2016). As our primary interface with the external environment, both organs are essential to the maintenance of physiologic homeostasis. Cumulative evidence has demonstrated an intimate, bidirectional connection between the gut and skin, and numerous studies link gastrointestinal (GI) health to skin homeostasis and allostasis (Figure 1) (Levkovich et al., 2013; O’Neill et al., 2016). GI disorders are often accompanied by cutaneous manifestations and the GI system, particularly the gut microbiome, appears to participate in the pathophysiology of many inflammatory disorders (Shah et al., 2013; Thrash et al., 2013; Gloster et al., 2016). In this review, we will discuss the gut microbiome’s contribution to three common skin disorders – acne, atopic dermatitis (AD), and psoriasis – (Figure 1) as well as review data on how the microbiome’s influence can be harnessed for therapeutic purpose via probiotic supplementation.

介紹

腸道和皮膚是具有重要的免疫和神經內分泌作用的密集血管化和神經支配的器官，在目的和功能上有著獨特的聯繫（O’Neill等人，2016）。作為我們與外部環境的主要接口，兩個器官對於維持生理穩態都是必不可少的。累積的證據表明腸道和皮膚之間存在密切的雙向聯繫，並且許多研究將胃腸道（GI）健康與皮膚穩態和同種異體聯繫聯繫起來（圖11）（Levkovich等，2013; O'Neill等，2016）。 ）。胃腸道疾病常伴有皮膚表現，並且胃腸道系統，尤其是腸道微生物組，似乎參與了許多炎症性疾病的病理生理（Shah等人，2013; Thrash等人，2013; Gloster等人，2016） 。在這篇綜述中，我們將討論腸道微生物組對三種常見皮膚疾病-痤瘡，特應性皮炎（AD）和牛皮癬-的貢獻（圖圖11），以及有關如何通過微生物組將其用於治療目的的綜述數據。益生菌補充。

Gut Microbial Ecology

Our gut microbiome is a vast collection of bacteria, viruses, fungi, and protozoa colonizing our GI system (Ipci et al., 2017). This collection of microbes outnumbers host cells 10-fold and contains genetic material 150 times greater than the host’s own karyosome (Wu and Lewis, 2013; Ipci et al., 2017). Recent advances in metagenomics and the advent of high-throughput DNA-sequencing technology has enhanced our understanding of the microbiome and its dynamic influence on human health and pathology (Boyle et al., 2011; Moore-Connors et al., 2016).

The intestinal microbiome provides important metabolic and immune benefits to the host. Gut flora contribute to the breakdown of indigestible complex polysaccharides and are vital to the production of certain nutritional components such as vitamin K. The gut microbiome’s influence on the host immune system is vast, and the relationship is intricately regulated to both enable immune tolerance of dietary and environmental antigens and provide protection against potential pathogens. The intestinal microbiome protects against invasion by exogenous pathogens directly, by competitively binding to epithelial cells, and indirectly, by triggering immunoprotective responses (Boyle et al., 2011; Kosiewicz et al., 2014).

Commensal bacteria prime the gut immune system through specific interactions between bacterial antigens and pattern recognition receptors expressed by a variety of host cells (Kosiewicz et al., 2014). For example, gut microbes are a source of peptidoglycan capable of altering the expression of toll-like receptors (TLRs), pattern recognition receptors on the surface of many innate immune cells. TLRs recognize pathogen associated molecular patterns and trigger cascades of events linking the innate to the adaptive immune system through the activation of the nuclear factor kappa B (NF-κB) signaling pathway (Macpherson and Harris, 2004; Clarke et al., 2010; Thomas and Versalovic, 2010; Boyle et al., 2011; Kosiewicz et al., 2014). The contribution of the gut microbiome to the adaptive immune system has been well-characterized and involves the induction of immunoglobulin A and the maintenance of homeostasis between effector T cells (Th1, Th2, and Th17) and regulatory T cells (Kosiewicz et al., 2014). Certain microbes can also contribute to intestinal epithelial barrier function via “cross-talk” with elements of mucosal immunity (Bik, 2009; Purchiaroni et al., 2013; Kosiewicz et al., 2014; Rajilić-Stojanović and de Vos, 2014; Sirisinha, 2016). For instance, one commensal gut microbe, Lactobacillus LGG, secretes p40, a protein capable of suppressing cytokine-mediated apoptosis and epithelial barrier disruption. Another species, Escherichia coli Nissle, contains flagella capable of inducing β-defensin 2 in epithelial cells (Kosiewicz et al., 2014).

Many human and animal studies suggest that the intestinal microbiome’s influence extends beyond the gut, and in fact contributes to the function, and dysfunction, of distant organ systems (Levkovich et al., 2013; Kim Y.G. et al., 2014). Short chain fatty acids (SCFAs), products of dietary fibers fermented by components of the gut microbiome, demonstrate a protective role against the development of inflammatory disorders including arthritis and allergy, in addition to colitis (Kim Y.G. et al., 2014). Intestinal dysbiosis, in the form of unbalanced bacterial composition or aberrant immune reactions to commensal flora, has been linked to metabolic, neurodegenerative, and neoplastic diseases. Altered gut flora may favor the production of effector over regulatory T cells, thereby contributing to the development of autoimmune disorders. For example, segmented filamentous bacteria in the gut have been associated with a variety of Th17-mediated diseases. Through mechanisms not yet completely understood, the gut microbiome’s influence clearly extends beyond the GI system. One distant organ known to have a particularly complex connection with the gut is the skin (Levkovich et al., 2013; Kim Y.G. et al., 2014; Kosiewicz et al., 2014).

腸道微生物生態學

我們的腸道微生物組是細菌，病毒，真菌和原生動物的大量集合，這些細菌定植在我們的GI系統中（Ipci等人，2017）。這種微生物的數量是宿主細胞的10倍，其遺傳物質比宿主自身的核體大150倍（Wu和Lewis，2013; Ipci等人，2017）。宏基因組學的最新進展以及高通量DNA測序技術的出現，加深了我們對微生物組及其對人體健康和病理學的動態影響的理解（Boyle等人，2011; Moore-Connors等人，2016）。

腸道微生物組為宿主提供重要的代謝和免疫益處。腸道菌群會導致難以消化的複雜多醣分解，並且對某些營養成分（例如維生素K）的產生至關重要。腸道微生物組對宿主免疫系統的影響巨大，並且這種關係被複雜地調節以使飲食具有免疫耐受性和環境抗原，並提供針對潛在病原體的保護。腸道微生物組可直接競爭性地與上皮細胞結合，並通過觸發免疫保護反應間接地抵禦外源性病原體的入侵（Boyle等人，2011; Kosiewicz等人，2014）。

共生細菌通過細菌抗原與多種宿主細胞表達的模式識別受體之間的特異性相互作用來激發腸道免疫系統（Kosiewicz等人，2014）。例如，腸道微生物是肽聚醣的來源，能夠改變許多先天免疫細胞表面上的toll樣受體（TLR），模式識別受體的表達。 TLR識別病原體相關的分子模式，並通過激活核因子kappa B（NF-κB）信號通路激活將先天與免疫系統聯繫起來的事件級聯（Macpherson和Harris，2004; Clarke等人，2010; Thomas和Versalovic，2010; Boyle等，2011; Kosiewicz等，2014）。腸道微生物組對適應性免疫系統的貢獻已被很好地表徵，包括誘導免疫球蛋白A以及維持效應T細胞（Th1，Th2和Th17）與調節性T細胞之間的體內平衡（Kosiewicz等， 2014）。某些微生物還可以通過與粘膜免疫成分的``串擾''來促進腸道上皮屏障功能（Bik，2009; Purchiaroni等，2013; Kosiewicz等，2014;Rajilić-Stojanović和de Vos，2014; Sirisinha ，2016）。例如，一種常見的腸道微生物Lactobacillus LGG分泌一種能夠抑制細胞因子介導的細胞凋亡和上皮屏障破壞的蛋白質p40。另一種大腸桿菌（Escherichia coli Nissle）含有鞭毛，能夠在上皮細胞中誘導β-防禦素2（Kosiewicz等人，2014）。

許多人類和動物研究表明，腸道微生物組的影響範圍超出了腸道，實際上是導致遠處器官系統功能失調的原因（Levkovich等，2013; Kim Y.G.等，2014）。短鏈脂肪酸（SCFA）是通過腸道微生物組的成分發酵而成的膳食纖維產品，除結腸炎外，還表現出對炎症性疾病發展的保護作用，包括關節炎和過敏症（Kim Y.G. et al。，2014）。腸道營養不良以細菌組成失衡或對共生菌群的免疫反應異常的形式，已與代謝性疾病，神經退行性疾​​病和腫瘤性疾病有關。腸道菌群改變可能比調節性T細胞更傾向於效應子的產生，從而促進自身免疫性疾病的發展。例如，腸道中分段的絲狀細菌已與多種Th17介導的疾病相關。通過尚未完全了解的機制，腸道微生物組的影響力顯然超出了胃腸道系統。已知與腸道有特別複雜聯繫的一個遠處器官是皮膚

Role of the Gut Microbiome in Skin Homeostasis

The skin effectively performs its functions – protection, temperature regulation, water retention, and more – when in a state of homeostasis. As an organ undergoing constant renewal, effective epidermal turnover, the process by which the skin regenerates itself, is essential to maintaining this state. Epidermal cells originate from stem cells in the basal layer of the epidermis and then undergo morphologic change while migrating to the skin surface. Cells differentiate into three cell types – basal cells, spinous cells, and granule cells – before ultimately becoming the corneocytes that make up the outermost layer of the epidermis, the stratum corneum. This process of epidermal differentiation, also referred to as keratinization, is under the control of dedicated transcriptional programs. For example, the expression of KRT5/K5 and KRT14, the genes which encode keratin 5 and keratin 14, respectively, is downregulated as migrating cells move outward, while the expression of genes encoding KRT1 and KRT10 is upregulated (Baba et al., 2012; Weaver et al., 2013; Gaur et al., 2014; Abhishek et al., 2016). Ultimately, this highly regulated process results in a stratum corneum consisting of approximately 15 layers of densely keratinized, stratified, and anucleated corneocytes held together with multiple lipid bilayers in a “brick and mortar” model. The corneocytes serve as the bricks, while ceramides, cholesterol, fatty acids, and cholesterol esters make up the mortar that holds the bricks together. When epidermal turnover functions appropriately, the resulting brick and mortar structure serves as an effective skin barrier with the ability to limit evaporation, preserve skin moisture, and protect from invasion by foreign organisms and substances (Baba et al., 2012; Weaver et al., 2013; Gaur et al., 2014). Through its influence on the signaling pathways that coordinate this process essential to skin homeostasis, the gut microbiome impacts integumentary health (O’Neill et al., 2016).

Though not yet fully explored, the mechanisms by which intestinal microbiota exert their influence on skin homeostasis appear to be related to the modulatory effect of gut commensals on systemic immunity (O’Neill et al., 2016). Certain gut microbes and metabolites – retinoic acid, polysaccharide A from Bacteroides fragilis, Faecalibacterium prausnitzii, and bacteria belonging to Clostridium cluster IV and XI promote the accumulation of regulatory T cells, lymphocytes which facilitate anti-inflammatory responses (Forbes et al., 2015). Segmented filamentous bacteria, alternatively, promote the accumulation of pro-inflammatory Th17 and Th1 cells. SCFAs, particularly butyrate, suppress immune responses by inhibiting inflammatory cells’ proliferation, migration, adhesion, and cytokine production. In addition, through their inhibition of histone deacetylase and inactivation of NF-κB signaling pathways, SCFAs regulate both the activation and apoptosis of immune cells. The inhibition of histone deacetylase promotes the proliferation of regulatory cells involved in various cutaneous physiologic functions including regulation of hair follicle stem cell differentiation and wound healing (Meijer et al., 2010; Loser and Beissert, 2012; Samuelson et al., 2015). In addition, there is new evidence that the intestinal microbiome may impact cutaneous physiology, pathology, and immune response more directly, through the metastasis of gut microbiota and their metabolites to the skin (Samuelson et al., 2015; O’Neill et al., 2016). In cases of disturbed intestinal barriers, intestinal bacteria as well as intestinal microbiota metabolites have been reported to gain access to the bloodstream, accumulate in the skin, and disrupt skin homeostasis (O’Neill et al., 2016). DNA of intestinal bacteria has been successfully isolated from the plasma of psoriatic patients (O’Neill et al., 2016). These findings represent evidence of a more direct link between the gut microbiome and cutaneous homeostasis that has just begun to be explored.

The gut microbiome appears to influence the skin microbiome as well. SCFAs resulting from fiber fermentation in the gut – propionate, acetate, and butyrate – are believed to play a pivotal role in determining the predominance of certain skin microbiomic profiles which subsequently influence cutaneous immune defense mechanisms. Propionibacterium, for example, is a genus capable of producing SCFAs, predominantly acetate and propionic acid. Propionic acid can exhibit a profound antimicrobial effect against USA300, the most prevailing community-acquired methicillin-resistant Staphylococcus aureus (Shu et al., 2013; Samuelson et al., 2015; Schwarz et al., 2017). S. epidermidis and P. acnes are examples of cutaneous commensals known to tolerate wider SCFA shifts than other flora. Altogether, these findings provide supportive evidence for a functional interactive mechanism between gut and skin.

The beneficial effects of gut bacteria on skin health and appearance have been documented in several rodent and human studies 

 In a study by Levkovich et al. (2013), mice who received Lactobacillus reuteri supplementation experienced increased dermal thickness, enhanced folliculogenesis, and increased sebocyte production which manifested as thicker, shinier fur. In another rodent study, Horii et al. (2014) reported that oral supplementation of Lactobacillus brevis SBC8803 in rats resulted in decreased cutaneous arterial sympathetic nerve tone and increased cutaneous blood flow, possibly via increased serotonin release from intestinal enterochromaffin cells and subsequent activation of parasympathetic pathways. A significant decrease in transepidermal water loss (TEWL), a marker of skin barrier function, was noted as well (Horii et al., 2014). This effect was reproduced in human clinical research. After taking L. brevis SBC8803 oral supplements for 12 weeks, human subjects had significantly decreased TEWL and significantly increased corneal hydration (Ogawa et al., 2016). In a separate placebo-controlled human study, bacterial supplementation was shown to have a positive effect on skin barrier function (Guéniche et al., 2013). Volunteers who took Lactobacillus paracasei NCC2461 supplements for 2 months had decreased skin sensitivity and TEWL, an effect attributed to an observed increase in circulating transforming growth factor beta (TGF-β), a cytokine known to have a favorable effect on barrier integrity (Guéniche et al., 2013; O’Neill et al., 2016). A study by Baba et al. (2006) found that when Lactobacillus helveticus-fermented milk whey was introduced to human epidermal keratinocyte cultures, there was increased expression of keratin 10 and involucrin, markers of early and late differentiation, respectively, suggesting that L. helveticus can promote epidermal differentiation. In addition, there was a dose-dependent increase in profilaggrin, a protein involved in the terminal differentiation of keratinocytes. Profilaggrin is ultimately cleaved to form filaggrin (FLG), a protein essential to normal epidermal flexibility and hydration, suggesting a potential moisturizing benefit of this bacteria as well (Baba et al., 2006).

腸道微生物組在皮膚穩態中的作用

處於體內平衡狀態時，皮膚可有效執行其功能-保護，調節溫度，保水等。隨著器官不斷更新，有效的表皮更新，皮膚自身再生的過程對於維持這種狀態至關重要。表皮細胞起源於表皮基底層的干細胞，然後在遷移到皮膚表面時發生形態變化。在最終成為構成表皮最外層即角質層的角質細胞之前，細胞可分化為三種細胞類型-基底細胞，棘細胞和顆粒細胞。表皮分化的過程，也稱為角質化，處於專用轉錄程序的控制之下。例如，隨著遷移細胞向外移動，分別編碼角蛋白5和角蛋白14的基因KRT5 / K5和KRT14的表達下調，而編碼KRT1和KRT10的基因的表達上調（Baba等，2012 ; Weaver等人，2013; Gaur等人，2014; Abhishek等人，2016）。最終，這種高度受控的過程導致角質層由大約15層密集的角質化，分層和無核的角質細胞與多層脂質雙層結合在一起構成“磚和砂漿”模型。角質細胞起著磚塊的作用，而神經酰胺，膽固醇，脂肪酸和膽固醇酯則構成了將磚塊結合在一起的砂漿。當表皮周轉功能正常發揮作用時，所得的磚瓦結構將成為有效的皮膚屏障，具有限制蒸發，保持皮膚水分和防止外來生物和物質入侵的能力（Baba等人，2012; Weaver等人。 ，2013; Gaur等人，2014）。腸道微生物組通過影響協調皮膚動態平衡過程的信號傳導途徑的影響，影響了皮層健康（O’Neill等，2016）。

儘管尚未完全探索，但腸道菌群對皮膚穩態產生影響的機制似乎與腸道菌對全身免疫的調節作用有關（O’Neill等，2016）。某些腸道微生物和代謝產物-維甲酸，脆弱擬桿菌的多醣A，普氏嗜藻桿菌以及屬於Clostridium IV和XI屬的細菌會促進調節性T細胞，淋巴細胞的積累，從而促進抗炎反應（Forbes等，2015） 。分段的絲狀細菌也可以促進促炎性Th17和Th1細胞的積累。 SCFA（尤其是丁酸）通過抑制炎症細胞的增殖，遷移，粘附和細胞因子產生來抑制免疫反應。此外，通過抑制組蛋白脫乙酰基酶和使NF-κB信號通路失活，SCFA可以調節免疫細胞的激活和凋亡。組蛋白脫乙酰基酶的抑製作用促進涉及多種皮膚生理功能的調節細胞的增殖，包括調節毛囊幹細胞分化和傷口癒合（Meijer等，2010; Loser和Beissert，2012; Samuelson等，2015）。此外，有新的證據表明，腸道微生物組可能通過腸道菌群及其代謝物向皮膚的轉移而更直接地影響皮膚生理，病理和免疫反應（Samuelson等人，2015; O'Neill等人。 ，2016）。據報導，在腸屏障受阻的情況下，腸道細菌以及腸道菌群代謝物可進入血液，在皮膚中積累並破壞皮膚穩態（O’Neill等，2016）。已成功從銀屑病患者血漿中分離出腸道細菌的DNA（O’Neill等，2016）。這些發現代表了腸道微生物組與皮膚穩態之間更直接的聯繫的證據。

腸道微生物組似乎也影響皮膚微生物組。據信，腸道中纖維發酵產生的SCFA（丙酸酯，乙酸酯和丁酸酯）在確定某些皮膚微生物特徵的優勢方面起著關鍵作用，這些特徵隨後會影響皮膚的免疫防禦機制。例如，丙酸桿菌屬是一種能夠產生SCFA，主要是乙酸和丙酸的屬。丙酸可以對USA300（最流行的社區獲得的耐甲氧西林金黃色葡萄球菌）USA300表現出深遠的抗菌作用（Shu等人，2013; Samuelson等人，2015; Schwarz等人，2017）。表皮葡萄球菌和痤瘡丙酸桿菌是已知比其他菌群更能耐受SCFA移位的皮膚痛經的例子。總之，這些發現為腸道和皮膚之間的功能性相互作用機制提供了支持性證據。

Gut Microbiota and Skin Allostasis

The intestinal microbiome contributes to skin allostasis, the restoration of homeostasis after a disturbance or stressor, through gut microbiota-mediated effects on both innate and adaptive immunity (Benyacoub et al., 2014; Kim Y.G. et al., 2014; Chen et al., 2017). Studies have demonstrated that gut bacteria can positively impact the response to disturbed skin barrier function. For example, a study by Baba et al. (2010) demonstrated that the administration of Lactobacillus helveticus decreased the severity of sodium dodecyl sulfate-induced dermatitis and subsequent TEWL. Another study showed improved recovery of skin barrier function and decreased signs of reactive skin inflammation – including mast cell degranulation, vasodilation, edema, and tumor necrosis factor alpha (TNF-α) release – following the administration of Lactobacillus paracasei CNCM I-2116 (ST11) (Branchet-Gumila et al., 1999; Guéniche et al., 2010; Philippe et al., 2011). Research conducted by Poutahidis et al. (2013) found that mice experienced accelerated wound healing following the consumption of Lactobacillus reuteri. Microscopic examination of wounds throughout the healing process revealed the usual histomorphologic stages of wound healing in both probiotic-treated and untreated mice, however, the time required for complete healing was markedly reduced in the treated group. Foxp3+ regulatory T cells were the prominent immune cell population in wound sites among the treated group, while neutrophils were almost completely absent. L. reuteri-induced oxytocin-mediated regulatory T cell trafficking resulted in the rapid clearance of neutrophils from the wounds of the treated group, ultimately resulting in decreased time-to-heal (Poutahidis et al., 2013).

The gut microbiome has also been shown to support restoration of skin homeostasis after ultraviolet (UV) radiation exposure. In one study, 10 days of oral supplementation with Lactobacillus johnsonii in hairless mice protected the mice against UV-induced contact hypersensitivity, an effect attributed to reduced epidermal Langerhans cells and increased systemic IL-10 levels (Guéniche et al., 2006). In a placebo-controlled study, Lactobacillus johnsonii La1 supplementation protected cutaneous immune homeostasis in 54 healthy volunteers following UV radiation exposure. This effect was mediated by the normalization of epidermal expression of CD1a, a transmembrane glycoprotein structurally similar to major histocompatibility complex that presents self and microbial glycolipids to T cells (Dougan et al., 2007; Peguet-Navarro et al., 2008).

Commensal gut flora can promote skin allostasis by influencing T cell differentiation in response to various immune stimuli. Oral administration of Lactobacillus casei DN-114 001 has been shown to impair differentiation of CD8+ T cells into cutaneous hypersensitivity effector cells and decrease their recruitment to the skin when exposed to 2-4-dinitrofluorobenzene (Table 1). This microbe also increased recruitment of FoxP3+ regulatory T cells to the skin, resulting in decreased apoptosis-mediated skin inflammation, thereby restoring homeostasis through immune-modulatory mechanisms (Chapat et al., 2004; Hacini-Rachinel et al., 2009).

Th17 cells are abundant in both the skin and intestine, as both organs contact the external environment (Weaver et al., 2013). These cells and their pro-inflammatory cytokines are thought to directly contribute to the pathogenesis of several chronic inflammatory dermatoses including psoriasis, Behcet’s disease, and contact hypersensitivity (Van Beelen et al., 2007; Esplugues et al., 2011; Huang et al., 2012). The balance between Th17 effector cells and their counterpart regulatory T cells is greatly influenced by the intestinal microbiome (Van Beelen et al., 2007). Th17 cells can be eliminated in the intestinal lumen, or they may acquire a regulatory phenotype with immunosuppressive characteristics (rTh17) that restricts pathogenicity (Esplugues et al., 2011).

腸道菌群和皮膚異體症

腸道微生物組通過腸道菌群對先天免疫和適應性免疫的介導作用，促進皮膚的異位代謝，干擾或應激後的體內穩態的恢復（Benyacoub等人，2014; Kim YG等人，2014; Chen等人。 ，2017）。研究表明，腸道細菌可以積極影響對受損的皮膚屏障功能的反應。例如，Baba等人的一項研究。 （2010）證明，瑞士乳桿菌的使用降低了十二烷基硫酸鈉引起的皮炎和隨後的TEWL的嚴重性。另一項研究表明，施用副乾酪乳桿菌CNCM I-2116（ST11）後，皮膚屏障功能的恢復得到改善，反應性皮膚炎症的跡象減少-包括肥大細胞脫粒，血管舒張，水腫和腫瘤壞死因子α（TNF-α）釋放。 ）（Branchet-Gumila等人，1999;Guéniche等人，2010; Philippe等人，2011）。 Poutahidis等人進行的研究。 （2013）發現食用羅伊氏乳桿菌後小鼠的傷口癒合加快。在整個癒合過程中對傷口進行顯微鏡檢查，發現在益生菌治療和未治療的小鼠中，傷口通常處於組織形態學階段，但是在治療組中，完全癒合所需的時間明顯減少。 Foxp3 +調節性T細胞是治療組中傷口部位的主要免疫細胞群，而嗜中性粒細胞幾乎完全不存在。羅伊氏桿菌誘導的催產素介導的調節性T細胞運輸導致從治療組的傷口中快速清除中性粒細胞，最終縮短了治愈時間（Poutahidis等，2013）。

腸道微生物組還被證明可以在紫外線（UV）照射後恢復皮膚穩態。在一項研究中，在無毛小鼠中口服約翰遜乳桿菌10天可以保護小鼠免受紫外線引起的接觸超敏反應，這種作用歸因於表皮朗格漢斯細胞減少和全身性IL-10水平升高（Guéniche等人，2006年）。在安慰劑對照研究中，約翰遜乳桿菌La1補充劑可保護54名健康志願者在紫外線輻射後的皮膚免疫穩態。這種作用是通過CD1a的表皮表達正常化來介導的，CD1a是一種跨膜糖蛋白，結構上類似於主要的組織相容性複合物，向T細胞呈遞自身和微生物醣脂（Dougan等，2007; Peguet-Navarro等，2008）。

共生腸道菌群可通過響應各種免疫刺激而影響T細胞分化，從而促進皮膚的異體感。已證明口服乾酪乳桿菌DN-114001會損害CD8 + T細胞分化為皮膚超敏效應細胞，並在暴露於2-4-二硝基氟苯時減少其向皮膚的募集（表1）。這種微生物還增加了FoxP3 +調節性T細胞向皮膚的募集，從而減少了凋亡介導的皮膚炎症，從而通過免疫調節機制恢復了體內平衡（Chapat等，2004; Hacini-Rachinel等，2009）。

由於兩個器官都與外部環境接觸，因此Th17細胞在皮膚和腸道中都非常豐富（Weaver等人，2013）。這些細胞及其促炎細胞因子被認為直接導致了幾種慢性炎性皮膚病的發病機理，包括牛皮癬，白塞氏病和接觸性超敏反應（Van Beelen等，2007; Esplugues等，2011; Huang等。 ，2012）。 Th17效應細胞與其對應的調節性T細胞之間的平衡受到腸道微生物組的極大影響（Van Beelen等，2007）。 Th17細胞可以在腸腔中被清除，或者獲得具有抑制病原性的免疫抑制特徵的調節表型（rTh17）（Esplugues等，2011）。

Dysbiosis and Skin Dyshomeostasis

Intestinal dysbiosis, a state of microbial imbalance, has the potential to negatively impact skin function. Free phenol and p-cresol, metabolic products of aromatic amino acids, are considered biomarkers of a disturbed gut milieu as their production is induced by certain pathogenic bacteria, most notably Clostridium difficile. These metabolites can access the circulation, preferentially accumulate in the skin, and impair epidermal differentiation and skin barrier integrity (O’Neill et al., 2016). Indeed, high p-cresol serum levels are associated with reduced skin hydration and impaired keratinization (Dawson et al., 2011; Miyazaki et al., 2014). Intestinal dysbiosis results in increased epithelial permeability which then triggers the activation of effector T cells, disrupting their balance with immunosuppressive regulatory T cells. Pro-inflammatory cytokines further enhance epithelial permeability and set up a vicious cycle of chronic systemic inflammation (Kosiewicz et al., 2014; O’Neill et al., 2016). These are just a few mechanisms by which a disturbed gut microbiome manifests in impaired skin function. Here, we will discuss mechanisms by which intestinal dysbiosis contributes to three common skin disorders – acne, AD, and psoriasis.

營養不良和皮膚異位症

腸道失調是一種微生物失衡的狀態，可能會對皮膚功能產生負面影響。游離酚和對甲酚是芳香族氨基酸的代謝產物，被認為是腸內環境紊亂的生物標誌物，因為它們的產生是由某些病原細菌（最主要是艱難梭菌）誘導的。這些代謝物可以進入循環系統，優先在皮膚中積累，並損害表皮分化和皮膚屏障完整性（O’Neill等，2016）。的確，對甲酚血清水平高與皮膚水分減少和角化受損有關（Dawson等人，2011; Miyazaki等人，2014）。腸道營養不良會導致上皮通透性增加，進而觸發效應T細胞的活化，破壞其與免疫抑制性調節性T細胞的平衡。促炎性細胞因子進一步增強了上皮通透性並建立了慢性全身性炎症的惡性循環（Kosiewicz等人，2014; O’Neill等人，2016）。這些只是腸道微生物組紊亂表現出皮膚功能受損的幾種機制。在這裡，我們將討論腸道營養不良導致三種常見皮膚疾病（痤瘡，AD和牛皮癬）的機制。

Acne Vulgaris

Acne vulgaris is a chronic disease of the pilosebaceous unit that manifests clinically as non-inflammatory comedones or inflammatory papules, pustules, and nodules (Yentzer et al., 2010; Bhate and Williams, 2013). Three primary factors are implicated in its pathophysiology – sebum oversecretion, abnormal keratinocyte desquamation leading to ductal obstruction, and superimposed inflammation mediated by Propionibacterium acnes (Dawson and Dellavalle, 2013; Agak et al., 2014; Fox et al., 2016; Dreno et al., 2017; Picardo et al., 2017; Rodan et al., 2017).

Approximately 85% of adolescents and young adults between the ages of 12 and 25 are affected by acne, and it represents the eighth most common medical disorder worldwide (Hay et al., 2014; Tan and Bhate, 2015; Lynn et al., 2016; Zaenglein et al., 2016). Acne is particularly prevalent in western countries, a phenomenon thought to be related to an abundance of carbohydrates in the typical western diet. A high glycemic load promotes an increase in insulin/insulin-like growth factor (IGF-1) signaling. This is thought to induce increased cytoplasmic expression of the metabolic forkhead box transcription factor (FoxO1), a sensor of cell nutrition state. FoxO1 ultimately triggers mammalian target of rapamycin complex 1 (mTORC1), a governor of metabolism and cell proliferation, to mediate sebaceous gland hyperproliferation, lipogenesis, and hyperplasia of acroinfundibular keratinocytes, thereby contributing to the development of acne (Melnik, 2015; Agamia et al., 2016; Zaenglein et al., 2016).

Gut microbiota influence the pathophysiology of acne via cross talk between intestinal commensal bacteria and the mTOR pathway (Noureldein and Eid, 2018). Metabolites produced by gut microbiota have been shown to regulate cell proliferation, lipid metabolism, and other metabolic functions mediated by the mTOR pathway. The mTOR pathway can in turn affect the composition of intestinal microbiota through regulation of the intestinal barrier. In cases of intestinal dysbiosis and disrupted gut barrier integrity, this bidirectional relationship can result in a positive feedback cycle of metabolic inflammation. Given the important role of mTORC1 in the pathogenesis of acne, this relationship serves as a mechanism by which the gut microbiome can influence acne pathophysiology.

The complex connection between acne and GI dysfunction may also be mediated by the brain, an idea first postulated by Stokes and Pillsbury (1930). Supporting this hypothesis is the frequent association of both psychological comorbidities – anxiety and depression – and GI distress with acne. These psychological stressors are hypothesized to cause the intestinal flora to either produce different neurotransmitters – serotonin, norepinephrine and acetylcholine – or trigger nearby enteroendocrine cells to release neuropeptides. These neurotransmitters not only increase intestinal permeability, leading to both intestinal and systemic inflammation, but also directly access the circulation through the compromised intestinal barrier resulting in systemic effects (Zhang et al., 2008; Do et al., 2009; Bowe and Logan, 2011; Bowe et al., 2012, 2014; Zouboulis, 2014; Duman et al., 2016; Jena and Sahoo, 2016; Prakash et al., 2016; Ramrakha et al., 2016; Vaughn et al., 2017). The gut-brain-skin axis hypothesis remained dormant for several decades but has been validated by recent advances in microbiome research and our understanding of its effect on health and disease (Bowe and Logan, 2011; Bowe et al., 2014). Consistent with this hypothesis, an upregulation of substance P containing nerves and a strong expression of this neuropeptide is mutually seen in both acne vulgaris and intestinal dysbiosis. Substance P can trigger inflammatory signals that result in the increase of pro-inflammatory mediators implicated in the pathogenesis of acne (IL-1, IL-6, TNF-α, PPAR-γ) (Lee et al., 2008; Arck et al., 2010; Bercik and Collins, 2014; Borovaya et al., 2014; Theodorou et al., 2014; Petra et al., 2015; Rokowska-Waluch et al., 2016).

Alternatively, the link may originate with GI dysfunction which then leads to psychological and cutaneous disorders. Hypochlorhydria is frequently associated with acne. Low levels of acidity allows for the migration of colonic bacteria to distal parts of the small intestine, creating a state of intestinal dysbiosis and small intestinal bacterial overgrowth (SIBO). A larger bacterial population competes for nutrients and impairs the absorption of fats, proteins, carbohydrates, and vitamins. Malabsorbed nutrients, including folic acid, zinc, chromium, selenium, and ω-3 fatty acids have been shown to influence one’s psychological state and, along with systemic oxidative stress, have been implicated in the pathophysiology of acne vulgaris (Katzman and Logan, 2007). SIBO also results in the production of toxic metabolites, which can injure enterocytes, increase intestinal permeability, and ultimately lead to systemic inflammation (Bures et al., 2010; Bowe and Logan, 2011; Bowe et al., 2014).

尋常痤瘡

尋常痤瘡是一種皮脂腺單位的慢性疾病，臨床表現為非炎性粉刺或炎性丘疹，膿皰和結節（Yentzer等人，2010; Bhate和Williams，2013）。其病理生理學涉及三個主要因素-皮脂分泌過多，導致導管阻塞的角質形成細胞脫屑異常以及痤瘡丙酸桿菌介導的炎症疊加（Dawson和Dellavalle，2013年; Agak等人，2014年; Fox等人，2016年; Dreno等人）等人，2017年;皮卡多等人，2017年;羅丹等人，2017年）。

大約85％的12至25歲的青少年患有痤瘡，它是全球第八大最常見的醫學疾病（Hay等人，2014年; Tan和Bhate，2015年; Lynn等人，2016年） ; Zaenglein等人，2016）。痤瘡在西方國家特別普遍，這種現像被認為與典型的西方飲食中碳水化合物的豐富有關。高血糖負荷促進胰島素/胰島素樣生長因子（IGF-1）信號傳導的增加。據認為，這會誘導代謝叉頭盒轉錄因子（FoxO1）（一種細胞營養狀態的傳感器）的細胞質表達增加。 FoxO1最終觸發了雷帕黴素複合物1（mTORC1）的哺乳動物靶點，後者是新陳代謝和細胞增殖的調控因子，可介導皮脂腺的過度增殖，脂肪生成和頂突腺角質形成細胞增生，從而促進痤瘡的發生（Melnik，2015; Agamia等人（2016年； Zaenglein等人，2016年）。

腸道菌群通過腸道共生細菌與mTOR通路之間的串擾影響痤瘡的病理生理（Noureldein and Eid，2018）。腸道菌群產生的代謝物已顯示出調節細胞增殖，脂質代謝和mTOR途徑介導的其他代謝功能的能力。 mTOR途徑進而可以通過調節腸屏障來影響腸菌群的組成。在腸道營養不良和腸屏障完整性受損的情況下，這種雙向關係會導致代謝炎症的正反饋週期。鑑於mTORC1在痤瘡發病機理中的重要作用，這種關係是腸道微生物組可以影響痤瘡病理生理的機制。

痤瘡和胃腸道功能障礙之間的複雜聯繫也可能是由大腦介導的，這是斯托克斯和皮爾斯伯里（Stokes and Pillsbury，1930）首先提出的想法。支持這一假設的是心理合併症（焦慮和抑鬱）與胃腸道不適和痤瘡的頻繁關聯。據推測，這些心理壓力會導致腸道菌群產生不同的神經遞質（血清素，去甲腎上腺素和乙酰膽鹼）或觸發附近的腸內分泌細胞釋放神經肽。這些神經遞質不僅增加腸道通透性，導致腸道和全身炎症，而且還通過受損的腸道屏障直接進入循環系統，從而導致全身性影響（Zhang等，2008; Do等，2009; Bowe和Logan， 2011年; Bowe等人，2012年; 2014年; Zouboulis，2014年; Duman等人，2016年; Jena和Sahoo，2016年; Prakash等人，2016年; Ramrakha等人，2016年; Vaughn等人，2017年）。腸-腦-皮軸假設一直處於休眠狀態數十年，但已被微生物組研究的最新進展以及我們對其對健康和疾病影響的理解所證實（Bowe and Logan，2011; Bowe et al。，2014）。與此假說相一致，在尋常痤瘡和腸道營養不良中都可以看到含有神經的P物質上調和該神經肽的強表達。 P物質可觸發炎症信號，導致痤瘡發病機理中涉及的促炎介質（IL-1，IL-6，TNF-α，PPAR-γ）增多（Lee等，2008; Arck等（2010年； Bercik和Collins，2014年； Borovaya等人，2014年； Theodorou等人，2014年； Petra等人，2015年； Rokowska-Waluch等人，2016年）。

或者，該鏈接可能源於胃腸道功能障礙，然後導致心理和皮膚疾病。胃酸過多症經常與痤瘡有關。低水平的酸度會使結腸細菌遷移到小腸的遠端，從而導致腸道營養不良和小腸細菌過度生長（SIBO）。較大的細菌種群競爭營養，並損害脂肪，蛋白質，碳水化合物和維生素的吸收。吸收不良的營養素，包括葉酸，鋅，鉻，硒和ω-3脂肪酸，已顯示會影響人的心理狀態，並伴隨系統性氧化應激，與尋常痤瘡的病理生理有關（Katzman和Logan，2007年）。 SIBO還導致有毒代謝產物的產生，這些代謝產物可損害腸細胞，增加腸道通透性並最終導致全身性炎症

Atopic Dermatitis

Atopic dermatitis is the most common chronic pruritic inflammatory dermatosis, affecting 15–30% of children and 2–10% of adults (Simpson et al., 2014; Seite and Bieber, 2015; Bin and Leung, 2016). It is a heterogeneous disorder with a variety of endotypes and phenotypes illustrated by wide variations in clinical features with respect to age, severity, and allergen response (Seite and Bieber, 2015; Bin and Leung, 2016; Irvine et al., 2016; Muraro et al., 2016; Huang et al., 2017).

Over the last few decades, our understanding of the pathogenesis of AD has improved with the discovery of more innate and adaptive immune cells and cytokines (Otsuka et al., 2017). Skin barrier dysfunction and altered immune responses are primary players in the pathogenesis of AD (Seite and Bieber, 2015; Bin and Leung, 2016; Irvine et al., 2016; Muraro et al., 2016; Huang et al., 2017). A compromised barrier secondary to environmental or genetic causes is typically the preceding event in AD development. The principal inherited cause of barrier dysfunction is loss of function mutations in the gene encoding FLG. FLG plays an essential role in maintaining epidermal homeostasis by assisting with water retention and barrier function. Therefore, a mutation in FLG results in increased TEWL as well as increased susceptibility to invasion by environmental antigens (Kelleher et al., 2015; Horimukai et al., 2016).

In the acute stage, allergens breaching a dysfunctional skin barrier will trigger the release of keratinocyte-derived cytokines such as TSLP, IL-33 and IL-25. IL-25 and IL-33 will in-turn activate type 2 innate lymphoid cells through their interaction with IL-17B and IL-1RL1, respectively, resulting in the production of IL-13 and IL-5 which will then stimulate a Th2 immune response. Activation of Th2 cells is further enhanced by TSLP-mediated maturation of Langerhans cells and CD11+ dendritic cells. In the chronic stage, IL-22 released from Th22 CELLS promotes the epidermal production of anti-microbial peptides, including defensins, which can participate in skewing the immune response toward a more predominant Th1 response. Tissue remodeling seen in this stage could be secondary to an IL-17 mediated release of pro-fibrotic cytokines such as IL-11 and TGF-β from eosinophils (Otsuka et al., 2017).

Allergic diseases including asthma, hay fever, and eczema have increased in prevalence over the past several decades (Wesemann and Nagler, 2016; Johnson and Ownby, 2017). As developed countries known for their sterile environments saw the most dramatic rise in AD and other allergic diseases, the hygiene hypothesis, first proposed by Strachan (1989), was a widely accepted theory used to explain this phenomenon. Dr. Strachan proposed that allergic disorders arise when our immune system inappropriately responds to harmless antigens via Th2-mediated responses. According to his hypothesis, early exposure to microbial antigens is essential to immune development, as it encourages Th1 rather than Th2-mediated immune responses. With more sterile environments in developed countries, the hygiene hypothesis explains the disproportionate rise of allergic disease in the western world. This theory, however, is flawed in that it fails to explain the parallel increase in prevalence of Th1-mediated autoimmune diseases. Another proposed explanation, the diet-microbiome theory, seeks to reconcile this flaw.

The diet-microbiome theory implies that the increased prevalence of allergic disease stems from a less robust state of immune homeostasis rather than from overresponse to innocuous environmental cues (Kim et al., 2013; Purchiaroni et al., 2013; Song et al., 2016; Johnson and Ownby, 2017). According to this theory, the gut microbiome’s contribution to immune homeostasis is impaired by the typical western diet. Immune homeostasis begins to take shape early in life through exposure to maternal microbiota, and the infant’s intestinal flora is further developed with exposure to breast milk, other food, and environmental microbes (Sironi and Clerici, 2010; Neu and Rushing, 2011; Clemente et al., 2012; Frei et al., 2012; Rook, 2012; Bendiks and Kopp, 2013; Kim et al., 2013; Purchiaroni et al., 2013; Bloomfield et al., 2016; Song et al., 2016; Johnson and Ownby, 2017). The low fiber and high fat content characteristic of the western diet fundamentally changes the gut microbiome, resulting in deficient production of immunomodulatory metabolites, particularly SCFAs. SCFAs are known for their anti-inflammatory actions mediated by G-protein coupled receptor 43 and for their contribution to epithelial barrier integrity (Maslowski et al., 2009). Anti-inflammatory activity is further mediated by regulatory T cells and driven by TGF-β and/or interleukin 10 (IL-10). IL-10 exerts its inhibitory function by inducing TGF-β and other cytokines as well as suppressive signaling molecules including CTLA-4 and PD-1. Reduced local and systemic immune tolerance resulting from an altered gut microbiome may help explain the observed rise of both autoimmune and atopic disease observed in the western world (Maslowski et al., 2009; Agrawal et al., 2011; Purchiaroni et al., 2013; Seite and Bieber, 2015; Johnson and Ownby, 2017).

Studies have sought to demonstrate the link between intestinal dysbiosis and atopic disease (Johnson and Ownby, 2017). In two Korean studies, metagenomic analysis of fecal samples from patients with AD demonstrated a significant reduction in Faecalibacterium prausnitzii species compared to control patients. A parallel decrease in SCFA production among AD patients was observed as well. The authors emphasized a possible positive feedback loop between intestinal dysbiosis regarding F. prausnitzii and epithelial barrier disruption secondary to uncontrolled epithelial inflammation (Kim et al., 2013; Song et al., 2016). Disruption in the intestinal barrier contributes to this feedback loop by allowing the penetration of poorly digested food, microbes, and toxins into the circulation to reach target tissue, including the skin, where they trigger Th2 immune responses resulting in further tissue damage (Purchiaroni et al., 2013; Seite and Bieber, 2015; Song et al., 2016; Johnson and Ownby, 2017).

特應性皮炎

特應性皮炎是最常見的慢性瘙癢性炎症性皮膚病，影響15％至30％的兒童和2％至10％的成人（Simpson等，2014; Seite和Bieber，2015; Bin和Leung，2016）。它是一種具有多種內型和表型的異質性疾病，其臨床特徵在年齡，嚴重性和過敏原反應方面存在很大差異（Seite和Bieber，2015年; Bin和Leung，2016年; Irvine等人，2016年; Muraro）等人，2016; Huang等人，2017）。

在過去的幾十年中，隨著對更多先天性和適應性免疫細胞和細胞因子的發現，我們對AD發病機理的了解得到了提高（Otsuka等人，2017）。皮膚屏障功能障礙和免疫應答改變是AD發病的主要因素（Seite和Bieber，2015年; Bin和Leung，2016年; Irvine等人，2016年; Muraro等人，2016年; Huang等人，2017年）。繼發於環境或遺傳原因的屏障受損通常是AD發展中的先前事件。屏障功能障礙的主要遺傳原因是編碼FLG的基因中功能突變的喪失。 FLG通過協助保水和屏障功能在維持表皮穩態方面起著至關重要的作用。因此，FLG中的突變導致TEWL升高以及對環境抗原侵襲的敏感性增加（Kelleher等人，2015; Horimukai等人，2016）。

在急性期，過敏原突破功能障礙的皮膚屏障會觸發角質形成細胞衍生的細胞因子，例如TSLP，IL-33和IL-25的釋放。 IL-25和IL-33分別通過與IL-17B和IL-1RL1的相互作用依次激活2型先天淋巴樣細胞，從而導致IL-13和IL-5的產生，從而刺激Th2免疫響應。 TSLP介導的Langerhans細胞和CD11 +樹突狀細胞的成熟進一步增強了Th2細胞的激活。在慢性階段，從Th22細胞釋放的IL-22促進表皮產生的抗微生物肽（包括防禦素），這些肽可以參與使免疫反應偏向更主要的Th1反應。在此階段看到的組織重塑可能是繼IL-17介導嗜酸性粒細胞釋放促纖維化細胞因子（如IL-11和TGF-β）後產生的（Otsuka et al。，2017）。

在過去的幾十年中，包括哮喘，花粉症和濕疹在內的過敏性疾病的患病率呈上升趨勢（Wesemann和Nagler，2016年; Johnson和Ownby，2017年）。正如以無菌環境而聞名的發達國家看到的AD和其他過敏性疾病增長最為明顯，Strachan（1989）首次提出的衛生學假設是用來解釋這種現象的一種被廣泛接受的理論。 Strachan博士提出，當我們的免疫系統通過Th2介導的反應不適當地響應無害抗原時，就會出現過敏性疾病。根據他的假說，儘早接觸微生物抗原對於免疫發展至關重要，因為它可以促進Th1而非Th2介導的免疫反應。隨著發達國家無菌環境的增多，衛生學假說解釋了西方世界過敏性疾病的不成比例上升。然而，該理論的缺陷在於它不能解釋Th1介導的自身免疫疾病患病率的平行上升。另一種提議的解釋是飲食微生物學理論，旨在調和這一缺陷。

飲食微生物組理論表明，過敏性疾病患病率增加的原因是免疫穩態的狀態較差，而不是對無害的環境提示反應過度（Kim等人，2013; Purchiaroni等人，2013; Song等人， 2016年; Johnson和Ownby，2017年）。根據這一理論，典型的西方飲食會損害腸道微生物組對免疫穩態的貢獻。免疫穩態在生命早期就開始通過暴露於母體微生物群而形成，並且嬰兒的腸道菌群隨著暴露於母乳，其他食物和環境微生物而進一步發育（Sironi和Clerici，2010; Neu和Rushing，2011; Clemente等）等人，2012; Frei等人，2012; Rook，2012; Bendiks和Kopp，2013; Kim等人，2013; Purchiaroni等人，2013; Bloomfield等人，2016; Song等人，2016; Johnson和Ownby，2017年）。西方飲食的低纖維和高脂肪含量特性從根本上改變了腸道微生物組，導致免疫調節代謝產物特別是SCFA的產生不足。 SCFA以其由G蛋白偶聯受體43介導的抗炎作用及其對上皮屏障完整性的貢獻而聞名（Maslowski等，2009）。抗炎活性進一步由調節性T細胞介導，並由TGF-β和/或白介素10（IL-10）驅動。 IL-10通過誘導TGF-β和其他細胞因子以及包括CTLA-4和PD-1在內的抑制性信號分子發揮其抑制功能。腸道微生物組改變引起的局部和全身免疫耐受降低可能有助於解釋西方世界觀察到的自身免疫和特應性疾病的上升（Maslowski等，2009; Agrawal等，2011; Purchiaroni等，2013 ; Seite和Bieber，2015年; Johnson和Ownby，2017年）。

研究試圖證明腸道營養不良與特應性疾病之間的聯繫（Johnson and Ownby，2017）。在兩項韓國研究中，對AD患者糞便樣本進行宏基因組學分析表明，與對照患者相比，普氏桿菌種類明顯減少。在AD患者中也觀察到SCFA產生的平行降低。作者強調腸道惡性瘧原蟲與prausnitzii和繼發於不受控制的上皮發炎的上皮屏障破壞之間可能存在正反饋迴路（Kim等人，2013; Song等人，2016）。腸壁屏障的破壞通過允許消化不良的食物，微生物和毒素進入循環以到達靶組織（包括皮膚），從而觸發Th2免疫反應，從而導致進一步的組織損傷，從而促進了這種反饋循環。

Psoriasis

Psoriasis is an immune-mediated chronic relapsing-remitting inflammatory dermatosis triggered by a multitude of environmental and internal factors in genetically susceptible individuals (Parisi et al., 2013; Rachakonda et al., 2014; Kulig et al., 2016; Takeshita et al., 2017). Histologic features include acanthosis, reflective of a state of keratinocyte hyperproliferation, and parakeratosis, indicative of dysregulated keratinocyte differentiation. Increased vascularity is characteristic as well, allowing for the accumulation of inflammatory subpopulations of neutrophils, dendritic cells, and T lymphocytes (Roberson and Bowcock, 2010; Kulig et al., 2016). Clinically, psoriasis commonly presents as recurrent episodes of well-demarcated scaly erythematous plaques but can rarely also manifest as generalized life-threatening erythroderma (Mari et al., 2017).

Treatment options have evolved as the pathophysiology of psoriasis has become better understood. Initially considered merely a hyperproliferative skin disorder, treatment once focused on anti-proliferative therapeutic modalities. In the 1980s, the Th1 subset of effector T cells their derived cytokines became the target of many psoriasis therapeutics. More recently, after the discovery of elevated IL-17 levels in psoriatic lesions, therapies have focused on Th17 cells, a novel subset of T cells, as a principal player. Th17 cytokines enhance the expression of the IL-10 cytokine family including; IL-20 and IL-22 cytokines capable of promoting the hyperproliferation of keratinocytes. Following the discovery of the Th17 pathway, most clinical and mechanistic evidence suggests that psoriasis is primarily driven by the IL-23/IL-17/Th17 axis (Baba et al., 2006; Fitch et al., 2007; Guttman-Yassky et al., 2008; Ma et al., 2008; Gaffen et al., 2015; Coates et al., 2016).

Psoriasis is commonly accompanied by inflammation in other organ systems. Seven to 11% of inflammatory bowel disease (IBD) patients are diagnosed with psoriasis, making the association with GI inflammation particularly strong (Huang et al., 2012; Eppinga et al., 2014; Takeshita et al., 2017). Certain shared genetic and environmental factors as well as immune pathways have been implicated in the etiopathogenesis of both diseases (Huang et al., 2012). For example, Th17 cells and their cytokines, known to play a principal role in the development of psoriasis, have been implicated in the pathophysiology of IBD as well (Eppinga et al., 2014; Verstockt et al., 2016). This subset of cells is also thought to play a role in the development of ankylosing spondylitis and rheumatoid arthritis, two autoimmune inflammatory joint diseases commonly reported in patients with psoriasis and IBD (Zhang et al., 2012). Evidence such as this suggests another possible tri-directional axis orchestrated by the gut and its influence on the skin (Eppinga et al., 2014).

Metabolites produced by the intestinal microbiome have immune-modifying potential, capable of altering the balance between immune tolerance and inflammation through their influence on the differentiation of naïve T cells into either regulatory or Th17 lineages. Effector T cells are generally anabolic and depend on glycolysis as their source of adenosine triphosphate (ATP). Memory and resting T cells, however, are considered catabolic and utilize fatty acids and amino acids, in addition to glucose, to generate ATP through oxidative phosphorylation. The primary transcription factors of the lipogenic and glycolytic pathways are adenosine monophosphate activated kinase and rapamycin, respectively. Both serve as energy sensors and are regulated by the accessibility of nutrients in the gut milieu, which can be modulated by gut microbiota (Omenetti and Pizarro, 2015).

The pattern of dysbiosis found in IBD patients has also been described in psoriatic patients with and without IBD (Scher et al., 2015). There is depletion of symbiont bacteria, including Bifidobacteria, Lactobacilli, and Faecalibacterium prausnitzii as well as colonization with certain pathobionts such as Salmonella, Escherichia coli, Helicobacter, Campylobacter, Mycobacterium, and Alcaligenes. One study revealed a decreased presence of Parabacteroides and Coprobacillus, two beneficial gut species, in psoriasis and psoriatic arthritis patients comparable to what is observed in patients with IBD. Reduced presence of beneficial phyla may translate into functional consequences including poor regulation of intestinal immune responses that may then affect distant organ systems (Scher et al., 2015). F. prausnitzii, one of the most common microbial inhabitants of the large intestine, provides many benefits to the host. It serves as an important source of butyrate, a SCFA that provides energy for colonocytes, reduces oxidative stress, and imparts anti-inflammatory action by triggering regulatory T cells, thereby conferring immune tolerance that extends beyond the GI system (Sokol et al., 2008; Lopez-Siles et al., 2012). Psoriatic patients harbor a significantly lower number of this microbe compared to healthy controls (Eppinga et al., 2016). It has also been theorized that the far-reaching effects of intestinal dysbiosis are the result of gut microbes and their metabolites breaching an impaired intestinal barrier and entering systemic circulation to directly target distant organs, including the skin and joints. Consistent with this hypothesis, DNA of gut microbial origin has been isolated from the blood of patients with active psoriasis (Ramírez-Boscá et al., 2015).

銀屑病

牛皮癬是由遺傳易感人群中的多種環境和內部因素觸發的免疫介導的慢性複發-緩解性炎症性皮膚病（Parisi等人，2013; Rachakonda等人，2014; Kulig等人，2016; Takeshita等人。，2017）。組織學特徵包括棘皮症，反映角質形成細胞過度增殖的狀態，以及角化不全，表明角質形成細胞分化失調。增加的血管也具有特徵性，允許嗜中性粒細胞，樹突狀細胞和T淋巴細胞的炎性亞群積累（Roberson和Bowcock，2010年; Kulig等人，2016年）。在臨床上，牛皮癬通常表現為界限分明的鱗狀紅斑的複發發作，但也很少表現為威脅生命的普遍性紅皮病（Mari等人，2017）。

隨著人們對牛皮癬的病理生理學的了解越來越多，治療方法也隨之發展。最初僅被認為是一種過度增殖性皮膚病，治療曾經集中在抗增殖性治療方式上。在1980年代，效應T細胞的Th1子集及其衍生的細胞因子成為許多牛皮癬治療藥物的靶標。最近，在發現銀屑病皮損中的IL-17水平升高後，治療方法主要針對Th17細胞（一種T細胞的新子集）進行了研究。 Th17細胞因子增強IL-10細胞因子家族的表達，包括：能夠促進角質形成細胞過度增殖的IL-20和IL-22細胞因子。發現Th17途徑後，大多數臨床和機制證據表明銀屑病主要由IL-23 / IL-17 / Th17軸驅動（Baba等，2006; Fitch等，2007; Guttman-Yassky等等人，2008年; Ma等人，2008年; Gaffen等人，2015年; Coates等人，2016年）。

銀屑病通常在其他器官系統中伴有炎症。 7％至11％的炎症性腸病（IBD）患者被診斷出患有牛皮癬，這使得與胃腸道炎症的關聯特別強烈（Huang等人，2012; Eppinga等人，2014; Takeshita等人，2017）。某些共享的遺傳和環境因素以及免疫途徑已與這兩種疾病的發病機制有關（Huang等，2012）。例如，已知在牛皮癬發展中起主要作用的Th17細胞及其細胞因子也與IBD的病理生理有關（Eppinga等，2014; Verstockt等，2016）。人們還認為這部分細胞在強直性脊柱炎和類風濕性關節炎的發展中起著作用，強直性脊柱炎和類風濕性關節炎是銀屑病和IBD患者中普遍報導的兩種自身免疫性炎性關節疾病（Zhang等人，2012）。這樣的證據表明，另一條可能是由腸胃組織的三向軸及其對皮膚的影響（Eppinga等，2014）。

腸道微生物組產生的代謝產物具有免疫調節潛力，能夠通過影響天然T細胞分化為調節性或Th17譜係而改變免疫耐受和炎症之間的平衡。效應T細胞通常是合成代謝的，並且依賴糖酵解作為其三磷酸腺苷（ATP）的來源。然而，記憶和靜止的T細胞被認為是分解代謝的，除了葡萄糖以外，還利用脂肪酸和氨基酸通過氧化磷酸化產生ATP。脂肪形成和糖酵解途徑的主要轉錄因子分別是單磷酸腺苷激活的激酶和雷帕黴素。兩者均用作能量傳感器，並受腸道環境中營養物質可及性的調節，可通過腸道菌群進行調節（Omenetti和Pizarro，2015）。

在患有和不患有IBD的銀屑病患者中，IBD患者中發現的營養不良的模式也已有描述（Scher等人，2015）。有共生細菌的枯竭，包括雙歧桿菌，乳酸桿菌和費氏桿菌，以及某些病原菌的定殖，如沙門氏菌，大腸桿菌，幽門螺桿菌，彎曲桿菌，分枝桿菌和產鹼桿菌。一項研究表明，與IBD患者相比，牛皮癬和牛皮癬關節炎患者中兩種有益的腸道菌種Parabacteroides和Coprobacillus的存在減少。減少有益的門可能會轉化為功能性後果，包括對腸道免疫反應的調節不良，繼而可能影響遠處的器官系統（Scher等人，2015）。 F. prausnitzii，大腸中最常見的微生物種群之一，為宿主提供了許多好處。它是丁酸的重要來源，是一種SCFA，它通過觸發調節性T細胞為結腸細胞提供能量，減少氧化應激並賦予抗炎作用，從而賦予了超出GI系統的免疫耐受性（Sokol等，2008）。 ; Lopez-Siles et al。，2012）。與健康對照相比，銀屑病患者攜帶這種微生物的數量要少得多（Eppinga等，2016）。從理論上講，腸道營養不良的深遠影響是腸道微生物及其代謝產物突破受損的腸道屏障並進入全身循環直接靶向遠處器官（包括皮膚和關節）的結果。與該假說相符的是，已從活動性牛皮癬患者的血液中分離出腸道微生物來源的DNA。

Modulation of the Gut Microbiota for Treatment and Prevention (Rehabilitation of the Gut Ecosystem)

The gut microbiome is greatly influenced by diet. Though long-term dietary habits shape bacterial composition, dramatic modulation of diet over the short term can rapidly alter gut bacteria as well. Given the gut microbiome’s influence on inflammatory disease, this provides an opportunity to intentionally modify the microbiome with therapeutic aims (Huang et al., 2017). Probiotic supplementation, the administration of live beneficial gut bacteria, has a promising potential role in the prevention and management of various skin conditions (Krutmann, 2009; Hill et al., 2014; Farris, 2016; Grant and Baker, 2017; Sánchez et al., 2017; Sarao and Arora, 2017). Prebiotics, non-viable bacterial components and metabolites, and synbiotics, the combination of pro- and prebiotics, offer similar health benefits (Muizzuddin et al., 2012; Frei et al., 2015).

調節腸道菌群以進行治療和預防（腸道生態系統的修復）

腸道微生物組受飲食的影響很大。儘管長期的飲食習慣會影響細菌的組成，但短期內飲食的劇烈調節也會迅速改變腸道細菌。考慮到腸道微生物組對炎性疾病的影響，這提供了一個以治療為目的故意修飾微生物組的機會（Huang等人，2017）。益生菌補充劑，即有益的腸道有益細菌的管理，在預防和控制各種皮膚疾病方面具有潛在的潛在作用（Krutmann，2009; Hill等人，2014; Farris，2016; Grant和Baker，2017;Sánchez等人） （2017年； Sarao和Arora，2017年）。益生元，不可生存的細菌成分和代謝產物以及益生元，益生元和益生元的組合具有相似的健康益處（Muizzuddin等人，2012; Frei等人，2015）。

Cosmetic Effect of Probiotics on Skin

Ultraviolet radiation is the primary external contributor to skin aging. Through its stimulation of signaling pathways which ultimately increase the transcription of target genes key to photoaging, UV radiation results in increased laxity, dryness, and pigmentation (Chen et al., 2015; Xia et al., 2015; Wiegand et al., 2016). Activator protein 1 is a matrix metalloproteinase (MMP) transcription factor with a primary role in UVB-induced skin aging. MMPs are zinc-dependent endopeptidases capable of degrading extracellular matrix macromolecules. Interstitial collagenase (MMP-1) cleaves collagen I and III fibrils in skin, while MMP-9 further degrades these fibrils into smaller peptides (Quan et al., 2013; Cavinato and Jansen-Dürr, 2017; Qin et al., 2017). MMP-2 and MMP-9, primarily expressed in the epidermis, break down collagen IV and VII found in the epidermal basement membrane (Pittayapruek et al., 2016). When keratinocytes are exposed to UVA radiation, there is increased expression of TNF-α, a pro-inflammatory cytokine (Jeong et al., 2016).

Studies have sought to demonstrate how modulation of the gut microbiome can influence immune signaling pathways in a way that counteracts UV damage. Lipoteichoic acid (LTA), a cell wall component of Lactobacillus species, is known for its anti-inflammatory properties (Jeong et al., 2016). In one Korean study, oral administration of Lactobacillus plantarum HY7714, resulted in the prevention of UV-induced photoaging in mice through the inhibition of MMP-1 expression in dermal fibroblasts (Kim H.M. et al., 2014). This anti-aging effect was reproduced in human research. In a double-blind, placebo-controlled study, oral supplementation of L. plantarum HY7714 in 110 middle-aged Korean subjects for 12 weeks resulted in improved cutaneous elasticity and increased skin hydration (Lee et al., 2015). Another study demonstrated that Lactobacillus sakei LTA is capable of reversing UV-induced skin aging through its immune modulating effect on monocytes (You et al., 2013).

益生菌對皮膚的美容作用

紫外線是導致皮膚衰老的主要外部因素。通過刺激信號通路最終增加了光老化關鍵的靶基因的轉錄，紫外線輻射導致鬆弛，乾燥和色素沉著增加（Chen等人，2015; Xia等人，2015; Wiegand等人，2016 ）。激活蛋白1是基質金屬蛋白酶（MMP）轉錄因子，在UVB誘導的皮膚衰老中起主要作用。 MMP是鋅依賴性內肽酶，能夠降解細胞外基質大分子。間質膠原酶（MMP-1）裂解皮膚中的I型和III型膠原原纖維，而MMP-9進一步將這些原纖維降解為較小的肽（Quan等人，2013年; Cavinato和Jansen-Dürr，2017年; Qin等人，2017年） 。主要在表皮中表達的MMP-2和MMP-9分解表皮基底膜中發現的IV型和VII型膠原（Pittayapruek等，2016）。當角質形成細胞暴露於UVA輻射時，促炎性細胞因子TNF-α的表達增加（Jeong等，2016）。

研究試圖證明腸道微生物組的調節如何以抵消紫外線損害的方式影響免疫信號通路。脂乳酸（LTA）是乳酸桿菌屬的一種細胞壁成分，以其抗炎特性而聞名（Jeong等，2016）。在一項韓國研究中，口服植物乳桿菌HY7714可以通過抑制皮膚成纖維細胞中MMP-1的表達來預防小鼠紫外線誘發的光老化（Kim H.M. et al。，2014）。這種抗衰老作用已在人類研究中再現。在一項雙盲，安慰劑對照研究中，對110名韓國中年受試者口服植物乳桿菌HY7714進行了12週的口服治療，從而改善了皮膚彈性並增加了皮膚水分（Lee等人，2015）。另一項研究表明，日本乳桿菌LTA通過對單核細胞的免疫調節作用能夠逆轉UV誘導的皮膚衰老（You等，2013）。

Probiotics and Acne Vulgaris

Topical and oral antibiotics are often included in traditional acne treatment regimens. Though effective, this approach risks antibiotic resistance and disruption of the microbiome. Given the role of intestinal dysbiosis in inflammatory skin conditions, probiotic supplementation represents a promising alternate, or adjuvant, acne treatment approach.

In an early study of probiotic supplementation, the ingestion of Lactobacillus acidophilus and Lactobacillus bulgaricus probiotic tablets by 300 acne patients resulted in acne improvement in 80% of subjects, particularly in subjects with inflammatory lesions (Siver, 1961; Bowe and Logan, 2011; Bowe et al., 2014). Probiotics can suppress Propionibacterium acnes through the secretion of antibacterial protein. Streptococcus salivarius and Lactococcus HY449 produce bacteriocin-like inhibitory substance and bacteriocins, respectively, which inhibit the growth of P. acnes (Bowe and Logan, 2011; Bowe et al., 2014; Kober and Bowe, 2015). In another clinical study, subjects who received oral Lactobacillus and Bifidobacterium species in conjunction with oral antibiotics experienced a significantly greater decrease in acne lesion count compared to an antibiotic-only control group (Table 2) (Volkova et al., 2001; Jung et al., 2013).

In addition to their antimicrobial effects, probiotics can disrupt the pathogenesis of acne through immunomodulatory and anti-inflammatory actions. In vitro studies of Streptococcus salivarius, a commensal microbe, attributed the anti-inflammatory effect of this strain to inhibition of IL-8 secretion, suppression of the NF-κB pathway, and downregulation of genes associated with the adhesion of bacteria to epidermal surfaces (Cosseau et al., 2008).

Probiotics may also lower the glycemic load, reduce IGF-1 signaling, and ultimately decrease keratinocyte proliferation and sebaceous gland hyperplasia. In one pilot study, the consumption of Lactobacillus rhamnosus SP1 for 12 weeks resulted in reduced expression of IGF-1 and oxidative stress markers (Table 2) (Fabbrocini et al., 2016). In a study of obese diabetic mice, administration of Bifidobacterium species resulted in inhibition of high-fat diet-induced endotoxemia and inflammation via a GLP-2-dependant mechanism. Increased glucagon-like peptide 2 (GLP-2), an intestinotrophic proglucagon-derived peptide, resulted in improved tight junction integrity and reduced intestinal permeability (Cani et al., 2009).

益生菌和尋常痤瘡

傳統的痤瘡治療方案通常包括局部和口服抗生素。儘管有效，但這種方法冒著抗生素耐藥性和微生物組破壞的風險。考慮到腸道失調在炎症性皮膚病中的作用，補充益生菌代表了一種有前途的替代性或輔助性痤瘡治療方法。

在對益生菌補充劑的早期研究中，300名痤瘡患者攝入嗜酸乳桿菌和保加利亞乳桿菌益生菌片後，痤瘡在80％的受試者中得到改善，尤其是在患有炎症性病變的受試者中（Siver，1961; Bowe and Logan，2011; Bowe等人，2014年）。益生菌可以通過分泌抗菌蛋白來抑制痤瘡丙酸桿菌。唾液鏈球菌和HY449乳球菌分別產生類似細菌素的抑制物質和細菌素，從而抑制痤瘡丙酸桿菌的生長（Bowe和Logan，2011; Bowe等人，2014; Kober和Bowe，2015）。在另一項臨床研究中，與僅口服抗生素的對照組相比，口服口服乳酸桿菌和雙歧桿菌物種以及口服抗生素的受試者的痤瘡病變數量明顯減少（表2）（Volkova等人，2001; Jung等人）。 。，2013）。

益生菌除了具有抗菌作用外，還可以通過免疫調節和抗炎作用破壞痤瘡的發病機理。唾液鏈球菌是一種共生微生物的體外研究，認為該菌株的抗炎作用是抑制IL-8分泌，抑制NF-κB通路以及下調與細菌粘附到表皮表面相關的基因（ Cosseau等，2008）。

益生菌還可以降低血糖負荷，減少IGF-1信號傳導並最終減少角質形成細胞增殖和皮脂腺增生。在一項先導研究中，鼠李糖乳桿菌SP1的食用12週導致IGF-1和氧化應激標誌物的表達降低（表2）（Fabbrocini et al。，2016）。在對肥胖糖尿病小鼠的一項研究中，雙歧桿菌物種的給藥通過GLP-2依賴性機制抑制了高脂飲食誘導的內毒素血症和炎症。胰高血糖素樣肽2（GLP-2）（一種來自腸道營養的胰高血糖素衍生的肽）的增加導致緊密連接完整性的改善和腸通透性的降低（Cani等，2009）。

Probiotics and Atopic Dermatitis

The primary treatment approach to AD combines topical emollients and anti-inflammatory drugs to compensate for disrupted barrier function and poor immune tolerance, respectively (Muraro et al., 2016). Given the gut microbiome’s integral role in immune development and homeostasis, probiotics may be useful in both the prevention and treatment of allergic disorders including AD via microbial, epithelial, and immune effects. Probiotics modify microbial composition, prevent pathogen invasion by competitively binding to epithelial cells, and suppress growth of pathogens by secreting bacteriocin. They also contribute to the restoration of impaired barrier function by increasing the expression of tight junction proteins as well as the production of SCFAs. Immune benefits include the inhibition of proinflammatory cytokines (IL-4, INFγ, IL-17) and the promotion of anti-inflammatory cytokines (IL-10, TGF-β). Probiotics can increase the number of regulatory T cells that suppress the cutaneous expression of thymic stromal lymphopoietin involved in the stimulation of dendritic cells, effectively preventing the differentiation of naïve T cells into Th2 and Th17 subtypes. Regulatory T cells can migrate to the skin and inhibit Th2 and Th17 responses, thereby exerting a therapeutic role in addition to a preventative one (Kim et al., 2013; Chang et al., 2016; McCusker and Sidbury, 2016; Rather et al., 2016).

Lactobacillus and Bifidobacterium species are the most commonly tested probiotics in AD (Kim et al., 2010; Enomoto et al., 2014). Oral supplementation with Lactobacillus rhamnosus Lcr35 in an AD mouse model resulted in the upregulation of CD4+CD25+Foxp3+ regulatory T cells and the downregulation of interleukin-4 and thymic stromal lymphopoietin (Table1) (Kim et al., 2012). In a separate study, supplementation of another AD mouse model with Lactobacillus plantarum CJLP55, CJLP133, and CJLP136 resulted in inhibition of house dust mite-induced dermatitis via increased production of IL-10 and alteration of the Th1/Th2 balance (Won et al., 2011). After supplementation with Lactobacillus rhamnosus IDCC 3201, there was suppression of mast cell mediated inflammation in the same mouse model (Lee et al., 2016).

In humans, prenatal and postnatal probiotics have proven efficacy in the management, and even prevention, of AD in high risk infants. In one placebo-controlled study, Bifidobacterium bifidum BGN4, Bifidobacterium lactis AD011, and Lactobacillus acidophilus AD031 supplements were given to pregnant Korean women with a positive family history of AD 4–8 weeks before delivery and to their infants for the first 2 months of life. The incidence of AD was significantly lower in the probiotic-treated group compared to the control group (Kim et al., 2010). In a separate study, prenatal and postnatal probiotic milk supplementation in Norwegian women and their infants was also associated with a reduced incidence of AD (Bertelsen et al., 2014). In a third study, maternal and infant supplementation with Bifidobacterium breve M-16V and Bifidobacterium longum BB536 further supported the preventative effect of probiotics in AD (Enomoto et al., 2014). Regarding AD treatment, a recent meta-analysis was conducted of studies investigating the efficacy of probiotics in AD symptom-control. This analysis concluded that probiotic use improved AD, reflected by a significant reduction in the Severity Scoring of AD index, in all ages except infants under 1 year (Chang et al., 2016).

益生菌和特應性皮炎

AD的主要治療方法是結合局部潤膚劑和抗炎藥，分別補償屏障功能受損和免疫耐受差（Muraro等人，2016）。鑑於腸道微生物組在免疫發展和體內平衡中的不可或缺的作用，益生菌可能通過微生物，上皮和免疫作用，在預防和治療包括AD在內的過敏性疾病中均可能有用。益生菌可改變微生物組成，通過競爭性結合上皮細胞來防止病原體入侵，並通過分泌細菌素來抑制病原體的生長。它們還通過增加緊密連接蛋白的表達以及SCFA的產生來促進受損屏障功能的恢復。免疫益處包括抑制促炎細胞因子（IL-4，INFγ，IL-17）和促進抗炎細胞因子（IL-10，TGF-β）。益生菌可以增加調節性T細胞的數量，從而抑制參與刺激樹突狀細胞的胸腺基質淋巴細胞生成素的皮膚表達，從而有效地防止幼稚T細胞分化為Th2和Th17亞型。調節性T細胞可以遷移至皮膚並抑制Th2和Th17反應，從而在預防性細胞中發揮治療作用（Kim等人，2013; Chang等人，2016; McCusker和Sidbury，2016; Rather等人） 。，2016）。

乳酸桿菌和雙歧桿菌是AD中測試最普遍的益生菌（Kim等，2010; Enomoto等，2014）。在AD小鼠模型中口服鼠李糖乳桿菌Lcr35導致CD4 + CD25 + Foxp3 +調節性T細胞上調，白介素4和胸腺基質淋巴細胞生成素下調（表1）（Kim等，2012）。在另一項研究中，用植物乳桿菌CJLP55，CJLP133和CJLP136補充另一種AD小鼠模型可通過增加IL-10的產生和改變Th1 / Th2平衡來抑制屋塵蟎誘發的皮炎（Won等。 ，2011）。補充鼠李糖乳桿菌IDCC 3201後，同一小鼠模型中肥大細胞介導的炎症得到抑制（Lee等人，2016）。

在人類中，產前和產後益生菌已被證明可有效控制甚至預防高危嬰兒的AD。在一項安慰劑對照研究中，對分娩前4-8周有陽性AD家族史的韓國孕婦及其嬰兒在出生後的頭2個月給予了雙歧雙歧桿菌BGN4，乳酸雙歧桿菌AD011和嗜酸乳桿菌AD031補充劑。 。與對照組相比，在益生菌治療組中AD的發生率明顯更低（Kim等，2010）。在另一項研究中，挪威婦女及其嬰兒的產前和產後補充益生菌牛奶也與AD發生率降低相關（Bertelsen等人，2014）。在第三項研究中，母嬰補充短短雙歧桿菌M-16V和長雙歧桿菌BB536進一步支持了益生菌對AD的預防作用（Enomoto等，2014）。關於AD治療，最近進行了一項薈萃分析，研究益生菌在AD症狀控制中的功效。該分析得出的結論是，除1歲以下嬰兒以外的所有年齡段，益生菌的使用均改善了AD，這反映在AD嚴重程度評分的顯著降低上

Probiotics and Psoriasis

Data on probiotic supplementation in psoriasis treatment are limited, but promising outcomes have been documented. One study evaluating the effect of Lactobacillus pentosus GMNL-77 on an imiquimod-induced psoriasis mouse model found that probiotic-treated mice experienced significantly less erythema, scaling, and epidermal thickening compared to untreated control mice (Chen et al., 2017). Oral administration of L. pentosus GMNL-77 appeared to suppress expression of TNF-α, IL-6, and proinflammatory cytokines in the IL-23/IL-17 cytokine axis. Though the mechanism for reduced T cell activity was unclear, the study authors proposed that this effect was mediated by suppression of CD103+ dendritic cells, intestinal antigen presenting cells that have been shown to modulate regulatory T cells in the GI tract. In a separate placebo-controlled study of psoriasis patients, Bifidobacterium infantis 35624 supplementation led to significantly reduced plasma levels of TNF-α in the probiotic-treated group (Table 2) (Groeger et al., 2013). In one documented case of severe pustular psoriasis unresponsive to steroids, dapsone, and methotrexate, clinical improvement was observed within 2 weeks of initiating Lactobacillus sporogenes supplementation three times per day, with almost complete resolution achieved at 4 weeks (Vijayashankar and Raghunath, 2012).

益生菌和牛皮癬

牛皮癬治療中補充益生菌的數據有限，但已記錄了有希望的結果。一項評估戊糖乳桿菌GMNL-77對咪喹莫特誘導的牛皮癬小鼠模型影響的研究發現，與未治療的對照小鼠相比，益生菌治療的小鼠出現的紅斑，脫屑和表皮增厚明顯更少（Chen等人，2017）。口服戊糖乳桿菌GMNL-77似乎抑制了IL-23 / IL-17細胞因子軸中TNF-α，IL-6和促炎細胞因子的表達。儘管尚不清楚降低T細胞活性的機制，但該研究作者提出，這種作用是通過抑制CD103 +樹突狀細胞介導的。在一項針對銀屑病患者的安慰劑對照研究中，嬰兒雙歧桿菌35624的補充導致益生菌治療組的血漿TNF-α水平顯著降低（表2）（Groeger等，2013）。在一例有記錄的嚴重膿皰型銀屑病病例中，對類固醇，氨苯砜和甲氨蝶呤無反應，在每天補充3次孢子乳桿菌的2週內觀察到臨床改善，在4週時幾乎完全消退

Conclusion and Future Perspectives

Basic science research and clinical studies have demonstrated the gut microbiome’s contribution to host homeostasis, allostasis, and the pathogenesis of disease. Through complex immune mechanisms, the influence of the gut microbiome extends to involve distant organ systems including the skin. With intentional modulation of the microbiome, probiotics, prebiotics, and synbiotics have proven beneficial in the prevention and/or treatment of inflammatory skin diseases including acne vulgaris, AD, and psoriasis. In this up-and-coming field, future research should improve our understanding of the complex mechanisms underlying the gut-skin axis, investigate the therapeutic potential of long-term modulation of the gut microbiome, and potentially expand therapeutic manipulation to include commensal gut fungi and viruses in order to fully harness the gut microbiome’s influence in the treatment of skin disease.

結論與未來展望

基礎科學研究和臨床研究表明，腸道微生物組對宿主體內穩態，同態代謝和疾病發病機理的貢獻。 通過複雜的免疫機制，腸道微生物組的影響擴展到涉及包括皮膚在內的遙遠器官系統。 通過對微生物組的有意調節，已證明益生菌，益生元和合生元有益於預防和/或治療包括尋常痤瘡，AD和牛皮癬在內的炎性皮膚疾病。 在這個新興領域，未來的研究應增進我們對腸皮軸基礎複雜機制的理解，研究對腸道微生物組進行長期調節的治療潛力，並可能將治療操作擴展到包括共生腸真菌。 和病毒，以充分利用腸道微生物組在皮膚疾病治療中的影響。