Autoimmunity Reviews 14 (2015) 183–191

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Review

The intestinal microbiota and microenvironment in liver☆,☆☆ Hong-Di Ma a, Yin-Hu Wang a, Christopher Chang b, M. Eric Gershwin b, Zhe-Xiong Lian a,c,⁎ a Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China b Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA c Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China

a r t i c l e

i n f o

Article history: Received 1 October 2014 Accepted 5 October 2014 Available online 12 October 2014 Keywords: Intestinal microbiota Gut–liver axis Inflammatory bowel disease Primary sclerosing cholangitis Primary biliary cirrhosis Mucosal immunity

a b s t r a c t The intestinal microbiome plays a significant role in the development of autoimmune diseases, in particular, inflammatory bowel diseases. But the interplay between the intestinal tract and the liver may explain the increased association with autoimmune liver diseases and inflammatory bowel diseases. The gut–liver axis involves multiple inflammatory cell types and cytokines, chemokines and other molecules which lead to the destruction of normal liver architecture. Triggers for the initiation of these events are unclear, but appear to include multiple environmental factors, including pathogenic or even commensal microbial agents. The variation in the gut microbiome has been cited as a major factor in the pathogenesis of autoimmune liver disease and even other autoimmune diseases. The unique positioning of the liver at the juncture of the peripheral circulation and the portal circulation augments the interaction between naïve T cells and other hepatic cells and leads to the disruption in the development of tolerance to commensal bacteria and other environmental agents. Finally, the innate immune system and in particular toll-like receptors play a significant role in the pathogenesis of autoimmune liver disease. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gut microbiota participates in the initiation and maintenance of autoimmune liver diseases by modulating the innate immune system 2.1. Biliary innate immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Innate immune cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Intestinal micro-environment affects T and B lymphocyte immunity in autoimmune liver disease . . . . . . . . . . . . . . . 3.1. Molecular mimicry and production of autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Activation of autoreactive T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. The association of intestinal status with inflammatory cytokines in the context of autoimmune liver diseases . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

☆ Financial support: Financial support was provided by the National Basic Research Program of China (973 Program-2013CB944900, 2010CB945300) and the National Natural Science Foundation of China (81130058, 81430034). ☆☆ There are no conflicts of interests regarding the publication of this article. ⁎ Corresponding author at: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. Tel./fax: +86 551 63600317. E-mail addresses: [email protected] (H.-D. Ma), [email protected] (Y.H. Wang), [email protected] (C. Chang), [email protected] (M.E. Gershwin), [email protected] (Z.-X. Lian).

http://dx.doi.org/10.1016/j.autrev.2014.10.013 1568-9972/© 2014 Elsevier B.V. All rights reserved.

The liver and the gastrointestinal tract are intimately connected in the context of metabolic activity and immune responses, primarily resulting from their close anatomical and physiological relationship [1]. The liver has a dual blood supply. A quarter of the blood supply is derived from the systemic circulation which reaches the liver through the hepatic artery. The other three quarters are gut derived nutrient-rich blood that enters the liver through the portal vein. The term “gut–liver axis” has been coined to reflect the immunological phenomenon linking the two in health and disease [2].

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Microbes exist in the gut environment and play a significant role in digestion, and are a part of the mucosal immune system that helps shape our ability to distinguish safe and danger signals [3,4]. Since the liver receives blood from both systemic circulation and the intestines, microbes in the intestines may also affect the immune environment in the liver. Portal venous blood returning from the intestines contains the products of digestion, along with antigens and microbial products that originate from the bacteria in the small and large intestines [5]. The exposure of liver cells to antigens, and to microbial products derived from the intestinal bacteria, results in a distinctive local immune environment that modulates immune tolerance in the liver [6–8]. To establish this tolerogenic environment, hepatic immune cells including Kupffer cells, natural killer cells, dendritic cells and lymphocytes, together with other nonparenchymal cells including endothelial cells and stellate cells orchestrate a controlled and organized response to these potentially highly inflammatory factors from the intestines [9, 10]. However, this tolerance is quite metastable and can be reversed by the right combination of signals, resulting in active local immunity [5]. For example, changes in the composition of the microbiome or alterations in gut permeability can promote translocation of microbes into the portal circulation that delivers blood directly to the liver [2]. These gut-derived microbial components represent danger signals for the host cells in liver, activate the inflammatory cascade in immune cells and modulate the function of liver parenchymal cells [9]. There is a growing body of evidence showing that the intestinal microbiome possesses critical functions in liver physiology and metabolic homeostasis [11]. Gut-derived bacterial products aggravate hepatic fibrosis [12,13], whereas, gut sterilization helps prevent hepatic fibrosis after bile-duct ligation [12]. Moreover, disruption of the intestinal mucosal barrier facilitates bacterial translocation and promotes the progression of liver fibrosis [13]. Prior studies also suggested that the gut microbiota may affect the progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) [14,15]. This dysbiosis in the digestive tract results in the exacerbation of hepatic steatosis and obesity [16]. The relationship between intestinal homeostasis and autoimmune liver diseases is summarized in this review by discussing the potential involvement of intestinal homeostasis in the pathogenesis of autoimmune liver diseases [17–19], the understanding of which will ultimately steer the development of novel clinical treatments. 2. Gut microbiota participates in the initiation and maintenance of autoimmune liver diseases by modulating the innate immune system As the first line of defense against pathogens, the innate immune system mediates interactions between the hosts and their intestinal microflora [20]. Pattern recognition receptors widely expressed on innate immune cells and parenchymal cell are essential for the recognition and clearance of commensal and pathogenic microflora [21]. The conflict between the innate immune system and gut microflora is not only necessary to repel the invasion of pathogenic microorganisms, but also critical to maintain a balanced immune response that is reflected in good overall health [22,23]. Evidence has been shown that the dysbiosis of innate immunity in the gastrointestinal tract is one of the most important factors in the initiation and perpetuation of autoimmune liver injury [24]. The gut microflora thereby plays a significant role in the pathogenesis of autoimmune liver diseases. 2.1. Biliary innate immunity Bile ducts are a significant component of liver architecture, as biliary epithelial cells (BECs) maintain contact with pathogen associated molecular patterns (PAMPs) originating from intestinal microflora derived from bile [25]. As part of the lining of the bile duct, BECs act as a barrier and express a series of molecules associated with immune recognition

and response, including toll-like receptors (TLRs), histocompatibility complex (MHC) antigens, adhesion molecules and co-stimulatory molecules [26]. BECs thus play a role in both the innate and adaptive immune systems. This distinct characteristic of BECs facilitates their role in the defense against microbial infection, but also renders such cells uniquely susceptible to autoimmune disorders such as PBC and PSC (Fig. 1A) [27–31]. Biliary epithelial cell antibodies (BEC-Abs), which have been found to be present in high frequency in the bile ducts of patients with PSC, up-regulate expression of TLR4 and TLR9 as well as MyD88 on cultured BECs [32]. TLR-expressing BECs, when further stimulated with lipopolysaccharide and CpG DNA, produce proinflammatory cytokines and chemokines including interleukin-1β, interleukin-8, interferon-γ, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, and transforming growth factor-β (Fig. 1A) [32,33]. Upregulation of TLRs as a result of binding of PSC BEC-Abs demonstrated that BEC-Ab may be a critical regulator of cholangitis in PSC. Specifically, binding of lipopolysaccharide and CpG DNA to their respective TLRs induces BECs to produce pro-inflammatory cytokines and chemokines, leading to the further recruitment of inflammatory cells and resulting in cholangitis in PSC. This indicates that environmental factors are essential triggers that can initiate inflammation in the livers of patients with PSC [32]. Interestingly, PSC often coexists with ulcerative colitis [34], suggesting that alteration of the gut microbiome may also play a role in inflammatory bowel disease. Furthermore, accentuated responses of both TLR4 and TLR9 have been reported in the intestinal epithelium of patients with ulcerative colitis [35,36]. These observations suggest that stimulators of TLRs from the digestive tract in PSC patients with ulcerative colitis may play a role in the pathogenesis of PSC. Based on evidence, we can surmise that gut microbes render BECs active participants and mediators of their own destruction in PSC (Fig. 1A). On the one hand, microbial pathogens from the gut can possibly circulate to bile ducts in the liver and activate an inflammatory response via TLR activation. On other hand, the adaptive immune response mediated by BEC-Ab may facilitate the innate immune responses by induction of functional TLRs on the bile duct epithelium of PSC patients. Thus, both the innate and adaptive immune responses cooperate to establish a pro-inflammatory loop, resulting in an enhanced or sustained inflammatory signaling in BECs, leading to the autoimmune injury found in BECs in PSC patients. Bacterial products have also been implicated in the pathogenesis of bile duct diseases other than PSC [37]. Several bacterial products have been detected in liver tissue from patients with PBC, suggesting an association with the development of PBC [38,39]. Similar to PSC, TLR4 was found to be expressed at high levels on BECs in PBC patients. This aberrant expression of TLR4 was also observed in periportal hepatocytes of PBC livers and extended to interlobular hepatocytes in advanced stages of PBC [40]. The deviant distribution of TLR4 in the livers of PBC patients suggests the involvement of bacterial pathogens and TLR4 in different stages of PBC.

2.2. Innate immune cells Liver innate immune cells are essential effector cells that undergo various forms of activation in response to stimuli, including microbial signals originating from the gut. Many autoimmune disorders have been linked to dysfunctional innate immune cells responding against commensal microflora. Such aberrant immune responses partially contribute to the pathogenesis of PBC. The innate immune cells of patients with PBC demonstrate higher reactivity than controls (Fig. 1B). For example, the frequency and absolute number of blood and liver natural killer (NK) cells in patients with PBC, as well as their cytotoxic activity and perforin expression, are increased [41,42]. Moreover, monocyte-derived macrophages (MDMϕ) in patients with PBC polarize most likely to M1, and they exhibit strong

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Fig. 1. Gut microbiota participates in the initiation and maintenance of autoimmune liver diseases by modulating the innate immune system. A. Biliary innate immunity. Bile ducts form an especially critical architecture, in which BECs act as a barrier and are constantly exposed to bacterial products from enteric microflora. The microbial pathogens from the gut get into the intrahepatic bile ducts following circulation and activate inflammatory responses via TLR expressed on BECs. Moreover, in PSC, BEC-Ab facilitated this TLR activation and induced BECs to produce more cytokines/chemokines, leading to the possible recruitment of inflammatory cells and causing cholangitis in PSC. B. Innate immune cells. On the one hand, there are increased frequency and number of innate immune cells (such as NK cells and monocytes) in autoimmune disorders. On the other hand, innate immune cells from patients with autoimmune liver diseases demonstrate higher reactivity via TLR activation by potential gut derived stimuli.

reactivity when they interact with AMAs and apoptotic bodies of BECs [41]. Toll-like receptors (TLRs), as evolutionarily conserved germlineencoded pattern recognition receptors, have a crucial role in early host defense by recognizing pathogen associated molecular patterns (PAMPs) and may serve as an important link between innate and adaptive immunity [28,43–45]. While a robust TLR response is critical for survival and defense against invading pathogens, inappropriate signaling in response to alterations in the local microflora environment can be detrimental [46,47]. Such “off-normal TLR responses” may form the basis for a large number of gastrointestinal and liver disorders [48–50]. Different chemical and infectious agents derived from the outside environment, or in vivo metabolism, can potentially activate various TLRs on monocytes and amplify the inflammatory responses, leading to the breakdown of immune tolerance and the initiation of autoimmunity [51]. In particular, liver autoimmunity, due to the close relationship of the liver and gastrointestinal tract, can be associated with TLRs' modulators from the gut. While receiving large volumes of blood via the portal vein, the liver is constantly exposed to bacterial products from enteric microflora. Under normal circumstances, the immune system of healthy individuals exhibits liver tolerance to TLR ligands. However, injuries, infections or other causes may lead to a breakdown of this tolerance and result in inflammatory disorders of the liver. In these cases, pathogens from intestinal microbiota may inappropriately activate TLRs on innate immune cells in liver which may contribute to the pathogenesis of autoimmune liver diseases. Indeed, peripheral monocytes from patients with PBC secrete high levels of cytokines via TLR activation [41]. In addition to BECs, monocytes from patients with PBC are also more susceptible to activation of TLRs (Fig. 1B). Mao et al. reported that monocytes from patients with

PBC were more sensitive to signaling via selective TLRs (TLR2, TLR3, TLR5 and TLR9) compared with healthy controls [41]. This resulted to enhanced secretion of pro-inflammatory cytokines by PBC monocytes which would be integral to the inflammatory response and critical in the breakdown of self-tolerance [41]. It has also been demonstrated that after LPS stimulation, the level of TLR4 expression is significantly increased in PBC monocytes. Further research has confirmed that the TLR4 signaling pathway is able to be highly activated in PBC patients [52,53]. In response to the TLR ligands, the activation of NF-κB and expression of MyD88 mRNA have been shown to be significantly increased in PBC PBMCs as compared with controls. Notably, the surface expression of RP105, which is considered a negative regulator of TLR4 responses, is decreased in PBC monocytes in comparison with controls [54]. The hypersensitivity to TLR4 signaling in PBC monocytes suggests a role of TLR4 in the pathogenesis of PBC. In addition, TLR3 has also been reported to be capable of aggravating PBC. Ambrosini et al. reported that the addition of polyI:C, a viral RNA mimetic and TLR3 agonist, to a PBC mouse model caused a profound exacerbation of autoimmune cholangitis, including a significant increase in infiltrating CD8+ T cells, a marked increase of proinflammatory cytokines and signs of fibrosis in liver tissues [55]. 3. Intestinal micro-environment affects T and B lymphocyte immunity in autoimmune liver disease 3.1. Molecular mimicry and production of autoantibodies Serologically, PBC is characterized by the presence of antimitochondrial antibodies (AMAs) in 90–95% of patients [56]. The

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presence of autoantibodies may precede the occurrence of symptoms by many years [57]. AMAs react with mitochondrial antigens of the 2oxoacid dehydrogenase complex (2-OADC), including an epitope on the E2 subunit of the pyruvate dehydrogenase enzyme complex (PDC-E2) and the E2 subunit of functionally related 2-oxo-acid dehydrogenase complexes, branched chain 2-oxo-acid dehydrogenase (BCOADC-E2), and 2-oxo-glutarate dehydrogenase (OGDC-E2) [58]. PDC-E2 is a well-conserved molecule among various species, especially at the lipoic acid binding sites which is the major epitope for both autoantibodies and for reactive CD4 and CD8 T cells in PBC [26,59,60]. Because of its evolutionary conservation, sera from patients with PBC have been shown to react with both human and Escherichia coli PDC-E2 [61]. The reactivity of AMA to both human and gut bacterial molecules has provided clues to the relationship between the onset of PBC and intestinal microflora (Fig. 2A). Earlier work has shown that PDC-E2 specific autoreactive CD4 T cell clones recognize E. coli PDC-E2 [62]. In addition, bacterial homologous peptides have been shown to have an agonistic effect on autoreactive CD8 T cells specific for PDC-E2 [63]. Molecular mimicry is one of the mechanisms by which an individual may fail to discriminate between self and non-self [64], thus disrupting the balance between a hypo- and hyperimmune state, leading to either

infectious diseases or autoimmunity respectively [65]. These nonspecific reactions to PDC-E2 of gut bacteria such as E. coli may result in the activation of the human immune system to cross-react with the conserved human PDC-E2, evoking strong autoreactive responses and development of the disease [62,66]. In addition to TLR3 and TLR4, activation of TLR9 has been demonstrated to contribute to the development of PBC (Fig. 2B). Kikuchi et al. reported that after exposure to bacterial CpG-B, the frequency of intracellular IgM-positive B cells was markedly increased in PBMCs from PBC patients. These B cells produced high levels of IgM and were identified as functional CD27+ memory B cells [67]. The prevalence and unusually high levels of antimitochondrial antibodies (AMAs) in patients with PBC suggest a profound loss of B cell tolerance [68,69]. Further studies have provided evidence that the AMA production of these B cells is significantly promoted by CpG-B stimulation [70]. Since a number of studies have suggested a bacterial etiology in PBC, it can be hypothesized that the promotion of a hyper-IgM state and the increased production of AMA by bacterial CpG-B may be a reflection of the role of the CpG ligand, TLR9, in the development of a chronic polyclonal innate immune response in patients with PBC. As previously mentioned, pathogens from enteric microflora may be considered to be an important cause of inappropriate response of innate immune

Fig. 2. Intestinal micro-environment affects T and B lymphocyte immunity in autoimmune liver diseases. A. Reactions to PDC-E2 of gut bacteria such as E. coli may result in the crossactivation of the immune system to cross-react with conservative PDC-E2 of self-evoking strong autoreactive responses and initiate PBC by this molecular mimicry event. B. Long-term exposure to pathogen-associated molecular patterns (such as bacterial CpG-B, ligand of TLR9 or other PAMPs from the gut) may sensitize TLRs and result in aberrant humoral immune responsiveness in B cells. C. Aberrantly increased chemokines guide intestinal primed T lymphocytes homing to the liver, which causes T cell mediated hepatic disorders in PSC. D. Liver sinusoidal endothelial cells (LSECs) are the link between the intestinal micro-environment and the hepatic immune compartment. By gut-derived antigen presentation and metabolite conversion, LSECs induce Treg differentiation leading to anergy and tolerance in liver.

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cells in PBC. Thus, microorganisms from the gut may sensitize TLRs on innate immune cells and result in aberrant humoral immune responsiveness in B cells of PBC patients [71]. 3.2. Activation of autoreactive T cells The liver stands at a hemodynamic confluence [5], where blood from the systemic circulation and the intestinal tract converge into hepatic sinusoids. This distinct architecture not only enables circulating naïve T cells to make direct contact with various cell types in the liver such as hepatocytes, hepatic stellate cells (HSC), Kupffer cells as well as liver sinusoidal endothelial cells (LSECs) and bile duct epithelial cells, but also allows primed effector T cells from the intestinal tract to migrate into the liver. As characterized by progressive bile duct destruction, primary sclerosing cholangitis (PSC) also develops as an extra-intestinal complication of inflammatory bowel disease (IBD) [72,73]. The prevalence of IBD (typically chronic ulcerative colitis (CUC)) among PSC patients is approximately 70–80% while 2–7.5% of patients with CUC will develop PSC [74]. An aberrant homing of intestinal T lymphocytes to the liver is thought to be an important factor for the development of T cell mediated hepatic disorders associated with gut inflammation (Fig. 2C) [75]. Furthermore, PSC can develop for the first time many years after IBD has become quiescent and even after previous proctocolectomy [76]. In consideration of this fact, Eksteen et al. hypothesized that PSC is mediated by long-lived memory T cells originally primed in the gut, and were able to eventually cause extra-intestinal inflammation in the absence of active IBD [77]. This is supported by the evidence that mucosal T cells are recruited to the liver by the aberrant expression of the gutspecific chemokine CCL25 in the liver of PSC patients, which mediates the binding of α4β+ 7 T cells with mucosal addressin cell adhesion molecule 1 on the hepatic endothelium [77]. Sinusoids are specialized hepatic structures with thin-walled vessels that allow oxygenated blood from the arterial system to mix with portal venous blood returning from the intestine. They are the link between the intestinal micro-environment and the hepatic immune compartment (Fig. 2D). Liver sinusoidal endothelial cells (LSECs) are believed to shift the hepatic immune response toward tolerance by presenting major histocompatibility complex (MHC) I-restricted antigens, thereby inducing anergy and tolerance [78,79]. In particular, Kruse et al. reported that priming of CD4+ T cells by liver sinusoidal endothelial cells induces CD25low FoxP3− regulatory T cells that suppress autoimmune hepatitis, as shown by their effects on reducing the levels of alanine aminotransferase and cellular infiltrates in a T cell-mediated autoimmune hepatitis model in vivo [80]. In addition to various types of immune cells, metabolites including antigens derived from food and biological molecules from the intestinal tract are also transferred into the liver through normal vascular channels. Food antigens and microbiome brought from the intestinal tract are considered to be the main contributors to the development of liver tolerance [81]. Products of metabolism from the intestinal tract such as retinoic acid (RA), a derivative of vitamin A, have also been reported as an important factor in the “gut–liver axis” [1,82,83]. T cells acquire a gut-homing phenotype with high levels of α4β7 integrin and of CC chemokine receptor 9 (CCR9) [84,85], which is dependent on retinoic acid (RA) provided by dendritic cells (DCs) from the gut-associated lymphoid tissue (GALT) [86,87]. RA is able to induce the expression of gut homing molecules on T cells [88,89]. Neumann and colleagues found that LSECs expressed functional retinal dehydrogenases which can convert vitamin A to RA. Moreover, in addition to GALT-DCs, LSECs can also prime CD4+ T cell and promote gut tropism via the action of vitamin A [82]. This liver–gut trafficking is a novel feature of gut–liver axis and in that the interaction between the liver and gut is bidirectional [1]. The effect of RA on T-cell activation and differentiation is closely related to liver immunity [90]. It has been reported that RA may regulate a

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much broader range of CD4+ T cell priming and differentiation, including serving as a cofactor for the development of induced regulatory T (iTreg) cells [91,92]. Vitamin A is absorbed by the intestinal tract and transported into the liver through the circulation. Lack of absorption or low efficiency of conversion of vitamin A can potentially lead to a decreased number of iTreg cells, thereby breaking down the balance of liver immunity and creating a precarious environment for the development of autoimmune liver disease. Mehal proposed that the loss of vitamin A may result in eventual loss of RA and a reduction in LSEC-mediated production of regulatory CD4+ T cells, opening up the possibility that derangements in RA-based signaling have a role in autoimmune hepatitis [1]. It should be noted that although growing evidence supports the notion that aberrant intestinal T lymphocytes and intestinal metabolic disturbance trigger the development of intestinal and liver disorders, the intestinal tract and liver disorders are characterized by distinct pathogenesis. 4. The association of intestinal status with inflammatory cytokines in the context of autoimmune liver diseases Tumor necrosis factor (TNF), a major factor in the immune response to bacterial infection, contributes to the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (RA) and Crohn's disease [93–96]. Proven as the most efficient therapy for RA thus far, TNF antagonists have attracted considerable attention in the treatment of autoimmune diseases [97]. Likewise, circulating levels of TNF was most significantly correlated with hepatobiliary injury in autoimmune diseases [98]. Moreover, genetic studies have identified a significant association between possession of the TNF2 allele and susceptibility to PSC [99]. Although the role of TNF in the development and progression of PSC has yet to be clearly defined, it has been proposed that the inflammatory responses in PSC may be initiated by the secretion of cytokines like TNF by hepatic macrophages in response to exposure to intestinal bacterial antigens in the portal venous blood (Fig. 3A). TNF and endotoxin may stimulate biliary epithelial cells to secrete chemokines and cytokines that would in turn attract and activate neutrophils, monocytes, macrophages, T cells and fibroblasts. The accumulation of these effector cells resulted in biliary damage [100]. In autoimmune liver diseases, it has been reported that the frequency of IFN-γ+ cells is significantly increased in the cellular infiltrates in livers of patients with autoimmune hepatitis [101]. In addition, the frequency of IFN-γ expressing cells is predominantly found in association with damaged bile ducts in PBC patients [102]. At the same time, it has been reported that IFN-γ can increase epithelial permeability as indicated by markers of paracellular permeability and bacterial transcytosis, with at least a portion of the bacteria using the transcellular permeation pathway (Fig. 3B) [103,104]. Although IFN-γ appears to be involved in both autoimmune liver diseases and gut bacterial translocation [105–107], solid and reliable evidence is needed to prove that IFN-γ induced gut bacterial translocation contributes to the development of these autoimmune liver diseases. IL-17 is the signature cytokine of T helper (Th)17 cells, which play an important role in defense against extracellular bacteria and fungi [108, 109], particularly at epithelial and mucosal surfaces [110]. Both functional and genetic evidence suggests the involvement of IL-17 in the pathogenesis of mucosal immune disorders in gut colitis [111–113]. For example, in both Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of IBD in humans, increased expression of IL-17 and IL-23 has been found in the intestinal lesions [113–116]. Moreover, IL-17 producing cells have also been implicated in the pathogenesis of several other human autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis, psoriasis, and rheumatoid arthritis [111,117–120]. In particular, an increase in the frequency of IL-17+ lymphocytic infiltration in liver tissues from PBC patients has also been reported [121–123]. Similar observations have been made in

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Fig. 3. The association of intestinal status with inflammatory cytokines in the context of autoimmune liver diseases. A. Hepatic macrophages primed by intestinal bacterial antigens in the portal venous blood secrete cytokines like TNF and initiate inflammatory recruitment. The recruited effector cells destroy the bile duct in PSC. B. IFN-γ can increase epithelial permeability by increasing paracellular permeability and bacterial transcytosis. IFN-γ induced gut bacterial translocation may contribute to the inflammation in the liver. C. PAMPs derived from intestinal commensal bacteria are recognized by antigen presenting cells in the gut and presented to T cells. Primed T cells produce inflammatory cytokines such as IL-17 and IL-23 to amplify the inflammatory responses and finally lead to disorders in the liver.

IL-2Rα−/− mice, a murine model of human PBC, where marked aggregations of IL-17+ cells are found within portal tracts and increased numbers of Th17 cells in the liver may be found when compared to the periphery [121]. In recent genome-wide association studies (GWAS), several loci have been found to be associated with PSC [124,125]. Among these, polymorphisms within genes which code for molecules involved in Th17 differentiation and transduction of signals received by toll-like receptor (TLR) and dectin-1 have been found. These PPRs (pattern recognition receptors), which recognize conserved molecules of bacterial and fungal species [126], are of particular interest. Katt et al. reported that IL-17A-expressing lymphocytes as well as bacterial RNA were found within the portal tracts of PSC livers and demonstrated an increased Th17 response to microbial stimulation in patients with PSC [127]. Since IL-17 secreted by Th17 cells may link pathogen defense to autoimmunity [128], it is likely that an increased exposure to pathogens or a change in the microbial community in bile may induce an increase in IL-17 secretion by Th17 cells, which may then contribute to uncontrolled portal and biliary inflammation in PSC [129]. It should also be mentioned that specific gut commensals, such as segmented filamentous bacteria (SFB), promote the generation of an intestinal subset of Th17 cells and enhance the expression of interferon-γ (IFN-γ) or Foxp3 in gut T cell subsets [130–133]. In a T cell transfer

model of arthritis, it has been shown that in the local microenvironment of gut-associated lymphoid tissues, inflammatory cytokines elicited by the commensal flora dynamically enhance the antigen responsiveness of T cells that were otherwise tuned down to a systemic self-antigen. This ultimately leads to an enhanced recruitment of pathogenic T cells and the development of a more severe form of autoimmune arthritis [134]. Similarly, the severity of autoimmune liver diseases is associated with gut commensal flora and the predominant effector cells in autoimmune liver diseases are also T cells. Antigens from intestinal commensal bacteria (such as SFBs) can be recognized by DCs or macrophages in the gut and presented to T cells (Fig. 3C). Primed T cells proliferate and differentiate into effector cells which produce inflammatory cytokines such as IL-17 and IL-23, which amplify the inflammatory responses and finally lead to the breakdown of tolerance in the liver. Likewise, whether inflammatory cytokines elicited by the commensal flora can dynamically enhance the antigen responsiveness or affect the function of effector T cells in autoimmune liver diseases deserves to be further studied [51]. 5. Conclusion Autoimmune liver diseases are complex diseases arising from the interaction of both environmental factors and genetic background. In

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the last few years, the incidence of autoimmune liver diseases has been increasing [135]. The reasons for this observation are unclear, but may reflect a change in our lifestyles and environments, which may include changes in the microbiome to which we are exposed. Since the immune-modulating capabilities of microorganisms in the gut have become a significant topic for recent research, the role of intestinal micro-environment factors in the pathogenesis of autoimmune liver diseases has been better appreciated and has taken on greater importance. Although the effect of the intestinal micro-environment on autoimmune liver diseases has not yet been thoroughly investigated, strong evidence suggested that pathogen-derived compounds and products of metabolism from the gut play an important role in modulating liver diseases. In this review, we summarize the effects of the intestinal microbiota on the liver immune microenvironment through the gut–liver axis. On the one hand, agents from the intestinal tract are transported to the liver through normal blood circulation and enter the hepatic sinusoids through the portal vein. At this junction of blood flow, innate immune cells, such as DCs and Kupffer cells, present antigens to prime naïve T cells near hepatic sinusoids. Intensive abnormal priming of hepatic infiltrated T cells by inappropriate stimulators from the gut can potentially lead to disorders in liver immunity. Inside the liver, TLR-expressing BECs and hepatic infiltrating monocytes activated by abnormal signals from the gut result in aggravated innate and adoptive immune responses, which cause persistent inflammation in the liver. On the other hand, the dysbiosis of gut microbiota leads to an immune imbalance in the intestinal tract. In this context, aberrantly activated T cells, which expressed specific chemokine receptors as well as integrins, can migrate from the gut into the liver, and further induce chronic liver inflammation. Lastly, we review the critical effects of inflammatory cytokines on the initiation and development of autoimmune liver diseases. Pro-inflammatory cytokines link pathogen defense to liver autoimmunity by recruiting inflammatory immune effector cells into the liver. The accumulation of these “attackers” results in autoimmune liver disease and chronic liver tissue damage. In addition, proinflammatory cytokines can increase intestinal epithelial permeability and lead to bacterial transcytosis, resulting in the breakdown of mucosal immune balance and acting as a “fuse” toward the development of liver autoimmunity. To this date, critical questions remain unanswered regarding the interaction between the intestinal mucosa and the hepatic microenvironment [136,137]. In particular, the relationship between intestinal homeostasis and autoimmune liver disease has yet to be fully understood. Future studies directed at these questions are needed to identify predictors for autoimmune liver diseases and to provide important guidance for the development of new therapies with applications in autoimmune liver disease and autoimmunity in general [138–143]. Take-home messages • Autoimmune liver diseases are complex diseases arising from the interaction of both environmental factors and genetic background. • Gut microbiota participates in the initiation and maintenance of autoimmune liver diseases by modulating the innate immune system. • Multiple cell types and cytokine molecules may be involved in the pathogenesis of autoimmune liver disease. • The gut–liver axis allows greater interaction between the peripheral circulation and the liver, leading to an association between autoimmune liver disease and inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. • In addition to bacteria and other microbes as potential triggers of autoimmunity, a variety of other environmental exposures including chemical agents may affect the development of liver immune disease through disruption of normal tolerogenic physiologic mechanisms.

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