Zhengrui You

T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-γt, IL-6 and IL-1β in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis.

Objective Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. Design We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. Results Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host–microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host–microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. Conclusions Our data reveal that IgG4-SC and PSC possess divergent host–microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.

Background: Increasing data suggests an interaction between bile acids and intestinal microbiota in the pathogenesis of primary biliary cholangitis (PBC). Bile acid sequestrants are widely used to bind bile acids in the intestinal lumen and are therefore posited to impact gut bacteria. Herein we aimed to investigate the effects of cholestyramine on the bile acid profile and gut microbiome in a cohort of icteric PBC patients.Results: Thirty-three PBC patients were treated with cholestyramine, serum and stool samples were collected at baseline, 4 and 16 weeks. Shotgun metagenomic sequencing and targeted metabolomic profiling were performed. Following cholestyramine administration, patients exhibited a high interpersonal variability in remission of cholestasis, and were therefore dichotomized according to the decrease of total bilirubin. Gut microbial co-abundance networks showed distinct taxa interactions between subjects with superior remission (SR) and those with inferior remission (IR) at baseline. After treatment, compositional shifts of the microbiome in the SR group were characterized with enrichment of two Lachnospiraceae species, typically producing short-chain fatty acids (SCFAs). In contrast, Klebsiella pneumonia, a commensal pathobiont, was only increased in the IR group. Correspondingly, metabolome analysis demonstrated that patients with SR, but not IR, were marked by elevations of SCFAs including valeric acid and caproic acid. Finally, integrative analysis identified robust associations between the variations of microbiota, metabolites, and inflammatory cytokines in SR group, indicating potential mechanistic links.Conclusions: Beneficial responses caused by cholestyramine were closely related with compositional and functional alterations in gut commensal, highlighting the possibility of exploring bile acid-microbiota interactions for treating PBC.

Background and Aims The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. Approach and Results We report herein that CD69 + CD103 + CD8 + tissue‐resident memory T cells (T RM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8 + T RM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8 + T RM cells decreased significantly. CD69 + CD8 + and CD69 + CD103 + CD8 + T cells, also known as CD8 + T RM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL‐15 and TGF‐β on inflammatory cells, and extensive hepatic expression of E‐cadherin; these factors likely contribute to the development and localization of CD8 + T RM cells. Based on these data and, in particular, the relationships between disease severity and CD8 + T RM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8 + T RM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8 + T RM cells induced by IL‐15 and TGF‐β and with direct down‐regulation of the nuclear factor Blimp1 of CD8 + T RM cells. Conclusions Our data suggest that CD8 + T RM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8 + T RM cell expansion.

There is increasing awareness of the immunologic roles of liver mononuclear populations, including myeloid‐derived suppressor cells (MDSCs). We took advantage of a large well‐defined cohort of 148 patients with liver inflammation and 45 healthy controls to focus on the qualitative and quantitative characteristics of MDSCs. We investigated the frequency, phenotype, and functional capacities of MDSCs by using peripheral blood MDSCs in a cohort of 55 patients with primary biliary cholangitis (PBC), 40 with autoimmune hepatitis, 39 with chronic hepatitis B, 14 with nonalcoholic fatty liver disease, and 45 healthy controls. This was followed by a liver‐targeted determination in 27 patients with PBC, 27 with autoimmune hepatitis, 20 with chronic hepatitis B, 14 with nonalcoholic fatty liver disease, and 6 controls. We then focused on mechanisms of this expansion with PBC as an example, using both ursodeoxycholic acid‐naive and treated patients. HLA‐DR −/low CD33 + CD11b + CD14 + CD15 − monocytic MDSCs were elevated in diseases characterized by liver inflammation compared to healthy controls. Using PBC as a focus, there was a significant correlation between levels of circulating MDSCs and disease‐related biochemical markers (alkaline phosphatase, total bilirubin). We found higher amounts of MDSCs in patients with PBC who were responsive to ursodeoxycholic acid. MDSCs from PBC were found to manifest a potent immunosuppressive function. There was a significant correlation in the accumulation of hepatic MDSCs in the inflamed lesions of PBC with histologic changes, such as fibrosis. We also found that cysteine‐rich protein 61 (CCN1), a highly expressed protein in impaired cholangiocytes and hepatocytes, contributes to MDSC expansion and MDSC inducible nitric oxide synthase‐associated immune suppression. Conclusion : CCN1 modulates expansion and a suppressive function of MDSCs. Our data highlight the potential functions of CCN1 on MDSCs and suggest therapeutic implications in inflammatory liver diseases. (H epatology HEPATOLOGY 2018;67:232‐246).