Year-end Sale % OFF 
Abstract
The gut–liver axis has been increasingly recognized as a major autoimmunity modulator. However, the implications of intestinal barrier in the pathogenesis of autoimmune hepatitis (AIH) remain elusive. Here, we investigated the functional role of gut barrier and intestinal microbiota for hepatic innate immune response in AIH patients and murine models. In this study, we found that AIH patients displayed increased intestinal permeability and pronounced RIP3 activation of liver macrophages. In mice models, intestinal barrier dysfunction increased intestinal bacterial translocation, thus amplifying the hepatic RIP3-mediated innate immune response. Furthermore, GSK872 dampened RIP3 activation and ameliorated the activation and accumulation of liver macrophages in vitro and in vivo experiments. Strikingly, broad-spectrum antibiotic ablation significantly alleviated RIP3 activation and liver injury, highlighting the causal role of intestinal microbiota for disease progression. Our results provided a potentially novel mechanism of immune tolerance breakage in the liver via the gut-liver axis. In addition, we also explored the therapeutic and research potentials of regulating the intestinal microbiota for the therapy of AIH.
Highlights
Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory liver disease
We try to explore the causality between the leaky gut/dysbiosis and autoimmune hepatitis (AIH), demonstrating that loss of gut barrier integrity breaks liver immune homeostasis and augments liver injury
The intestinal epithelial barrier (IEB) is a single layer of epithelial cells held together by a complex junctional system composed of tight junctions, adherent junctions, and desmosomes [38]
Summary
Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory liver disease. As macrophages accumulate gut-derived products such as lipopolysaccharide (LPS) and undergone activation, necrosis of macrophages and uncontrolled release of inflammatory cytokine and chemokine results in inflammation and fibrosis of liver tissues [16, 17]. As reveled by the tandem model of dextran sulfate sodium (DSS) - concanavalin A (Con A), the disruption of intestinal barrier prior to hepatitis aggravated the activation and accumulation of liver macrophages. This finding highlighted RIP3 as an important interface that mediated liver inflammation. The RIP3-mediated activation of liver macrophage in EAH mice was canceled by gut sterilization, suggesting that immune responses in the liver are potentially regulated by gut microbiota
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
