Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2016; 22(42): 9257-9278
Published online Nov 14, 2016. doi: 10.3748/wjg.v22.i42.9257
Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis
Albert J Czaja
Albert J Czaja, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
Author contributions: Czaja AJ researched, designed, and wrote this article specifically for this journal, and it has never been published previously; The tables are original, constructed by Dr. Czaja, fully referenced, and developed solely for this article; The one color figure is also original, drawn by Dr. Czaja, and never published previously; The entire presentation is original, current, comprehensive.
Conflict-of-interest statement: Albert J Czaja has not received fees for serving as a speaker, consultant, or advisory board member for any commercial organization. He has not received research funding from, been employed by, or received stocks and/or shares from such an organization.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Albert J Czaja, MD, Professor Emeritus, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, United States.
Telephone: +1-507-2842691 Fax: +1-507-2840538
Received: August 13, 2016
Peer-review started: August 14, 2016
First decision: September 12, 2016
Revised: October 7, 2016
Accepted: October 30, 2016
Article in press: October 31, 2016
Published online: November 14, 2016

The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.

Keywords: Intestinal microbiome, Inflammasomes, Autoimmune hepatitis, Dysbiosis, Toll-like receptors

Core tip: The intestinal microbiome is a reservoir of microbial antigens and activated immune cells that have been implicated in the pathogenesis of diverse systemic immune-mediated diseases. Dysbiosis, increased intestinal permeability, and molecular mimicry between microbial and self-antigens may initiate or sustain autoimmune hepatitis. Multiple drug, molecular, dietary, and probiotic interventions can modify the intestinal microbiome and attenuate the immune response. The role of the intestinal microbiome in autoimmune hepatitis warrants rigorous study, and new therapies may emerge that strengthen current treatment regimens.