Gut Microbiota Dysbiosis is Strongly Associated with Autoimmune Hepatitis Pathogenesis, Progression, and Severity

Background: The gut-liver axis is increasingly recognised as a critical determinant of autoimmune liver disease. Gut microbiota dysbiosis — characterised by reduced alpha-diversity, depletion of butyrate-producing commensals, and enrichment of gram-negative pathobionts — has been implicated in breaking hepatic immune tolerance. However, the mechanistic relationships between specific microbial alterations, intestinal barrier dysfunction, and AIH pathogenesis remain incompletely characterised. Methods: We conducted a systematic review and meta-analysis of studies examining gut microbiota composition in AIH patients versus healthy controls and disease comparators (2010–2024). Studies employing 16S rRNA gene sequencing and/or shotgun metagenomics were included. Additionally, functional analyses of short-chain fatty acid (SCFA) profiles, serum lipopolysaccharide (LPS) levels, T-regulatory/Th17 cell balance, and intestinal permeability markers were synthesised. Correlation analyses with Histological Activity Index (HAI), Ishak fibrosis stage, MELD score, and Child-Pugh classification were performed. Results: Fifteen eligible studies encompassing 1,842 AIH patients and 1,219 healthy controls were analysed. AIH patients showed significantly reduced alpha-diversity (Shannon index: 2.78 ± 0.42 vs 3.82 ± 0.35 in controls; p<0.001), distinct beta-diversity clustering (PERMANOVA p<0.001), and characteristic phylum-level shifts: increased Proteobacteria (18% vs 4%), decreased Firmicutes (38% vs 52%), and decreased Bacteroidetes (26% vs 38%). Faecalibacterium prausnitzii and Akkermansia muciniphila showed the strongest depletions (log2FC −3.4 and −2.8, respectively; both p<0.001). Butyrate levels inversely correlated with HAI (r=−0.68, p<0.001), fibrosis stage (r=−0.62, p<0.001), and MELD score (r=−0.71, p<0.001). Serum LPS correlated positively with disease severity across all parameters. Pilot FMT studies demonstrated adjunctive benefit with 74–81% remission rates versus 52% with standard immunosuppression alone. Conclusions: Gut microbiota dysbiosis is mechanistically linked to AIH pathogenesis through at least three overlapping pathways: intestinal barrier disruption with endotoxemia, altered SCFA metabolism reducing hepatic immune tolerance, and dysregulated Treg/Th17 balance favouring autoimmunity. These findings establish gut microbiota as both a diagnostic biomarker and therapeutic target in AIH, with microbiome-targeted interventions showing promising adjunctive benefit.