Hepatic Histopathological Benefit, Microbial Cost: Oral Vancomycin Mitigates Non-Alcoholic Fatty Liver Disease While Disrupting the Cecal Microbiota.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) encompasses a spectrum of liver conditions and involves gut-liver axis crosstalk. We aimed to evaluate whether oral vancomycin modifies liver injury and the cecal microbiota in a methionine-choline-deficient (MCD) diet model of NASH. Male C57BL/6J mice (n = 28) were block-randomized to four groups (n = 7 each) for 10 weeks: standard diet (STD); MCD diet; STD + vancomycin (VANC); and MCD + VANC (2 mg/mouse ≈ 50 mg/kg, every 72 h). After 10 weeks, liver tissues were analyzed for histological changes, cytokine levels [interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor beta 1 (TGF-β1)], and immunohistochemical markers [ubiquitin and cytokeratin 18 (CK18)]. Cecal microbiota composition was evaluated with 16S ribosomal RNA (rRNA) sequencing. The MCD reproduced key NASH features (macrovesicular steatosis, lobular inflammation). Vancomycin shifted steatosis toward a microvesicular pattern and reduced hepatocyte injury: CK18 and ubiquitin immunoreactivity were decreased in MCD + VANC vs. MCD, and hepatic IL-8 and TGF-β1 levels were lower in MCD + VANC vs. STD. Taxonomically, STD mice had -rich microbiota. The MCD diet alone reduced alpha diversity (α-diversity), modestly lowered Firmicutes and increased /. Vancomycin alone caused a much larger collapse in richness, depleting Gram-positive commensals and promoting blooms of , , , and . In the MCD + VANC group, vancomycin profoundly remodeled the microbiota, eliminating key commensals (e.g., ) and enriching , , and . Oral vancomycin in the MCD model of NASH improved liver injury markers and altered steatosis morphology, but concurrently reprogrammed the gut into a low-diversity, pathobiont-enriched ecosystem with near-loss of . These findings highlight a therapeutic trade-off-hepatic benefit accompanied by microbiome cost-that should guide microbiota-targeted strategies for NAFLD/NASH.