Rifaximin Protects Against Inflammation and Fibrosis in MASH: Any Role for Ethanol-Producing Bacteria?

Abstract

Metabolic Dysfunction-Associated Steato-Hepatitis (MASH) is a multiple-hit disease. Endotoxins, ethanol, and other metabolites of certain gut microbiota can reach the liver and accelerate inflammation and disease progression. Targeting ethanol-producing colonic bacteria with rifaximin could affect the progress of MASH. In the present study, thirty mice were assigned to three groups (= 10 mice per group). Mice received either a normal diet, a Western diet, or a Western diet with oral rifaximin. After 12 weeks, liver function, serum levels of TNF-α, interleukin (IL)-1β, IL-6, and lipopolysaccharides (LPS) were measured. Liver specimens were assessed for pathological changes, lipid deposition, and fibrosis. Expression of,,, andin the liver was also assessed. Faecal samples were evaluated for ethanol contents.in addition to ethanol-producingand, were isolated, quantified, and tested for sensitivity to rifaximin. Rifaximin was able to ameliorate Western diet-induced biochemical changes and elevated TNF-α, IL-1β, IL-6, and LPS levels. Changes in liver histology, fibrosis, and lipid content were attenuated. Expressions of,,, andin the liver were all reduced. The Western diet-induced increases in faecal ethanol or ethanol-producing bacteria were not corrected by rifaximin. After 12 weeks, isolated bacteria from the rifaximin group were rifaximin-resistant. Our findings imply that the protective impact of rifaximin in the MASH model is unlikely to be mediated by alteration of ethanol-producing colonic bacteria because of acquired rifaximin resistance. Rifaximin-induced reduction in endotoxemia and inflammation in the liver appears to be a more relevant explanation.