Bile acid-axis dysregulation in MASLD/MASH progression: from metabolic mismatch to inflammatory-fibrotic remodeling

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) arise from overlapping metabolic stress, gut-derived inflammatory input, immune activation, and fibrotic remodeling. Bile acids participate in cholesterol metabolism and lipid absorption, and they also regulate metabolic, intestinal barrier, immune, and inflammatory responses through farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (TGR5/GPBAR1), fibroblast growth factor 19 (FGF19), and related signaling pathways. Accordingly, bile acids may constitute an important interface linking intrahepatic metabolic abnormalities with gut–liver inflammatory crosstalk, although many human findings remain associative and require cautious mechanistic interpretation. This review summarizes bile acid-axis dysregulation in MASLD/MASH, focusing on intrahepatic bile acid synthesis and transport, microbiota-mediated bile acid pool remodeling, intestinal barrier disruption, and the intrahepatic inflammatory-fibrotic niche. We propose that bile acid dysregulation should be interpreted beyond simple increases or decreases in total bile acid levels. Instead, it may reflect a systemic mismatch among bile acid pool composition, compartmental distribution, microbial transformation, and receptor-mediated signaling output. Future studies should integrate multi-compartment bile acid profiling with microbial enzyme activity, intestinal barrier assessment, and tissue-specific receptor signaling to support mechanism-based stratification, treatment-response monitoring, and rational combination strategies.