Bile acids (BAs) act as hormonal ligands of the hepatic and intestinal receptor farnesoid X receptor and stimulators of fibroblast growth factor 19 (FGF-19) and glucagon-like peptide-1 (GLP-1) secretion. Although metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to BAs dysregulation, the effects of advanced fibrosis on plasma and fecal BAs profiles remain unclear. We compared 35 plasmatic and fecal BAs concentrations and qualitative pools, including primary, secondary, unconjugated, and conjugated BAs in the fasting state between individuals with advanced fibrosis stages (F3-F4/4) (= 28) and individuals without advanced fibrosis (= 26). Median age (interquartile range (IQR)) (56 [48-65] vs. 57 [49-66] yr), sex (62 vs. 60% man), and body mass index (32 [29-36] vs. 34 [32-38] kg/m) were comparable between groups. Total plasmatic BAs concentration was increased in the advanced stage of fibrosis (< 0.01), whereas total stool BAs concentration did not differ between groups (= 0.36). Participants with advanced fibrosis had higher chenodeoxycholic acid family BAs, which were driven by increased glyco- and tauro-conjugated forms (< 0.05). Plasma unconjugated secondary BA lithocholic acid was also higher in advanced fibrosis (< 0.01), but we did not find a change in intestinal microbiota bile salt hydrolase enzymatic activity, which is responsible for the deconjugation of BAs. There were no differences in FGF-19 and GLP-1 concentrations between groups. Overall, our results lead us to hypothesize that the increase in hepatic bile acid production in cases of MASLD with advanced fibrosis may occur mainly via the acid pathway or leakage of BAs from the liver into the plasma caused by hepatic inflammation, without changes in intestinal BAs metabolism. This profile of increased hydrophobic plasma BAs may contribute to MASLD progression, inflammation, and oxidative stress.This study explored detailed plasma and fecal concentrations of 35 bile acids in MASLD with advanced fibrosis. Total, primary, and secondary plasmatic bile acids, particularly the CDCA family, were increased in advanced fibrosis without changes in their effectors, FGF-19/GLP-1. This profile may lead to a proinflammatory BA profile. We also showed that novel, unstudied BAs species are of interest in advanced fibrosis, such as glucuronides. n n P P P P2NEW & NOTEWORTHY
