Alcohol-related liver disease disrupts bile acid homeostasis and gut microbial bile acid metabolism

<h4>Background & aims</h4>Alcohol overuse disrupts liver function and alters gut microbial communities, with alcohol-related liver disease (ALD) causing half of all liver-related deaths worldwide. Bile acids (BAs) regulate liver and gut function, but their homeostasis becomes disrupted in ALD. Gut microbes transform primary BAs to secondary BAs, which are reabsorbed via enterohepatic circulation, but BA metabolism during ALD progression remains poorly understood.<h4>Methods</h4>We investigated BA homeostasis in a cross-sectional ALD cohort (n = 462), alongside matched healthy controls (n = 148), and validated key findings in two independent ALD cohorts (n = 34 and n = 52). We integrated BA concentrations, measured by targeted mass spectrometry in feces and plasma, with liver proteomics and gut microbiome profiles from metagenomic and metatranscriptomic sequencing.<h4>Results</h4>Advanced fibrosis states were associated with decreased hepatic BA synthesis, impaired hepatic BA uptake from blood but with increased levels of primary and secondary BAs in plasma (inprimis, taurocholic acid: F = 69.9, p = 8.6e-66) and feces (inprimis, cholic acid: F = 5.5, p = 1.4e-4). The abundance of microbial secondary BA dehydroxylation and epimerization pathways in the gut microbiome community increased with disease severity. Genes encoding the oxidation arm in the multistep dehydroxylation pathway (including baiB) increased, whereas those in the reduction arm (baiN) were depleted. In patients with ALD, we suggest Eggerthella lenta, Mediterraneibacter torques, and Bacteroides thetaiotaomicron as relevant microbes for BA metabolism.<h4>Conclusion</h4>Fibrotic ALD is characterized by disrupted primary BA synthesis and hepatic uptake, leading to hepatotoxic BA accumulation in the gut and blood circulation. Altered microbial secondary BA metabolism reflects a functional shift in the gut microbiome throughout the fibrosis stages. Our findings highlight the gut-liver axis as an important factor influencing ALD progression, even in early, asymptomatic fibrosis stages.<h4>Impact and implications</h4>This study shows that integrating different omics approaches provides insight into metabolic disruptions across the gut-liver axis that drive ALD progression. Additionally, our study identifies specific bacterial species influencing BA concentrations in ALD using data from human fecal metagenomics and metatranscriptomics. These findings could inform the design of future therapeutic targets focusing on either the liver or the gut for treating ALD.