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| Item Type: | Article |
|---|---|
| Title: | Alcohol-related liver disease disrupts bile acid homeostasis and gut microbial bile acid metabolism |
| Creators Name: | Keller, Marisa Isabell, de Zawadzki, Andressa, Thiele, Maja, Suvitaival, Tommi, Sulek, Karolina, Kuhn, Michael, Schudoma, Christian, Podlesny, Daniel, Nishijima, Suguru, Fullam, Anthony, Kim, Chan Yeong, Niu, Lili, Wretlind, Asger, Hansen, Johanne Krag, Israelsen, Mads, Johansen, Stine, Akanni, Wasiu, Hazenbrink, Diënty, Juel, Helene Baek, Mann, Matthias, Hansen, Torben, Krag, Aleksander, Bork, Peer and Legido-Quigley, Cristina |
| Abstract: | BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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 multi-step dehydroxylation pathway (e.b. baiB) increased, whereas those in the reduction arm (baiN) were depleted. In ALD patients, we suggest Eggerthella lenta, Mediterraneibacter torques, and Bacteroides thetaiotaomicron as relevant microbes for BA metabolism. CONCLUSION: 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. |
| Keywords: | Steatotic Liver Disease (SLD), Enterohepatic Circulation, Gut Microbiome, Gut-Liver Axis |
| Source: | JHEP Reports |
| ISSN: | 2589-5559 |
| Publisher: | Elsevier |
| Page Range: | 101848 |
| Date: | 2 April 2026 |
| Official Publication: | https://doi.org/10.1016/j.jhepr.2026.101848 |
| PubMed: | View item in PubMed |
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