Alcohol-related liver disease disrupts bile acid synthesis and is associated with compensatory gut microbiota changes

BackgroundAlcohol overuse disrupts liver function and alters microbial gut communities, with alcohol-related liver disease (ALD) accounting for half of all liver-related deaths worldwide. Bile acids (BAs) regulate liver and gut function, but their metabolism becomes disrupted in ALD. While it is known that gut microbes transform primary to secondary BAs, which are subsequently reabsorbed via the enterohepatic circulation, BA metabolism during ALD progression remains poorly understood. MethodsWe investigated BA co-metabolism in a cross-sectional cohort of individuals with ALD (n=462) and healthy controls (n=148). We 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 derived from metagenomic and metatranscriptomic sequencing of fecal samples. ResultsAdvanced fibrosis was associated with decreased hepatic BA synthesis and impaired BA transport. Despite this, disease progression corresponded with increased levels of primary and secondary BAs in plasma and feces. The abundance of microbial secondary BA dehydroxylation and epimerization pathways in the gut microbiome changed with disease severity. Genes encoding early steps in the multi-step dehydroxylation pathway increased, whereas those involved in later steps were depleted, indicating a community-level microbial imbalance. In ALD, we identified Eggerthella lenta as a key mediator of BA dehydroxylation, while Mediterraneibacter torques and Bacteroides thetaiotaomicron facilitated most of the BA epimerization as a detoxification mechanism. ConclusionFibrotic ALD is characterized by disrupted primary BA synthesis and transport, leading to BA accumulation in the gut and blood circulation. Altered microbial secondary BA metabolism reflects a compensatory mechanism that becomes impaired at advanced fibrosis stages. Our findings highlight the gut-liver axis as an important factor influencing ALD progression. Impact and ImplicationsO_LIWith the progression of alcohol-related liver disease (ALD), levels of bile acids (BA) in serum and feces increase, but BA production and transport are impaired in the liver. C_LIO_LISecondary microbial BA metabolism, particularly epimerization and dehydroxylation, increases in ALD. However, a key enzyme, baiN, is depleted, illustrating a microbial community-level metabolic dysbiosis. C_LIO_LIThe main contributing microbial species were, among others, Mediterraneibacter torques, Bacteroides thetaiotaomicron, and Eggerthella lenta, which could serve as potential targets for future microbial-targeted interventions. C_LI Lay summaryAlcohol-related liver disease (ALD) from long-term alcohol overuse affects how the liver and gut interact, especially in handling bile acids (BAs), which are molecules produced by the liver and transformed by gut bacteria. Our study found that in people with ALD, the liver produces fewer BAs, but BAs accumulate in the gut and blood because their transport is impaired. We also observed that bacterial transformations of these BA change as the disease progresses, most likely due to an imbalance in the gut microbiome. For the first time, we identify specific bacterial species that strongly influence BA levels in ALD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/25332046v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@19966f0org.highwire.dtl.DTLVardef@352be6org.highwire.dtl.DTLVardef@d5146dorg.highwire.dtl.DTLVardef@1304022_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 0:C_FLOATNO Graphical Abstract C_FIG