biostudies-literatureHaag MNovo Nordisk FoundationEuropean Research CouncilSciLifeLab and Wallenberg National Program for Data-Driven Life SciencePMU-FFFSwedish Research CouncilRuth and Richard Julin Foundation for GastroenterologyERC Consolidator Grant 3DMASHRobert Bosch Stiftung, Stuttgart, Germanye180943https://www.ebi.ac.uk/biostudies/studies/S-EPMC12016937biostudies-literatureUnknown10(8)BACKGROUNDAlterations in circulating metabolites have been described in obese metabolic dysfunction-associated steatotic liver disease (MASLD), but data on lean MASLD are lacking. We investigated serum metabolites, including microbial bile acids and short-chain fatty acids (SCFAs), and their association with lean and obese MASLD.METHODSSerum samples from 204 people of European descent were allocated to groups: lean healthy, lean MASLD, obese healthy, and obese MASLD (n = 47). Liquid chromatography-mass spectrometry-based metabolomics and linear model analysis were performed. MASLD prediction was assessed based on least absolute shrinkage and selection operator regression. Functional effects of altered molecules were verified in organotypic 3D primary human liver cultures.RESULTSLean MASLD JCI insightCirculating metabolite signatures indicate differential gut-liver crosstalk in lean and obese MASLD.PMC12016937E-18/28/148-FELna2021-02801,2023-03015,2024-034012021-00158WASPDDLS22:006101170408NNF23OC0085944,NNF23OC0084420Winter SFeldman AFelder TKTevini JHaag MDatz CSchwab MLiebisch GEder SKAigner ELauschke VMKemas AMBurk OPaulweber BfalseCirculating metabolite signatures indicate differential gut-liver crosstalk in lean and obese MASLD.BACKGROUNDAlterations in circulating metabolites have been described in obese metabolic dysfunction-associated steatotic liver disease (MASLD), but data on lean MASLD are lacking. We investigated serum metabolites, including microbial bile acids and short-chain fatty acids (SCFAs), and their association with lean and obese MASLD.METHODSSerum samples from 204 people of European descent were allocated to groups: lean healthy, lean MASLD, obese healthy, and obese MASLD (n = 47). Liquid chromatography-mass spectrometry-based metabolomics and linear model analysis were performed. MASLD prediction was assessed based on least absolute shrinkage and selection operator regression. Functional effects of altered molecules were verified in organotypic 3D primary human liver cultures.RESULTSLean MASLD 2025-01-01T00:00:00Z2025 Apr2026-07-15T05:01:27.56Z2026-06-30T03:07:54.465ZS-EPMC120169374010031210.1172/jci.insight.180943