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Abstract
Gut-microbiota derived metabolites are important regulators of host biology and metabolism. To understand the impacts of the microbial metabolite 4-cresol sulfate (4-CS) on four chronic diseases [type 2 diabetes mellitus, metabolic syndrome (MetS), non-alcoholic fatty liver disease, and chronic kidney disease (CKD)], we conducted association analyses of plasma 4-CS quantified by liquid chromatography coupled to mass spectrometry (LC–MS) in 3641 participants of the Nagahama study. Our results validated the elevation of 4-CS in CKD and identified a reducing trend in MetS. To delineate the holistic effects of 4-CS, we performed a phenome-wide association analysis (PheWAS) with 937 intermediate biological and behavioral traits. We detected associations between 4-CS and 39 phenotypes related to blood pressure regulation, hepatic and renal functions, hematology, sleep quality, intraocular pressure, ion regulation, ketone and fatty acid metabolisms, disease history and dietary habits. Among them, 19 PheWAS significant traits, including fatty acids and 14 blood pressure indices, were correlated with MetS, suggesting that 4-CS is a potential biomarker for MetS. Consistent associations of this gut microbial-derived metabolite on multiple endophenotypes underlying distinct etiopathogenesis support its role in the overall host health, with prospects of probiotic-based therapeutic solutions in chronic diseases.
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1 Kyoto University, Center for Genomic Medicine, Graduate School of Medicine, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); McGill University, Department of Human Genetics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
2 Kyoto University, Center for Genomic Medicine, Graduate School of Medicine, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033)
3 Kyoto University, Center for Genomic Medicine, Graduate School of Medicine, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); Shimadzu Corporation, Life Science Research Center, Technology Research Laboratory, Kyoto, Japan (GRID:grid.274249.e) (ISNI:0000 0004 0571 0853)
4 Kyoto University, Center for Genomic Medicine, Graduate School of Medicine, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); McGill University, Department of Human Genetics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); University Paris Cité, INSERM UMR1124, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602)
5 McGill University, Department of Human Genetics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, Institute of Parasitology, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)