The Mechanism Of CYP2C9 Polymorphism Regulates The Expression Of ACSM6 And Affects Oxygen Consumption Of Colon Epithelial Cells

Background: The Gut microbiota can not only influence the occurrence of diseases but also have interactions with multiple drugs.The changes in microbiome composition are associated with host genetic variation,but the mechanism remains unknown.The discovery of microbiome features related to host genetics and the exploration of its mechanism could be of great significance for realizing individual diagnosis or treatment of diseases and explaining individual differences in drug response.Objective: To explore the molecular mechanism of CYP2C9 polymorphism affects the oxygen consumption of colon epithelial cells and thereby alters the abundance of gut microbiota via regulating ACSM6 expression.Methods:(1)Collecting 59 stool samples from adult human for16 S r DNA sequencing to analyze the relationship between CYP2C9 polymorphism and gut microbial composition.(2)Collecting 312 clinical information from adult human to analyze the correlation between CYP2C9 polymorphism and disease.(3)Using bioinformatics database,Sanger sequencing and Dual-Luciferase Reporter Assays to explore the relationship between rs9332218 and ACSM6.(4)Utilizing UPLC/MS/MS,oxygen consumption rate detection and other experiments to explore the effect of ACSM6 on butyrate metabolism and cell oxygen consumption.(5)Using transcriptomic sequencing to explore the potential mechanisms of ACSM6 in fatty acid metabolism.Results:(1)CYP2C9*3 was significantly associated with the decrease of intestinal Faecalibacterium,Phascolarctobacterium,Collinsella,Faecalibacterium Prausnitzii.(2)The frequency of CYP2C9*3 in patients with Ischemic Stroke was 21.2%.(3)The insertion mutation of rs9332218 was in high linkage disequilibrium with CYP2C9*3and enhanced the transcriptional activity of ACSM6.(4)The ability of sodium butyrate to activate PPAR-γ and increase extracellular oxygen consumption was attenuated when ACSM6 was overexpressed.(5)The expression of ACSM6 was positively correlated with 16 gene sets,including FATTY ACID METABOLISM,ADIPOGENESIS,GLYCOLYSIS,and PEROXISOME.Conclusion: rs9332218 is in high linkage disequilibrium with CYP2C9*3 and enhances the transcriptional activity of ACSM6.ACSM6 can metabolize sodium butyrate in colon epithelial cells to reduce oxygen consumption of colonic epithelial cells.rs9332218 significantly downregulates the abundance of obligate anaerobic bacteria such as Faecalibacterium Prausnitzii in the gut may be related to ACSM6 altering the oxygen consumption of colonic epithelial cells.