Effects Of Probiotics On The Expression Profiles Of Host Drug-Processing Genes And Pharmacokinetics

Background:Oral drugs are absorbed,distributed,metabolized and excreted in the body,and the liver plays a very important role in drug metabolism.In recent years,studies have found that gut microbiota also plays a role in drug metabolism.Therefore,with the increasing use of probiotic products in daily and clinical practice,it is very necessary to systematically understand the expression of probiotics on the expression profiles of host drug-processing genes and their impact on metabolic kinetics.At present,the research on the effect of probiotics on the expression of host drug-processing genes is scattered and single,and there is a lack of systematic research on the gene expression profiles of probiotics on the whole drug disposal of the host.Therefore,this study mainly investigated the effects of probiotic VSL#3 on gut microbiota,the expression profiles of host drug-processing genes and pharmacokinetics.Methods:SPF healthy Wistar rats were randomly divided into a probiotic group and a control group.The probiotic group was treated with 5×10¹⁰bacteria/kg/d of VSL#3 probiotics in drinking water,and the control group was treated with give normal drinking water.After 14 days,the six drug mixtures of omeprazole,tolbutamide,midazolam,metoprolol,phenacetin and chlorzoxazone were administered by oral gavage in the way of Cocktail.Blood samples were collected at time points of 0,0.083,0.167,0.250,0.333,0.75,1,1.5,2,4,6,8,and 12 h from rat tail microcapillary method,and analyzed by UPLC-MS/MS.The concentrations of each drug and metabolite were detected,and the pharmacokinetic changes were analyzed.16S rRNA method to measure changes in gut microbiota.Liver RNA were extracted and RNA-seq technology was used to analyze the effect of probiotics on the gene expression profiles of the host.Changes in serum bile acid metabolism were analyzed by targeted metabolomics.The changes of gene expression profiles,gut microbiota,bile acid metabolism profiles and pharmacokinetics of the two groups were analyzed and compared.Results:Compared with the control group,there was no significant difference in blood biochemical indexes and liver and kidney tissue sections in the probiotic group.Probiotics significantly changed the composition of rat gut microbiota at all classification levels.The expression profiles of drug-processing genes in probiotic group rats changed significantly,including a variety of phase I and phase II metabolic enzymes.Probiotics significantly changed the pharmacokinetics of omeprazole,tolbutamide,midazolam,phenacetin and chlorzoxazone,and the duodenal villi became shorter and the ileal villi became longer.The content of conjugated bile acids in probiotic group decreased significantly,and a variety of different bile acids were significantly correlated with Bacteroides.Conclution:Probiotics changed the gene expression profiles of host drug-processing genes,the composition of gut microbiota and the proportion of bile acids.At the same time,they also changed the pharmacokinetic behavior of omeprazole,tolbutamide,midazolam,phenacetin and chlorzoxazone.