{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Escalante V"],"funding":["National Institute of Arthritis and Musculoskeletal and Skin Diseases","National Institute of Diabetes and Digestive and Kidney Diseases","NHLBI NIH HHS","National Center for Complementary and Integrative Health","National Heart, Lung, and Blood Institute","National Institute of General Medical Sciences","NCCIH NIH HHS","NIDDK NIH HHS","Burroughs Wellcome Fund","NIAMS NIH HHS","Chan Zuckerberg Biohub-San Francisco","NIGMS NIH HHS","National Science Foundation"],"pagination":["372-386"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10940213"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["122(3)"],"pubmed_abstract":["Drugs intended to target mammalian cells can have broad off-target effects on the human gut microbiota with potential downstream consequences for drug efficacy and side effect profiles. Yet, despite a rich literature on antibiotic resistance, we still know very little about the mechanisms through which commensal bacteria evade non-antibiotic drugs. Here, we focus on statins, one of the most prescribed drug types in the world and an essential tool in the prevention and treatment of high circulating cholesterol levels. Prior work in humans, mice, and cell culture support an off-target effect of statins on human gut bacteria; however, the genetic determinants of statin sensitivity remain unknown. We confirmed that simvastatin inhibits the growth of diverse human gut bacterial strains grown in communities and in pure cultures. Drug sensitivity varied between phyla and was dose-dependent. We selected two representative simvastatin-sensitive species for more in-depth analysis: Eggerthella lenta (phylum: Actinobacteriota) and Bacteroides thetaiotaomicron (phylum: Bacteroidota). Transcriptomics revealed that both bacterial species upregulate genes in response to simvastatin that alter the cell membrane, including fatty acid biogenesis (E. lenta) and drug efflux systems (B. thetaiotaomicron). Transposon mutagenesis identified a key efflux system in B. thetaiotaomicron that enables growth in the presence of statins. Taken together, these results emphasize the importance of the bacterial cell membrane in countering the off-target effects of host-targeted drugs. Continued mechanistic dissection of the various mechanisms through which the human gut microbiota evades drugs will be essential to understand and predict the effects of drug administration in human cohorts and the potential downstream consequences for health and disease."],"journal":["Molecular microbiology"],"pubmed_title":["Simvastatin induces human gut bacterial cell surface genes."],"pmcid":["PMC10940213"],"funding_grant_id":["7028823","R25GM056847","R01 DK114034","R01AT011117","R01 HL122593","R01 AT011117","1650113","P30 DK098722","R25 GM056847","F32GM140808","RM1 GM135102","RM1GM135102","1017921","K08 AR073930","R01HL122593","F32 GM140808","R01DK114034","R01 AR074500","R01AR074500"],"pubmed_authors":["Escalante V","Babdor J","Deutschbauer AM","Spitzer M","Noecker C","Nayak RR","Turnbaugh PJ"],"additional_accession":[]},"is_claimable":false,"name":"Simvastatin induces human gut bacterial cell surface genes.","description":"Drugs intended to target mammalian cells can have broad off-target effects on the human gut microbiota with potential downstream consequences for drug efficacy and side effect profiles. Yet, despite a rich literature on antibiotic resistance, we still know very little about the mechanisms through which commensal bacteria evade non-antibiotic drugs. Here, we focus on statins, one of the most prescribed drug types in the world and an essential tool in the prevention and treatment of high circulating cholesterol levels. Prior work in humans, mice, and cell culture support an off-target effect of statins on human gut bacteria; however, the genetic determinants of statin sensitivity remain unknown. We confirmed that simvastatin inhibits the growth of diverse human gut bacterial strains grown in communities and in pure cultures. Drug sensitivity varied between phyla and was dose-dependent. We selected two representative simvastatin-sensitive species for more in-depth analysis: Eggerthella lenta (phylum: Actinobacteriota) and Bacteroides thetaiotaomicron (phylum: Bacteroidota). Transcriptomics revealed that both bacterial species upregulate genes in response to simvastatin that alter the cell membrane, including fatty acid biogenesis (E. lenta) and drug efflux systems (B. thetaiotaomicron). Transposon mutagenesis identified a key efflux system in B. thetaiotaomicron that enables growth in the presence of statins. Taken together, these results emphasize the importance of the bacterial cell membrane in countering the off-target effects of host-targeted drugs. Continued mechanistic dissection of the various mechanisms through which the human gut microbiota evades drugs will be essential to understand and predict the effects of drug administration in human cohorts and the potential downstream consequences for health and disease.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Sep","modification":"2026-05-28T20:25:02.272Z","creation":"2026-04-08T03:03:50.545Z"},"accession":"S-EPMC10940213","cross_references":{"pubmed":["37712143"],"doi":["10.1111/mmi.15151"]}}