{"doi":"10.1186/s40168-021-01137-3","title":"Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis","abstract":"BACKGROUND: P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical link in communication between intestinal mucosal barrier function and the innate immune system. Yet, despite knowledge for over 10 years that P-gp plays a central role in gastrointestinal homeostasis, the precise molecular mechanism that controls its functional expression and regulation remains unclear. Here, we assessed how the intestinal microbiome drives P-gp expression and function. RESULTS: We have identified a \"functional core\" microbiome of the intestinal gut community, specifically genera within the Clostridia and Bacilli classes, that is necessary and sufficient for P-gp induction in the intestinal epithelium in mouse models. Metagenomic analysis of this core microbial community revealed that short-chain fatty acid and secondary bile acid production positively associate with P-gp expression. We have further shown these two classes of microbiota-derived metabolites synergistically upregulate P-gp expression and function in vitro and in vivo. Moreover, in patients suffering from ulcerative colitis (UC), we find diminished P-gp expression coupled to the reduction of epithelial-derived anti-inflammatory endocannabinoids and luminal content (e.g., microbes or their metabolites) with a reduced capability to induce P-gp expression. CONCLUSION: Overall, by means of both in vitro and in vivo studies as well as human subject sample analysis, we identify a mechanistic link between cooperative functional outputs of the complex microbial community and modulation of P-gp, an epithelial component, that functions to suppress overactive inflammation to maintain intestinal homeostasis. Hence, our data support a new cross-talk paradigm in microbiome regulation of mucosal inflammation. Video abstract.","journal":"Microbiome","year":2021,"id":148821,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":118,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":632964,"name":"Christine Tuohy","orcid":"0009-0007-3846-4694","position":1,"is_corresponding":false},{"id":633794,"name":"Merran Dunford","orcid":null,"position":2,"is_corresponding":false},{"id":312085,"name":"Michael J. Grey","orcid":"0000-0001-7805-7398","position":3,"is_corresponding":false},{"id":313187,"name":"Heidi De Luca","orcid":null,"position":4,"is_corresponding":false},{"id":632965,"name":"Caitlin Cawley","orcid":"0000-0002-8071-4200","position":5,"is_corresponding":false},{"id":494418,"name":"Rose L. Szabady","orcid":"0000-0002-1281-7064","position":6,"is_corresponding":false},{"id":632966,"name":"Ana Maldonado‐Contreras","orcid":"0000-0002-5967-9623","position":7,"is_corresponding":false},{"id":633795,"name":"Jean Marie Houghton","orcid":null,"position":8,"is_corresponding":false},{"id":19838,"name":"Doyle V. Ward","orcid":"0000-0002-4952-824X","position":9,"is_corresponding":false},{"id":632967,"name":"Randall J. Mrsny","orcid":"0000-0001-8505-8516","position":10,"is_corresponding":false},{"id":625978,"name":"Beth A. McCormick","orcid":"0000-0001-5992-2673","position":11,"is_corresponding":false},{"id":628945,"name":"Sage E. Foley","orcid":"0000-0002-4197-8086","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T23:42:46.224799Z","pmid":"34493329","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}