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dc.contributor.advisorBeth McCormick
dc.contributor.authorFoley, Sage E
dc.date2022-08-11T08:08:47.000
dc.date.accessioned2022-08-23T16:08:12Z
dc.date.available2022-08-23T16:08:12Z
dc.date.issued2022-03-22
dc.date.submitted2022-04-29
dc.identifier.doi10.13028/zbvt-nr94
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32394
dc.description.abstractP-glycoprotein (P-gp) protects the mammalian intestinal epithelium by effluxing toxins from the epithelial cells as well as release of human endocannabinoids that inhibit neutrophil infiltration. Diminished or dysfunctional P-gp is associated with intestinal inflammation including ulcerative colitis (UC). Due to the microbiome dysbiosis associated with UC, we hypothesize that the healthy microbiota promote colonic P-gp expression. Utilizing mouse models of antibiotic treatment, microbiota reconstitution, and metabolite perturbation, we have shown butyrate and secondary bile acids, dependent on vancomycin-sensitive bacteria, induce P-gp expression in vivo. We have shown these metabolites together potentiate induction of P-gp in intestinal epithelial cell lines in vitro, which is sufficient to inhibit primary human neutrophil transmigration. Furthermore, in UC patients we find diminished P-gp expression is coupled to reduction of anti-inflammatory endocannabinoids and luminal content with reduced capability to induce P-gp expression. Additionally, we have found butyrate contributes to P-gp expression via histone deacetylase inhibition, and secondary bile acids regulate P-gp expression via nuclear receptors pregnane X receptor and vitamin D receptor. Employing RNA sequencing (RNAseq) in IECs uncovered signaling networks that are uniquely triggered with the combination of butyrate and secondary bile acids, suggesting additional pathways required for maximal P-gp expression in the colon. Together we identify a mechanistic link between cooperative functional outputs of the complex microbial community and suppression of intestinal inflammation. These data emphasize the importance of the intestinal microbiome in driving the P-gp axis to suppress aberrant neutrophil infiltration and identify potential therapeutic targets for promoting P-gp expression in an inflamed colon to reset homeostasis.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectP-glycoprotein
dc.subjectMicrobiome
dc.subjectIntestine
dc.subjectInflammatory bowel disease
dc.subjectUlcerative colitis
dc.subjectInflammation
dc.subjectShort-chain fatty acids
dc.subjectSecondary bile acids
dc.subjectHomeostasis
dc.subjectMetabolite
dc.subjectIntestinal epithelium
dc.subjectEpithelial cells
dc.subjectBacteria
dc.subjectBiology
dc.subjectCell Biology
dc.subjectDigestive, Oral, and Skin Physiology
dc.subjectDigestive System
dc.subjectDigestive System Diseases
dc.subjectGastroenterology
dc.subjectImmunology and Infectious Disease
dc.subjectMicrobiology
dc.titleGut Microbiota Regulation of P-Glycoprotein in the Mammalian Intestinal Epithelium to Suppress Aberrant Inflammation and Maintain Homeostasis
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2193&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/1183
dc.legacy.embargo2024-04-28T00:00:00-07:00
dc.identifier.contextkey28909015
html.description.abstract<p>P-glycoprotein (P-gp) protects the mammalian intestinal epithelium by effluxing toxins from the epithelial cells as well as release of human endocannabinoids that inhibit neutrophil infiltration. Diminished or dysfunctional P-gp is associated with intestinal inflammation including ulcerative colitis (UC). Due to the microbiome dysbiosis associated with UC, we hypothesize that the healthy microbiota promote colonic P-gp expression.</p> <p>Utilizing mouse models of antibiotic treatment, microbiota reconstitution, and metabolite perturbation, we have shown butyrate and secondary bile acids, dependent on vancomycin-sensitive bacteria, induce P-gp expression <em>in vivo</em>. We have shown these metabolites together potentiate induction of P-gp in intestinal epithelial cell lines <em>in vitro</em>, which is sufficient to inhibit primary human neutrophil transmigration. Furthermore, in UC patients we find diminished P-gp expression is coupled to reduction of anti-inflammatory endocannabinoids and luminal content with reduced capability to induce P-gp expression. Additionally, we have found butyrate contributes to P-gp expression via histone deacetylase inhibition, and secondary bile acids regulate P-gp expression via nuclear receptors pregnane X receptor and vitamin D receptor. Employing RNA sequencing (RNAseq) in IECs uncovered signaling networks that are uniquely triggered with the combination of butyrate and secondary bile acids, suggesting additional pathways required for maximal P-gp expression in the colon.</p> <p>Together we identify a mechanistic link between cooperative functional outputs of the complex microbial community and suppression of intestinal inflammation. These data emphasize the importance of the intestinal microbiome in driving the P-gp axis to suppress aberrant neutrophil infiltration and identify potential therapeutic targets for promoting P-gp expression in an inflamed colon to reset homeostasis.</p>
dc.identifier.submissionpathgsbs_diss/1183
dc.contributor.departmentMicrobiology and Physiological Systems
dc.description.thesisprogramImmunology and Microbiology
dc.identifier.orcid0000-0002-4197-8086


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