ORCID ID

0000-0002-4197-8086

Publication Date

2022-03-22

Document Type

Doctoral Dissertation

Academic Program

Immunology and Microbiology

Department

Microbiology and Physiological Systems

First Thesis Advisor

Beth McCormick

Keywords

P-glycoprotein, Microbiome, Intestine, Inflammatory bowel disease, Ulcerative colitis, Inflammation, Short-chain fatty acids, Secondary bile acids, Homeostasis, Metabolite, Intestinal epithelium, Epithelial cells

Abstract

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.

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.

DOI

10.13028/zbvt-nr94

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Sunday, April 28, 2024

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