Bacterial targeting of the P-glycoprotein to reduce intestinal inflammation in ulcerative colitis

Abstract

Ulcerative colitis (UC) is a devastating chronic disease characterized by aberrant colonic inflammation and intestinal dysbiosis. The pathognomonic ulceration as well as intestinal epithelial damage is driven by excess luminal infiltration and activation of neutrophils. Recently our group discovered a system of lipid mediators regulating transmigration of neutrophils from the colonic lamina propria across the epithelial barrier. During homeostasis the multidrug resistance efflux pump p-glycoprotien (P-gp) maintains a gradient of endocannabinoids, which limits neutrophil transmigration. During inflammation however, P-gp is downregulated and Multidrug resistance-associated protein 2 (MRP2), which secretes the neutrophil chemoattractant hepoxilin A3 is upregulated, promoting luminal infiltration of neutrophils. In ulcerative colitis P-gp is significantly downregulated, resulting in the excess luminal accumulation of neutrophils found in ulcer bases. We discovered that the balance of these multidrug resistant efflux pumps is dependent on the microbiome and its secreted metabolites, which is significantly altered in UC. Consequently, we are designing a consortium of bacteria to optimize the expression of P-gp on the host epithelium and thus restrain neutrophil transmigration in UC.Using antibiotic stratification experiments and fecal xenograft models we have identified specific bacterial species that increase P-gp expression, and thus likely restrain neutrophil transmigration. Thus far we have validated the role of 15 candidate bacteria and 78 bacterial metabolites in regulating P-gp expression and function either directly or through interactions with other bacterial species. Leveraging this understanding of microbial regulation of host efflux pumps as well as in-vivo population dynamics data we are developing an algorithm to predict the P-gp induction ability of all possible combinations of candidate microbe. Using this algorithm we will design P-gp high, mid, and low inducing consortia, to study the role of these populations on intestinal inflammation using murine models of ulcerative colitis. The development of such consortia has wide ranging implications for research and clinical practice alike from facilitating further study of the underlying inter-microbial networks regulating key host defense systems in the intestine to the development of a probiotic with the potential to limit colonic neutrophil infiltration in patients with UC. This work is supported by R01DK125407, T32AI132152, and F30DK134110 by National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.