Peptide tyrosine tyrosine (PYY) is a highly conserved molecule in vertebrate organisms with diverse regulatory roles, including satiety, circadian rhythmicity, and intestinal physiology. It was previously thought that PYY was exclusively found in intestinal enteroendocrine cells (EECs), the brain stem, and epidermal dendritic cells. We now find that PYY appears to be expressed in small intestinal Paneth cells, raising the possibility that PYY has an additional role as an antimicrobial peptide. This possibility is furthe supported by similarities in the protein structure and charge distribution of PYY to other antimicrobial compounds. Additionally, upon stimulation with microbial products, ex vivo ileal tissues from conventionally raised (CONV) mice release PYY into culture, while tissues from germ-free (GF) animals does not, analogous to other antimicrobial peptides that are regulated by and involved in microbial assemblage. However, we find that PYY (0-25uM) does not appear to have anti-bacterial effects, but rather a selective action in inhibiting hyphae formation in Candida albicans, an important human fungal member and potential pathogen of the gut microbiota. Non-hyphae expressing fungi, or yeast, were unaffected by PYY. Based on these observations, we hypothesize that PYY is an important and selective antimicrobial compound that modulates the virulence of eukaryotic microorganisms of the intestinal microbiome. To test this hypothesis, we propose the following aims: (1) to characterize the regulation of Paneth cell PYY expression and release in response to stimulus and the localization and concentrations of PYY within the intestinal mucous and luminal compartments, and (2) to investigate the effect of PYY upon C. albicans hyphae formation (GFP-tagged), gene expression, and pathogenicity against human Caco-2 cell culture. We believe this work has the potential to be paradigm shifting in showing alternative roles for gut peptides such as PYY in host regulation of intestinal fungal organisms. These studies will also provide further training and opportunities in new research areas that will continue the applicant's career development in academic biomedical research.
This project seeks to test the hypothesis that the intestinal peptide hormone, PYY, which we recently found is expressed by Paneth cells, functions as a unique innate antimicrobial peptide that selectively inhibits the virulence of fungal pathogens. Defects in Paneth cell function observed in Crohn's disease may be associated with increased virulence of fungal species, possibly contributing to the pathogenesis of these disorders. Indeed, systemic antibodies against fungal components were classically utilized in the diagnosis of Crohn's. These studies will employ novel in vitro and in vivo approaches to gain physiological and mechanistic insights into host regulation of eukaryotic intestinal microorganisms.
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| Martinez, Kristina B; Pierre, Joseph F; Chang, Eugene B (2016) The Gut Microbiota: The Gateway to Improved Metabolism. Gastroenterol Clin North Am 45:601-614 |
| Pierre, Joseph F; Busch, Rebecca A; Kudsk, Kenneth A (2016) The gastrointestinal immune system: Implications for the surgical patient. Curr Probl Surg 53:11-47 |
