# Exploring the role, regulation, and antimicrobial function of Paneth cell peptides PYY and NPY in maintaining gut microbial commensalism and innate immune defense

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $719,417

## Abstract

PROJECT SUMMARY/ABSTRACT
Innate immune factors are critical for the selection and maintenance of regional commensal gut microbiota that
provide beneficial functions for the host and deterrence against pathogens and pathobionts. In the previous grant
cycle, we discovered that peptide YY (PYY), an anorexigenic or satiety-related gut hormone of intestinal
enteroendocrine L-cell origin, is expressed by innate immune intestinal Paneth cells (PC) and functions as an
antimicrobial peptide (AMP) in its unmodified PYY1-36 form (henceforth referred to as PC-PYY1-36). PYY's
structure differs from other PC-α and β−defensins but is remarkably similar to the amphibian AMP, magainin-2,
that has both anti-fungal and anti-bacterial properties. PC-PYY1-36 further differs from other PC-AMPs by
selectively targeting and killing the virulent (hyphal), but not commensal (yeast) forms of polymorphic gut fungi
like Candida albicans, thereby playing an important role in maintaining fungal (and also bacterial) commensalism
of the gut. PC-PYY1-36 also differs from the endocrine PYY3-36 that is derived from DPP-IV conversion of L-cell
PYY in structure and function by being vectorally secreted into and retained by intestinal mucus where its activity
is optimal and protected from dipeptidyl peptidase IV (DPP-IV) modification that would otherwise convert it to the
endocrine PYY3-36 form. We subsequently discovered that PCs also express another anorexigenic peptide highly
related to PYY, neuropeptide Y (NPY1-36), that also has AMP properties. However, its regulation, antimicrobial
spectrum, and compartmentalization upon secretion in luminal fluid rather than overlying mucus differs from that
of PC-PYY. Based on our findings, we hypothesize that PC-PYY and PC-NPY are a novel class of PC-
AMPs that play important roles in maintaining gut microbial commensalism and conferring innate
immune defense against certain pathogens and pathobionts. Two specific aims are proposed: (1) to define
and differentiate the drivers, mediators, and signaling pathways involved in regulation of PC-PYY and PC-NPY
gene expression, secretion, and regional compartmentalization under physiological and pathophysiological
conditions, and (2) to determine and differentiate the antimicrobial spectra of PC-PYY and -NPY in vitro and in
vivo and their impact on gene expression and adaptive responses of targeted bacterial and fungal species. These
studies will employ newly established in vivo (PC-PYY and PC-NPY KO and PC-PYY transgenic mice) as well
as in vitro and ex vivo approaches. The MPI team combines unique expertise and resources in experimental
research, multi'omic technologies, and host-microbe interactions (Chang, UChicago), experimental physiology
and pathophysiology (Pierre, UWisc-M), and microbiology, bioinformatics, and genetics (Peters, UTHSC). Thus,
the whole is much greater than the sum of the parts. The MPI groups have collaborated productively over the
past two years to acquire the preliminary a...

## Key facts

- **NIH application ID:** 10882653
- **Project number:** 2R01DK113788-05A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** EUGENE B CHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $719,417
- **Award type:** 2
- **Project period:** 2017-04-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882653

## Citation

> US National Institutes of Health, RePORTER application 10882653, Exploring the role, regulation, and antimicrobial function of Paneth cell peptides PYY and NPY in maintaining gut microbial commensalism and innate immune defense (2R01DK113788-05A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10882653. Licensed CC0.

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