# MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $434,135

## Abstract

PROJECT SUMMARY
The overall goal of this application is to establish avenues through which we can harness the intestinal microbiota
to enhance mucosal immune responses against Clostridium difficile. C. difficile infection (CDI) is a common
cause of diarrhea in hospitalized patients and represents a major health threat due to frequent treatment failures
and high risks of colectomy and mortality. Patients with recurrent CDI do not benefit from conventional
antimicrobial therapies; while transplantation of fecal microbiota derived from healthy donors might be a valid
option, regulation of fecal transplantation is problematic. In our preliminary data we show for the first time a
remarkable impact of microbiota-derived acetate on CDI, which may constitute a potential therapeutic avenue.
We show that acetate enhances neutrophil and innate lymphoid cells of type 3 (ILC3) responses through the
surface receptor FFAR2. Moreover, we show that lack of a decoy receptor for IL-22, known as IL-22 binding
protein (IL-22BP), amplifies the activity of IL-22 and modifies the microbiota, strengthening its resistance to CDI.
We propose three specific aims. In Specific Aim 1, we will test the mechanisms through which acetate-FFAR2
signaling activates the neutrophil response to CDI. We will perform in vitro functional and transcriptional
experiments to determine whether FFAR2 promotes neutrophil recruitment to chemoattractants, upregulates
expression of inflammasome components, alters the neutrophil transcriptional profile, and/or modifies neutrophil
metabolism. The impact of acetate on human neutrophils will be examined as well. In Specific Aim 2, using newly
generated mice lacking FFAR2 in ILC3s, along with mice lacking FFAR2 in neutrophils, we will determine
whether FFAR2 mediated activation of ILC3s is necessary and sufficient to recapitulate the protective effect of
acetate in vivo. Furthermore, we will determine whether FFAR2 impacts ILC3-mediated lymphoid organogenesis
in the steady state and whether FFAR2 modifies the transcriptome and/or metabolism of mouse and human
ILC3s. Finally, we will ascertain whether acetate can be used in a therapeutic mode. In Specific Aim 3, we will
test the hypothesis that lack of IL-22BP and the resulting increased basal activity of IL-22 modify the intestinal
microbiota in a manner that facilitates the colonization of bacterial cohorts that enhance protection against CDI.
This work is significant because it addresses the major health burden of dysbiosis and CDI, is innovative because
it evaluates alternative therapeutic approaches based on acetate and/or blockade of IL-22BP rather than live
microbiota and has potential to translate into novel treatments with implications for health and productivity. The
project will be accomplished through the ongoing collaboration between the Colonna lab in USA and the Vinolo
lab in Brazil, each with distinct and complementary sets of expertise on CDI, short chain fatty acids, and mucosal
innate...

## Key facts

- **NIH application ID:** 10098562
- **Project number:** 1R01DK126969-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MARCO COLONNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,135
- **Award type:** 1
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098562

## Citation

> US National Institutes of Health, RePORTER application 10098562, MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN (1R01DK126969-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10098562. Licensed CC0.

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