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

Award Number: R01DK126969
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN - 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 immunity that must be combined to successfully complete this project. The synergy between the two labs has already generated results that serve as the basis for this proposal and will produce fundamental research on the impact of the microbiota on mucosal responses to CDI and unveil new potential therapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $389,093 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/27/2023	NON-COMPETING CONTINUATION	$364,776
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/14/2024	NON-COMPETING CONTINUATION	$24,317
														Subtotal = $389,093

Issue Date FY: 2023 ( Subtotal = $410,302 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/11/2023	NON-COMPETING CONTINUATION	$410,302
														Subtotal = $410,302

Issue Date FY: 2022 ( Subtotal = $415,111 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/25/2022	NON-COMPETING CONTINUATION	$41,511
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/10/2021	NON-COMPETING CONTINUATION	$373,600
														Subtotal = $415,111

Issue Date FY: 2021 ( Subtotal = $434,135 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/23/2020	NEW	$434,135
														Subtotal = $434,135

Grand Total All Awards = $1,648,641

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

Award Number: R01DK126969

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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