Microbiota-dependent control of clostridium difficile: the role of acetate and IL-22 binding protein

Ended Project Grant Awarded Last action

Award ID
R01DK126969
Recipient
Awarding agency
Obligated
$4,195,615

Award facts

Completion date
Originally
Funding
  • $3,761,479.98 Federal
  • $434,135.00 Non-federal
Place of performance
Missouri, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Federal Non-federal Date
Amendment -$0 $0
Amendment $24,317 $0
Amendment $364,776 $0
Amendment $364,776 $0
Amendment $410,302 $0
Amendment $410,302 $0
Amendment $410,302 $0
Amendment $410,302 $0
Amendment $41,511 $0
Amendment $41,511 $0
Amendment $41,511 $0
Amendment $373,600 $0
Amendment $434,135 $0
Original award $434,135 $434,135
Show all 14

Subawards

Subrecipient Amount Awarded
Universidade Estadual De Campinas STATEMENT OF WORK – University of Campinas, Brazil Marco Colonna is the contact Principal Investigator responsible for ensuring proper conduct of the… $128,304
Universidade Estadual De Campinas $0
Universidade Estadual De Campinas $142,560
Universidade Estadual De Campinas $14,256
Universidade Estadual De Campinas $128,304
Universidade Estadual De Campinas $142,560

Quick answers

Who received award R01DK126969?

R01DK126969 was awarded to The Washington University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on January 1, 2021.

How much is award R01DK126969 worth?

$4,195,615 has been obligated on R01DK126969: $3,761,480 in federal funding and $434,135 in non-federal funding.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login