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Site specific gene-microbial interactions in children with early-onset Crohn’s disease

Award Number: R21AI194215
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/17/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Site specific gene-microbial interactions in children with early-onset Crohn’s disease - Crohn's disease (CD), one of the major forms of inflammatory bowel disease (IBD), is characterized by chronic inflammation that can affect any part of the gastrointestinal tract in children and adults. When IBD develops in children under the age of 6, it is defined as very early onset IBD (VEO-IBD). Children with VEO-IBD often have distinct phenotypes, characterized by a severe disease course that is more refractory to conventional therapies than older patients. Abnormal interactions between gut microbes and the immune system in genetically susceptible individuals are thought to contribute to CD. Unlike adult-onset CD, host genetics are recognized to play a more predominant role in VEO-IBD. Several genes located within the VEO-IBD- associated loci are involved in the regulation of barrier function and innate and/or adaptive immune responses, particularly against microbes, including NOD2-mediated bacterial sensing and phagocyte NADPH oxidase-mediated bacterial killing. Notably, we have found that a combined deficiency in NOD2 and CYBB, a component of the NADPH oxidase, triggers early- onset, spontaneous, microbiota-dependent colitis with skip lesions in mice that closely resembles the human disease. Since little is known about the role of microbes in the development of CD in young children (referred as early-onset CD), we have recently established a human microbiota- colonized mouse model in which germ-free doubly deficient Nod2/Cybb (DKO) mice are colonized with the microbiota from early-onset CD children or their healthy first-degree relatives. Our preliminary data indicate that the isolated colonic early-onset CD microbiota triggers colitis in the gnotobiotic DKO mice, which was characterized by colonic expansion of IL-17+ CD4+ T cells and group 3 innate lymphoid cells. Additionally preliminary results indicate that our humanized mouse model can recapitulate the site-specific disease phenotype (ileitis vs. colitis) observed in early- onset CD. Thus, it is our belief that this unique model is an important tool that can be used to study the relationship between the host and its gut microbiota as well as the biology of site-specific inflammatory disease. Ample epidemiological, genetic, and clinical evidence suggest that ileal CD represents a disease entity distinct from colonic CD. Since nutritional niches in the ileum are different than those in the colon, we postulate that distinct microbial triggers drive site-specific disease and inflammatory responses in early-onset CD. In two Specific Aims we propose to identify and characterize site-specific microbial triggers and inflammatory signatures of disease using our novel humanized mouse model that is based on genes associated with the human disease.


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: 2026 ( Subtotal = $244,468 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	7/17/2026	NEW	$244,468
														Subtotal = $244,468

Grand Total All Awards = $244,468

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Site specific gene-microbial interactions in children with early-onset Crohn’s disease

Award Number: R21AI194215

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/17/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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