NIH grant: Site specific gene-microbial interactions in children with early-onset Crohn’s disease (1R21AI194215-01A1)

retained text

NIH grant 1R21AI194215-01A1: Site specific gene-microbial interactions in children with early-onset Crohn’s disease
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Roberta  Caruso. Award: $244468.
Start: 2026-07-17T00:00:00.
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.

document fetched 2026-07-26 08:23