Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Hirschsprung associated enterocolitis (HAEC) is the most frequent complication in children with Hirschsprung disease (HSCR), resulting in frequent hospitalizations and half of deaths in this population. The mechanisms underlying HAEC are poorly understood. We reported in a microbiome study that Candida spp. are specifically enriched in stool of HAEC patients, and we report here that HAEC patients have elevated anti-Saccharomyces cerevisiae antibody (ASCA) titers. Since ASCA levels are known to be associated with inflammatory bowel disease (IBD), we hypothesized that other risk factors for IBD might be associated with HAEC. We genotyped single nucleotide polymorphisms (SNPs) in a small cohort of HSCR patients and found preliminary evidence that 37 SNPs previously found to associate with IBD may also be linked to the risk of developing HAEC. One of these genes, CARD9, particularly caught our interest because CARD9 is involved in host immune responses to intestinal microbes, especially fungi, as a signaling molecule involved in anti-fungal C-type lectin receptor signaling. We have established a mouse model of HAEC (Ednrb-null mouse model) and found that creating Ednrb-Clec7a double mutant mice (Clec7a gene encodes for the antifungal C-type lectin receptor Dectin-1) causes a 5-fold increase in fecal C. albicans and 4-fold increased enterocolitis severity compared with controls. We further observed in the Ednrb-null model that natural intestinal colonization with Candida utilis and Rhodotorula mucilaginosa is associated with the risk of developing HAEC. Finally, HAEC severity was reduced 65% when animals were treated with the antifungal drug isavuconazole. Together, these discoveries suggest new mechanisms for HAEC implicating intestinal fungi and antifungal immunity. Our overall hypothesis is that HSCR patients with genetic susceptibility to developing HAEC respond inappropriately to changes in the intestinal microbiota, (with a particular interest in fungi) leading to a difficult-to-treat colitis. This hypothesis will be investigated in the following two aims: 1) investigate the role of antifungal immunity gene Card9 in a mouse model of HAEC; 2) define the role of Candida utilis and Rhodotorula mucilaginosa in the same mouse model of HAEC. The line of investigation outlined here may lead to greater rationale for treating HAEC patients using personalized approaches and may lead to methods for early identification of patients at high risk of developing HAEC.
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