Grants and Contracts Details
Abstract Prospective studies in pediatric Crohn’s disease (CD) and ulcerative colitis (UC) indicate that mitochondrial dysfunction is a strong indicator of future disease activity. To repair mitochondrial function in inflammatory bowel disease (IBD) patients, we developed an oral agent, that increases mitochondrial respiration (oxygen consumption) and oxidative phosphorylation (OXPHOS) in intestinal epithelia cells (IEC) after in vivo dosing. Treatment of DSS colitis mice markedly improves mucosal healing and reduces clinical disease activity, mucosal pro-inflammatory cytokine levels and tissue colitis histologic levels. Given its effects on mitochondrial metabolism, we speculated that AuPhos-induced mucosal oxygen consumption would reduce oxygen availability to the microbiome thereby reducing pro-inflammatory (oxygen utilizing) facultative anaerobes while promoting restitution of obligate anaerobic flora. 16s rRNA-based microbial profiling of the stool in control mice revealed that the drug reduces the relative abundance of (colitis-associated) Proteobacteria, which predominantly represents LPS-producing, facultatively anaerobic Enterobacteriaceae in the gut. Conversely, drug treatment increases the relative abundance of signature anaerobic bacteria (Firmicutes) that correlated with increased levels of short chain fatty acids (SCFAs) butyrate, propionate and acetate in the stool. These findings led to the novel hypothesis that enhanced mucosal mitochondrial function regulates the intestinal microbiome by reducing oxygen availability. We propose that AuPhos-induced reductions in dysbiotic facultative anaerobes and enhanced obligate anaerobes will reverse dysbiosis in colitis patients. To examine the impact of this novel agent on colitis, we propose to interrogate the following aims using novel germ free (GF) wild type (WT) and IL-10 knockout (KO) mice reconstituted with stool from control and inflammatory bowel disease (IBD) human (Hu) donors: Aim 1. Determine the effect of AuPhos on intestinal microbiome in WT B6 GF mice reconstituted with human IBD stool (and normal Hu stool). Outcomes of AuPhos on the microbiome will be determined in the absence of intestinal inflammation using GF WT recipients by assessing A) microbial metagenomics and metabolism in transferred stool, and B) epithelial mitochondrial metabolism. Aim 2. Determine the effect of AuPhos on intestinal microbiome and colitis in GF IL-10 KO mice reconstituted with human (Hu) IBD stool. Studies here will assess A) effects of AuPhos on colitis in Hu IBD stool-reconstituted GF IL-10 KO mice, and B) shifts in microbial communities and metagenomics. The overall goal is to determine if this novel drug that improves mucosal mitochondrial function will 1) enhance mucosal repair in humanized colitis mice and 2) reverse dysbiosis in IBD.
|Effective start/end date||1/1/23 → 12/31/23|
- Crohns and Colitis Foundation of America: $110,000.00
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