Tu2033 Investigating the microbiome pre and post fecal microbiota therapy from active ulcerative colitis patients in a randomized placebo controlled trial

Abstract

Purpose: A key challenge post genome-wide association studies (GWAS) is mapping the associated disease/trait susceptibility loci to biological pathways and understanding their level of interconnectedness. Aberrant γ-interferon (INFγ) expression is associated with autoimmune diseases. In vitro and in vivo priming of human monocytes with INFγ leads to monocyte activation and augmentation of responses to various stimuli. Method(s): In order to study the early events of priming, RNA-seq was performed in the human monocyte cell line THP-1 at rest and after 1hr and 6hrs of INFγ stimulation. Results: We identified 893 genes with at least 2 fold differential up-regulation at either 1 or 6hrs compared to unstimulated cells. Strikingly, multiple previously unrecognized INFγ induced genes were found to be significantly enriched in autoimmune susceptibility loci including those related to inflammatory bowel disease (IBD) in general or Crohn’s disease or ulcerative colitis (UC) specifically, celiac disease, and multiple sclerosis (MS). For example, ODF3B (MS) and a specific isoform of SPRED2 (IBD) were found to be INFγ responsive. Further analyses revealed an enrichment of INFγ induced genes in metabolic traits including C4ORF32 (type II diabetes), TMEM229B (phospholipids) and FAM117C (HDL). These genes were independently confirmed to be INFγ inducible by qRT-PCR. Interestingly, TMEM229B and FAM117C have also been associated with Crohn’s disease, suggesting a connection between lipid metabolism and IBD via inflammatory signaling. Of note, many of such INFγ responsive genes show altered expression in normal vs. inflamed colonic samples of Crohn’s and/or UC patients. Integrating public CHIP-seq data, we found a significant enrichment in IRF1, STAT1, IRF8, VDR, and HNF4a binding near the INFγ regulated gene-set. The transcriptional regulator HNF4a, which is best characterized in controlling metabolism, is also encoded in an UC susceptibility locus, further suggesting a novel connection betweenmetabolic processes and INFγ responses. In summary, we have connected a number of autoimmune susceptibility and metabolic trait/disease loci to the INFγ signaling pathway. Ongoing functional characterization of these INFγ responsive genes may further elucidate the underpinnings of autoimmunity.