Tu1753 Intestinal Epithelial Vitamin D Receptor Deletion Leads to Defective Autophagy and Dysbiosis in Colitis

Abstract

Though the etiology of Ulcerative colitis (UC) is unknown, it is widely recognized as a disease influenced by environmental, genotypic andmicrobiological factors. Many established UC risk-alleles are involved in host response tomicrobes, though these genetic risks frequently do not span ethnic populations. In addition, both antibiotic use and high fat diet, factors common to Western lifestyle, have been shown to independently impact the gastrointestinal (GI) microbiome and increase UC risk. Interestingly, Asian migrants who translocate from their native country to Western nations and adopt a Western lifestyle develop UC at rates similar to, or greater than, the background population. These populations afford a unique opportunity to study the impact of ethnicity (genotype) and environment (e.g. dietary exposures) on UC development. Combined with findings regarding the immunomodulatory capabilities of GI microbiota, these observations have led us to hypothesize that first or second generation migrants (Asian or European) to the US, who exhibit distinct UC risk gene profiles, develop a compositionally distinct, dysbiotic microbiome enriched for similar pro-inflammatory metabolites that contribute to disease severity. To test our hypothesis, we employed 16S rRNA phylogenetic microarray analyses to identify differences in stool microbiome composition and used this data, in conjunction with PICRUSt, to predict the metagenomic content of samples obtained from migrant South Asian (SA) and European (EU) UC patients and familial, healthy controls. Consistent with previous reports, a distinct shift in gross stool microbiota composition in patients vs. controls, characterized by significant enrichment of unclassified Streptococcus across all UC patients (p<0.05, q<0.1), was observed. Multivariate regression revealed that, in addition to disease status and Simple Clinical Colitis Activity, patient origin was significantly associated with compositional variation in stool microbiome. Indeed, SA UC patients exhibited depletion of unclassified Lachnospiraceae, while EU patients were depleted in both Odoribacter and Pantoea. Analysis of the predicted metagenome of these communities identified a variety of metabolic pathways enriched in UC patients compared to controls. This included ubiquitin metabolism, a known immunogenic pathway previously linked to UC. Combined, these observations suggest that, though the microbiome of ethnically distinct UC patients is compositionally divergent, enrichment of a common set of immunomodulatory metabolic pathways characterizes these patients. Future work involving genetic profiling of UC risk-alleles as well as broad range fecal metabolite profiling will provide further insight into the mechanisms behind the observed functional shift in the microbiome and it's relationship to disease severity.