Spatial and Functional Organization of Intestinal Microbiome

The most prominent diseases of modern times--including inflammatory bowel diseases (IBD) such as Crohn's, ulcerative colitis, and colon cancer as well as metabolic diseases such as diabetes and obesity--are caused as a result of failure to maintain homeostatic interactions with commensal bacteria.  However, at the moment, we do not fully understand the mechanisms that regulate host-microbe interactions.  Moreover, attempts to identifiy common microbiome associated patterns linked with these diseases have either failed or are inconsistent at best.  It is likely that the intestinal flora is spatially stratified just like any other ecosystem; and so far, large-scale sequence analysis of intestinal microbiota that uses fecal biota or entire intestinal luminal content as a surrogate for looking at gut microflora has failed to pick up transverse stratification of intestinal microbiome.  We propose a novel approach for determining the structural and functional stratification of intestinal microbiome.  We will assess the role of host immunity in organizing bacterial communities by altering their functional gene content within the gut lumen.  Finally, we will delineate how clinically relevant antibiotic regimens alter spatial community structure of human mcirobiome by employing humanized gnotobiotic mouse models.  We will apply these approaches to understand how common genetic factors that are associated with IBD influence the function and structure of microbiota to cause dysbiosis and chronic inflammation.