The human large intestine is host to a complex microbial community dominated by obligate anaerobic bacteria. However, conditions of intestinal inflammation lead to an increased relative abundance of facultative anaerobic Enterobacteriaceae, such as Escherichia coli. Adherent- invasive E. coli (AIEC) are isolated more commonly from the intestinal mucosa of individuals with Crohn's disease than from healthy controls. Our central hypothesis is that terminal respiratory electron acceptors are generated as a by-product of the inflammatory response and enable E. coli to efficiently edge out competing obligate anaerobic bacteria, a process that can fuel a bloom of AIEC, which in turn further irritates the intestinal mucosa. We will test key aspects of our hypothesis by determining whether a bloom of AIEC fueled by anaerobic respiration sustains and exacerbates intestinal inflammation (Aim 1). The proposed work is innovative because it is among the first to elucidate a molecular mechanism that controls the balance between the host and its microbiota. Successful completion of this work will have broad relevance for understanding changes in the microbial community structure during conditions of intestinal inflammation by establishing anaerobic respiration as one of the fundamental principles that governs growth of E. coli in the gut lumen.
Over 90% of the cells in the human body are microbes, the majority of which reside in the large intestine, where they provide benefit to the host by educating the immune system and by providing nutrients as well as niche protection. The vast majority of microbes in the large intestine are obligate anaerobic bacteria and this bacterial community structure is conserved between humans and mice. However, conditions of inflammation in the large bowel are accompanied by a microbial imbalance, which is characterized by a marked increased relative abundance of facultative anaerobic bacteria, such as Escherichia coli. Here we will investigate the mechanisms that lead to this microbial imbalance. By elucidating the molecular mechanisms that control the balance between the host and its microbiota, the proposed experiments will usher in important conceptual advances that have a strong potential to exert a high impact on this field of science.
