Crohn's disease (CD) is a chronic gastrointestinal disorder that affects approximately 0.7 million people in the United States. Abnormal accumulation of potentially pathogenic members of the microbiota, referred to as pathobionts, is thought to contribute to the pathogenesis of CD. For example, adherent invasive Escherichia coli (AIEC), a potential pathobiont associated with CD, is isolated from the ileal mucosa of more than 35% of CD patients, but fewer than 6% of healthy individuals. However, the precise mechanism used by pathobionts including AIEC to thrive in the gut in CD patients remains largely unknown. The long-term goal of this application is to unravel the mechanism whereby CD-associated pathobionts accumulate in the intestine of patients. Under homeostatic conditions, the majority of commensal bacteria are obligate anaerobes. Prominent facultative anaerobes, such as Enterobacteriaceae, constitute only a minor fraction of the microbiota. Intestinal inflammation in patients with CD is known to promote thrive of Enterobacteriaceae (e.g. E. coli). However, inflammation alone does not explain why pathogenic E. coli, such as AIEC, is able to out-compete other, non- pathogenic commensal E. coli strains. Thus, it is conceivable that pathogenic E. coli has strategies at its disposal to overcome members of its own species in inflamed intestine. Our preliminary results suggest that pathogenic E. coli can outgrow over commensal E. coli strains in the inflamed gut. Interestingly, this growth advantage, associated with pathogenic E. coli, is blunted when the availability of dietary amino acids, particularly serine, is depleted. Based on these results, our central hypothesis for this application is that diet- derived amino acids, particularly serine, selectively control the competitive fitness of pathogenic E. coli during inflammation. We plan to test our central hypothesis by pursing the following three specific aims: 1. Identify the mechanisms by which pathogenic E. coli utilizes dietary amino acids to increase its competitive fitness in the inflamed gut. We will identify the mechanisms involved in amino acid utilization as inflammation in the gut induces E. coli to preferentially catabolize amino acids. 2 Determine the role of serine uptake as it relates to competitive fitness of pathogenic E. coli in the inflamed gut. We will unravel the link between serine uptake and the ability of pathogenic E. coli strains to thrive in the gut. Furthermore, we will assess the therapeutic potential associated with selective prevention of serine uptake. Collectively, this proposal is expected to result in the development of novel therapies that target the nutrients specifically utilized by pathogenic E. coli to gain an edge over its commensal competitors
Crohn's disease (CD) is defined as chronic inflammation of the gastrointestinal tract. It affects more 0.7 million people in the United States alone. It has been reported that certain pathogenic strains of Escherichia coli are abnormally accumulated in the intestinal mucosa of patients with CD and contribute to disease pathogenesis. Since the precise mechanisms involved in the formation of pathogenic E. coli blooms remain largely unknown and poorly defined, the unraveling of this enigma is expected to provide a radical shift in our current understanding of the pathogenesis of CD as well as aid the development of novel treatment options for CD.
| Morhardt, Tina L; Hayashi, Atsushi; Kao, John Y et al. (2018) Regional control of regulatory immune cells in the intestine. Curr Pathobiol Rep 6:29-34 |
| Nagao-Kitamoto, Hiroko; Kamada, Nobuhiko (2017) Host-microbial Cross-talk in Inflammatory Bowel Disease. Immune Netw 17:1-12 |
