Inflammatory bowel disease (IBD) comprises distinct clinical subtypes, with unique microbial associations, pathological features and responses to treatment. Ileal Crohn’s disease (ICD) has the strongest association with over-proliferation of a specific family of bacteria, the Enterobacteriaceae. While their role in disease progression is poorly understood, they are considered an attractive target for therapies aimed at dampening IBD-associated inflammation. I will investigate the prevalence of tissue-invasive Enterobacteriaceae in a cohort of Irish patients and explore the potential of D-amino acids (DAAs) to inhibit virulence and proliferation of these bacteria using in vitro enteroid models. DAAs are garnering increasing interest for their ability to modulate the behaviour of pathogenic bacteria. Several DAAs were recently shown to be depleted in patients with ulcerative colitis and could reduce Enterobacteriaceae blooms, and inflammation in mouse models of colitis. Enterobacteriaceae burden in patient biopsies will be assessed by isolation on bacterial growth media, PCR strain profiling, shotgun metagenomics and histology. I will investigate whether ICD-associated bacterial taxa correlate with altered faecal DAA profiles, comparing our cohort of patients with ten healthy controls by chiral mass spectrometry. To assess toxicity, and efficacy in inhibiting the proliferation of Enterobacteriaceae in a model more reflective of human physiology, I will culture enteroids from this cohort and study the effect of DAAs on infection with Enterobacteriaceae. Importantly, DAAs are prevalent in many foods, particularly fermented foods. My team will include an IBD patient group to design a food questionnaire exploring how fermented foods modulate IBD symptoms and to identify other foods that trigger flare ups in symptoms. We will then profile the DAA content of these foodstuffs. The outcome of this study will be an enhanced understanding of the role of Enterobacteriaceae in ICD and a pre-clinical assessment of the suitability of DAAs as IBD biomarkers and therapeutics.
