Early Inflammatory Bowel Disease Progression

Inflammatory bowel disease (IBD), comprising Crohn ́s disease (CD) and ulcerative colitis (UC), is an idiopathic inflammatory condition of the gastrointestinal tract which is characterized by alternating periods of active disease and remission. IBD is often progressive and associated with significant morbidity. A common endpoint for a progressive course of CD or UC is the need for treatment escalation; initially with immunomodulators and subsequently - if disease activity persists - with biologic therapy or surgery. Early use of biologic therapy improves clinical outcomes and can prevent complications such as strictures, fistulae or severe and progressive disease, obviating need for surgery. The success of early initiation of biologic therapy is most likely related to a therapeutic "window of opportunity" for the implementation of effective therapies in patients with rapidly progressive disease. However, indiscriminate use of biologic therapy would entail exposure of IBD patients with indolent disease to unnecessary expensive treatments and their associated side effects. Unfortunately, the need for biomarkers to reliably guide IBD treatment in a timely manner remains unmet. The literature supports a relevant role for host-gut microbiota interactions in IBD progression. This interaction is often mediated by microbial-derived metabolites. Fecal short chain fatty acids (SCFA) and secondary bile acids (BA) are remarkable examples of such metabolites. They are reduced in IBD patients, and in animal models are capable of mitigating exaggerated host immune response with consequent improvement in gut inflammation. Recently, researchers have started to explore the capacity of taxonomic and metabolomic signatures to predict meaningful clinical outcomes in IBD. Given the role of gut microbes and their metabolites in immune response, they are plausible biomarkers of IBD progression and therapy response. However, most of the studies exploring biomarkers for IBD include patients with longstanding IBD or previous failure to first-line therapies, rendering their results incompatible with early risk stratification. An inception cohort of newly diagnosed IBD patients integrating clinical, transcriptomics, microbial and metabolomic profiling can overcome these limitations, increasing the sensitivity to detect biomarkers of progressive disease before the therapeutic "window of opportunity" has passed. In the clinical setting, such biomarkers would enable clinicians to maximize therapeutic efficacy of biologic agents and implement as early as IBD diagnosis, a cost-effective therapeutic approach.

The objective of this project is to establish whether an impaired gut microbial capacity to synthesize SCFA and secondary BA at the time of IBD diagnosis can predict early need for treatment escalation (progression). To achieve this objective, our specific aims are:

1. To define the gut taxonomic and metabolomic profiles of newly diagnosed IBD patients and their associations with early clinical outcomes. The investigators will recruit an inception cohort of treatment-naïve IBD patients before undergoing their first diagnostic colonoscopy. The global metabolome, including SCFA and secondary BA abundance will be analyzed, as well as the taxonomic profile of fecal samples and mucosal-luminal interface (MLI) aspirates obtained at colonoscopy. The identified "omics" signatures will be correlated to the need for treatment escalation to derive predictive biomarkers of progressive IBD course. 2) To establish the impact of gut microbial dysbiosis and dysmetabolism of SCFA and BA of newly diagnosed IBD patients on mucosal inflammation and host gene expression. Analysis of taxonomic and metabolomics profiles obtained in MLI samples will be integrated to mucosal host gene expression analysis to identify host transcripts affected by differential SCFA and secondary BA abundance.

2. To quantify the in vitro capacity of gut microbiota of newly diagnosed IBD patients to synthesize SCFA and secondary BA. Gut microbiota from IBD patients will be inoculated into a batch bioreactor which closely mimics the gut luminal environment. The investigators will then perform serial measurements of SCFA, BA and bacterial abundance, estimating rates of metabolite synthesis. The metabolic activity will be correlated to in vivo metabolite abundance and clinical outcomes.

The investigators anticipate that IBD patients requiring early therapy escalation (progressors) will have decreased in vivo concentrations of SCFA and secondary BA, and an impaired in vitro microbial capacity to synthesize these compounds compared to patients not requiring therapy escalation. The investigators also expect to find that the taxonomic and metabolomic signatures of these patients have a distinct impact on host gene expression. Our comprehensive approach will allow us to identify reliable biomarkers which can be exploited in the clinical setting to guide early biologic treatment using a 'personalized medicine' approach and will provide novel insight into the biologic mechanisms underlying need for premature therapy escalation as a proxy of early progressive and aggressive course in IBD.