Efficacy and Safety of Proteolytic Activity-Guided fecal Microbiota Transplantation for Irritable Bowel Syndrome (PRAGMAT trial)

ABSTRACT Irritable bowel syndrome (IBS) is estimated to affect 1 in 6 U.S. adults and results in significant morbidity and health care utilization. Studies over the last decade have highlighted proteases as important peripheral mediators in the pathophysiology of IBS, especially in inducing barrier dysfunction and visceral

hypersensitivity. Post-infection IBS (PI-IBS) is a defined subset of IBS where an acute injury results in subsequent development of long-standing gastrointestinal symptomatology. Twenty percent of those suffering from intestinal infection may be at risk for PI-IBS as shown in our study from a large cohort of prospectively

followed Minnesota residents. Our studies have demonstrated that impaired inactivation of luminal proteases due to absence of specific intestinal microbes is critical to the pathogenesis of PI-IBS. Our preliminary studies in humanized mouse models of PI-IBS associated high proteolytic activity (PA) have demonstrated that fecal

microbiota transplantation (FMT) from a donor that has low PA and presence of key microbes like Alistipes putredinis can reverse the high PA state. Based on these and other findings from PI-IBS patients, we hypothesize that targeted FMT where recipients have high PA and donors are specifically selected based on

their microbiota composition and low PA, will be safe and efficacious for improvement of symptoms in PI-IBS. We propose a pilot, randomized, double-blind, placebo-controlled clinical trial where PI-IBS patients will be administered either a single FMT from the donor or from their own stool (autologous control). In Aim 1, we will

determine efficacy defined by a ≥50-point improvement in IBS symptom severity score at 12 weeks post-FMT. We will determine microbiota engraftment at 12 weeks and assess predictors of successful response to the FMT. In Aim 2, we will determine effects of autologous and donor FMT on fecal metabolome and in vivo

colonic permeability. We hypothesize that successful FMT will be associated with changes in fecal metabolome that support inhibition of PA as well as improvement in colonic permeability. This trial will provide robust pilot and feasibility data to support larger trials investigating PA-based FMT approaches in broader

cohorts of IBS patients. In addition, the microbiota assessment will provide additional supportive data for commensal microbes that support suppression of PA. In future, these data can allow development of simplified microbial consortium for treating high PA states. The study team has the expertise in translational studies and

clinical trials for neurogastrointestinal disorders. Additionally, an investigational new drug approval from the FDA as well as IRB approval have been obtained.