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.
