Glutamine for the Treatment of Patients With Irritable Bowel Syndrome

Abstract Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is
estimated to affect 20% of the US population. IBS patients have significantly decreased
quality of life and utilize large amounts of health care resources. IBS patients suffer from
chronic abdominal pain associated with diarrhea, constipation, and/or bloating. Several
mechanisms that may lead to IBS have been proposed including: alterations in receptors and
neuropeptides, bacterial overgrowth and altered microbiota, altered intestinal transit,
anxiety and depressive symptoms, and increased intestinal membrane permeability. Several
recent studies have shown that diarrhea-predominant IBS (D-IBS) patients have increased
intestinal permeability that may lead to chronic gastrointestinal symptoms.

Our laboratory recently evaluated diarrhea-predominant IBS patients and reported that they
have increased membrane permeability. The investigators now have obtained preliminary
evidence that oral glutamine supplementation restores membrane permeability and improves
chronic gastrointestinal symptoms in these IBS patients. Previously, it has been well
established that deficiencies in glutamine may lead to increased membrane permeability and
supplementation with glutamine can restore intestinal membrane permeability. There are no
published studies to date to support the use of glutamine for Irritable Bowel Syndrome.
However, given our preliminary data and the mechanisms of action of glutamine on the
gastrointestinal tract, research testing whether oral glutamine is an effective therapy in
Irritable Bowel Syndrome is definitely needed.

Based on these new findings, the investigators hypothesize that oral glutamine
supplementation will improve the IBS Symptom Severity Scale and restore intestinal membrane
permeability in diarrhea-predominant IBS patients. The investigators propose to conduct a
randomized, double-blind, placebo-controlled clinical trial studying glutamine 10 g po tid
compared to placebo 10 g po tid for 8 weeks in 100 diarrhea-predominant IBS patients. The
IBS Symptom Severity Scale and intestinal membrane permeability will be measured at
baseline, 2, 4, 6, and at 8 weeks. The results of this study will lead to the following
specific aims:

Specific Aim 1: To determine if oral glutamine supplementation will improve the IBS Symptom
Severity Scale in IBS patients. To accomplish this aim, the investigators will measure the
change in the IBS Symptom Severity Scale following treatment with either oral glutamine
supplementation or placebo. The primary outcome measure will be an improvement of ≥50 from
the baseline score on the IBS Symptom Severity Scale. This constitutes a clinically
significant response to treatment.

Hypothesis 1. IBS patients will have an improvement of ≥50 on the IBS Symptom Severity Scale
following oral glutamine supplementation compared to placebo.

Specific Aim 2: To determine if oral glutamine supplementation will restore intestinal
membrane permeability in IBS patients. To accomplish this aim, the investigators will
measure the change in the intestinal membrane permeability following treatment with either
oral glutamine supplementation or placebo.

Hypothesis 2a. Oral glutamine supplementation will restore intestinal membrane permeability
in IBS patients compared to placebo.

Hypothesis 2b. Improvement in the IBS Symptom Severity Scale is correlated with restoration
of intestinal membrane permeability following oral glutamine compared to placebo.

Layman Statement: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder
characterized by chronic abdominal pain associated with an alteration in bowel habits with
diarrhea and/or constipation. IBS patients with diarrhea have been shown to have a "leaky
gut" in which bacteria and toxins may penetrate the gut wall, termed increased membrane
permeability. The current proposal will investigate oral glutamine supplementation as a
treatment of symptoms and "leaky gut" in diarrhea-predominant IBS patients.

Inclusion Criteria:

- men and women age 18-72 years old that meet the Rome III criteria for
diarrhea-predominant IBS (D-IBS) for at least 1 year prior to study

- increased intestinal membrane permeability on Lactulose/Mannitol permeability test

- score between 37 and 110 on the Functional Bowel Disorder Severity Index (FBDSI)

- able and willing to cooperate with the study

- *absence of alcohol ingestion for 2 weeks prior to inclusion into study and
throughout the study duration

Exclusion Criteria:

- current participation in another research protocol or unable to give informed consent

- women with a positive urine pregnancy test or breastfeeding

- history of inflammatory bowel disease, lactose intolerance, and/or celiac sprue

- + hydrogen breath test for bacterial overgrowth

- + antiendomysial antibody titer

- use of nonsteroidal antinflammatory drug(NSAIDs) 2 weeks before or during the study

- known allergy to glutamine

- abdominal surgery except for removal of gallbladder, uterus, or appendix >6 months
prior to entry into the study

- Beck Depression Inventory score of ≥30, State Trait Anxiety Inventory ≥53.

- Abnormal blood urea nitrogen(BUN) and/or creatinine