Original Research

Randomized, Double-Blind Placebo-Controlled Trial to Assess the Effect of Probiotics on Irritable Bowel Syndrome in Veterans With Gulf War Illness

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Background: Many veterans who served in Operation Desert Storm (August 1990 to March 1991) experienced a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly impacts the health and quality of life (QOL) and may have contributed to irritable bowel syndrome (IBS).

Methods: We performed a prospective, double-blind placebo-controlled study to determine the efficacy of the multistrain De Simone Formulation probiotic containing 8 strains of bacteria on symptoms of IBS and GWI. Veterans of Operation Desert Storm who had IBS and ≥ 2 nonintestinal symptoms of GWI were included. The primary study endpoint was change in bowel symptom score. The secondary endpoints were mean change in symptoms, QOL, and extra-intestinal and posttraumatic stress disorder (PTSD) symptoms.

Results: A total of 101 Gulf War veterans with IBS and GWI were screened at the Veteran Affairs Medical Center in Salt Lake City, Utah. The study was completed by 53 veterans; 47 (89%) were male with a mean (SD) age of 55 (8) years. The probiotic did not improve IBS symptoms or other extra-intestinal symptoms common to IBS and GWI.

Conclusions: Our study did not demonstrate statistically significant improvement in IBS symptoms or QOL after treatment with the probiotic. We also did not find any improvement in symptoms of GWI or PTSD.



About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).1 Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.2 Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.3

The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.4 Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.5 Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.6 In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.7 A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.

A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.10 Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.

If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.11 Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.12 Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.15 Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.16,17

Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.18-20


Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.21 Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.


After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.


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