Many of My Patients Want To Go With Natural Therapies. Where Do Probiotics Fit in the Management of Irritable Bowel Syndrome?
Brooks D.
Cash,
MD, FACP, FACG
The literature regarding the use of probiotics in irritable bowel syndrome (IBS) has been fraught with methodological problems. Chief among these have been small sample size and a lack of consistency in the number, strain, and method of delivery of the probiotic agent(s).1 Some studies have used a single purified strain of bacteria or yeast, whereas others have used a variety of probiotic “cocktails” with or without substrates designed to enhance the growth and viability of the organism. Various authors have confirmed an alteration in stool flora by performing quantitative stool cultures before and after therapy, whereas others have not. The World Health Organization and the Food and Agricultural Organization of the United Nations (WHO/FAO) define a probiotic as “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host.”2 The use of live microorganisms for purported health benefits, primarily as part of cultured milk products, dates back to at least the 7th century BC. The gastrointestinal tract, which is home to more than 500 different species of bacteria, has been the primary target of such remedies. Despite this long history, high-quality studies of the effects of probiotics on health and disease were not undertaken until the latter part of the past century.
The normal microbiota of the gut consists primarily of facultative anaerobes and obligate anaerobes, including Bacteroides, Bifidobacterium, Clostridium, Enterobacter, Enterococcus, Escherichia, Eubacterium, Klebsiella, Lactobacillus, Peptococcus, Peptostreptococcus, Proteus, and Ruminococcus species. These organisms perform numerous salutary functions, including metabolism of toxins, production of vitamins, and digestion of dietary products. Perhaps more importantly, they provide the first line of defense against colonization by pathogenic organisms. Given the complex relationship between our immune system and the endogenous microflora of our intestinal tracts, probiotics seem a “natural” choice as potentially therapeutic agents.
In 2004, Tsuchiya et al published data regarding the utility of the symbiotic mixture SCM-III in 68 consecutive adults with IBS.3 SCM-III contains not only live bacteria (in this case L. acidophilus, L. helviticus, and Bifidobacterium species) but also specific substrates known as prebiotics that improve microbial growth and survival. Participants were given either 10 mL of SCM-III three times a day or a placebo composed of a heat-inactivated version of the same preparation. Patients were assessed for overall clinical status (primarily abdominal discomfort) and “bowel habits” (a subjective composite of stool frequency and consistency) at baseline, 3, 6, and 12 weeks. Abdominal pain and bloating were independently assessed at similar intervals. Eighty percent of the SCM-III patients versus only 15% of the control patients reported that the treatment was “effective” to “very effective.” Nearly 40% of the placebo recipients felt SCM-III was “slightly effective,” consistent with the placebo effect found in other IBS treatment trials. Although abdominal pain improved, no significant change in bloating in drug patients versus placebo patients was noted at 12 weeks. Several other investigators, however, have shown reductions in bloating in IBS patients using VSL#3 and L. plantarum, respectively.4,5
The most significant article on this topic was published by O’Mahony et al.6 In this study, the investigators examined the effects of L. salivarius UCC4331 or B. infantis 35624 versus placebo in a randomized, double-blind trial of 77 IBS patients. What makes this study particularly intriguing is the assessment not only of the cardinal symptoms of IBS, but also of changes in the ratio of the interleukins IL-10 and IL-12 in peripheral blood mononuclear cells (PBMCs). IL-10 is the product of a number of immunomodulatory cells, including mast cells, B lymphocytes, Th1 and Th2 lymphocytes, and mononuclear phagocytic cells. It inhibits the production of interferons and interleukins, and TNF-a. Bifidobacterium has been associated with suppression of IFN-g, TNF-a, and IL-12. Prior to probiotic administration, the authors examined the IL-10 and IL-12 levels of IBS patients and 20 asymptomatic controls. The levels of IL-12 were higher, and IL-10 lower, in the IBS patients, indicating a proinflammatory state. The subjects were then given L. salivarius, B. infantis, or placebo for 8 weeks and followed for a 4-week washout period. The subjects taking B. infantis enjoyed a significant decrease in all symptomatic parameters, including abdominal pain/discomfort, bloating/distention, and bowel movement difficulties. L. salivarius produced a result no different than that of placebo. Interestingly, the IL-10/IL-12 ratio normalized in those taking B. infantis but not in those taking L. salivarius or placebo despite participants achieving increased levels of Lactobacillus in their stools. This finding adds biologic plausibility that the changes in symptoms were indeed due to the Bifidobacterium.
In one of the longest trials to date, Niv et al performed a 6-month, double-blind, randomized, placebo-controlled trial of a single organism, L. reuteri ATCC 55730, in 54 IBS patients.7 Patients all had significant symptoms at the onset of the study as measured by the Francis Severity Score (FSS) of greater than 75 (out of 100). Patients were followed for 6 months, and measured outcomes were changes in FSS and IBS-related quality of life. Thirty-nine patients completed the study, and no significant differences were noted between groups for changes in FSS or IBS quality of life. Although it is possible that a larger sample size might have revealed a subtle difference between the groups, this study provides compelling evidence for the lack of efficacy for this organism in IBS. Kim et al examined the utility of VSL#3 in a 4-week, double-blind, randomized, placebo-controlled trial in 48 IBS patients.4 The primary symptomatic outcome measure was bloating severity. Flatulence, stool-related symptoms (ease of stool passage, stool frequency, and number of days with incomplete evacuation), abdominal pain, and satisfactory relief of bloating (defined as improved >50% of the weeks) were secondary symptomatic outcomes. No significant difference was seen in the primary outcome of bloating, though a statistically significant decrease in flatulence was noted.
Although the use of probiotics is still in its infancy, the literature regarding the use of probiotics in IBS is rapidly growing. Our understanding of the possible physiologic mechanisms of improvement, particularly via alterations in immunomodulatory cytokines, represents the dawn of a new era in our approach to studying these therapies. We should be cautiously optimistic in our application of the current data. Most studies have small populations and a short length of treatment, especially given the waxing and waning nature of IBS. Trials of larger size and longer duration are needed to better clarify which probiotics work for which IBS symptom complex, as well as their mechanism of action and evidence for or against probiotics in patients with IBS remains elusive.
References
1. Young PE, Cash BD. Probiotic use in irritable bowel syndrome. Current Gastroenterology Reports. 2006;8:321-326.
2. Joint FAO/WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. London, Ontario, Canada: May 1, 2002. Available at: http://www.who. int/foodsafety/fs_management/en/probiotic_guidelines.pdf. Accessed June 13, 2006.
3. Tsuchiya J, Barreto R, Okura R, et al. Single-blind follow-up study on the effectiveness of a symbiotic preparation in irritable bowel syndrome. Chin J Dig Dis. 2004;5(4):169-174.
4. Kim HJ, Vasquez-Roque MI, Camilleri M, et al. A randomized controlled trial of a probiotic combination VSL #3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil. 2005;17(5):687-696.
5. Nobaek S, Johansson ML, Molin G, et al. Alteration in intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol. 2000,95(5):1231-1238.
6. O’Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-551.
7. Niv E, Naftali T, Hallak R, Vaisman N. The efficacy of Lactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndrome: a double blind, placebo-controlled, randomized study. Clin Nutr. 2005;24(6):925-931.