Using Metabolomics to Decipher Probiotic Effects in Patients With Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common disorder that has been estimated to affect anywhere from 5% to 20% of the population.1 The symptoms of IBS include abdominal pain, irregular bowel movements, constipation, and/or diarrhea, and vary from individual to individual. The pathophysiology of IBS is multifactorial, and includes dysregulated brain-gut interactions, alterations in autonomic responses, mucosal immune activation, altered gut motility, and heightened visceral perception.2 Recent evidence has supported a role for gut microbes in the pathogenesis of IBS due to 3 primary areas of evidence. First, a clear relationship has been established between gut infections and the subsequent development of postinfectious IBS.3 Second, IBS symptoms can be improved by treatments that target the gut flora, including antibiotics and probiotics. A recent study published in the New England Journal of Medicine4 showed that in IBS patients without constipation, treatment with the antibiotic rifaximin for 2 weeks provided relief of bloating, abdominal pain, and loose and watery stools. In that rifaximin has very low systemic absorption and broad-spectrum activity against gram-positive and gram-negative aerobes and anaerobes, this strongly suggests that approaches aimed at modifying the gut microflora may have a role in the treatment of IBS. The study published in the Journal of Clinical Gastroenterology by Hong et al5 showing that treatment of IBS patients with a daily probiotic-fermented drink resulted in the improvement of IBS symptoms adds to the growing literature showing positive effects of probiotics in patients with IBS. Finally, newer studies using culture-independent methodology show that the composition and/or diversity of gut microbes are altered in patients with IBS at phylum and/or genus/species levels.6 However, as discussed by Salonen et al,6 it is unknown at this point of time how these changes in gut microbial composition actually impact on human health or what role changes may have in disease pathogenesis. In examining functional changes in gut microbes in patients with IBS, targeted research has focused on the changes in short-chain fatty acid production and hydrogen gas production.7 However, to more fully understand the implications of changing gut microbial diversity or composition, a broader analysis of the gut environment and also the host response to changing microbial communities is required. Metabolomics is one of the newer “omics” disciplines, and seeks to identify and quantify all metabolites in a biological system.8 This type of analysis follows naturally from, and complements the study of genes and gene expression (genomics) and protein expression (proteomics). The scrutiny of such a functional disorder as IBS at the metabolomic level is welcome, and has the potential to uncover fundamental underlying pathology in patients with IBS. Indeed, the metabolome, being classified as the total collection of all small molecular-weight compounds (metabolites) that are produced by gene expression, could be considered to be the final downstream product of the genome.8 This assessment of the metabolome in patients with IBS should theoretically make it possible to more fully understand disease pathogenesis and in particular, how the human system reacts to various interventions, including probiotics. Hong et al5 shows the feasibility of such an approach, and in the process shows a potential dysregulation in energy homeostasis and liver function in patients with IBS that could potentially be treated with probiotics. Probiotics are microbial organisms administered in supplements or in foods to enhance the health of the host.9 There exists substantial evidence that in a strain and dose-dependent manner, probiotics can modulate systemic and mucosal immune function, improve intestinal barrier function, alter gut microecology, and exert metabolic effects on the host.9 Although numerous studies have examined the effects of probiotics in patients with IBS, currently there is no consensus regarding their usefulness. In a recent systemic review, Moayyedi et al10 discusses that due to the use of many different species, stains, and doses of probiotics in IBS trials, it is not possible at this time to come to any conclusion regarding an optimum probiotic strategy for patients with IBS. However, in a second systemic review, Brenner et al11 did support the efficacy of Bifidobacterium infantis in ameliorating symptoms in patients with IBS. One of the problems with the use of probiotics as treatment for disease is the fact that individual probiotic strains differ greatly in their effects on all aspects of host function. This is becoming increasingly clear, as more complex studies are being undertaken. The use of metabolomics in animal models has helped in our understanding how probiotics may influence health and disease processes.12–14 In an animal model, Martin et al12 clearly showed that oral supplementation with a probiotic, Lactobacillus rhamnosus, resulted in changes in host systemic lipid, carbohydrate, and amino acid metabolism. Alterations in liver, kidney, pancreas, and adrenal function were described, indicating that probiotics were able to modulate energy homeostasis, antioxidation, and steroidogenesis.12 These effects were shown to be dependent on the type of probiotic supplementation used, and reinforces the concept that each probiotic strain is unique in its effects on its host. These results also clearly show the far-reaching effects of probiotic consumption on host physiological function. In the current trial reported by Hong et al,5 74 patients with IBS meeting Rome criteria were randomized into a parallel-group double-blind, placebo-controlled clinical study of a probiotic fermented milk product 3× daily for 8 weeks. Disease activity was assessed according to questionnaires and serum and fecal samples taken for 1H nuclear magnetic resonance metabolic profiling before and after supplementation. In this study, it was found that probiotic treatment significantly reduced defecation discomfort and stool frequency.5 However, perhaps of more interest, in a subset of female patients with IBS, nuclear magnetic resonance profiling uncovered alterations in blood glucose, lactate, and tyrosine that were normalized by probiotics treatment.5 Similar findings in patients with IBS were reported by Gulcan et al,15 who showed increased frequency of prediabetes in patients with IBS and increased levels of blood glucose, as were seen in this study. Obviously these initial results will need to be confirmed and effects of probiotics validated in larger clinical studies. In conclusion, the use of metabolomics is a welcome addition to the study of functional disorders such as IBS, and also to the study of how probiotics alter physiological systems of the human host. Information obtained by performing these types of nontargeted simultaneous quantification of small molecular metabolites can be added to more traditional and targeted analysis of patient symptoms and effects on known biochemical and immune pathways. Information from metabolomic analyses provides a more “holistic” view of the host, and can be invaluable in shedding light on how gut microbes may influence human health and help to maintain homeostasis. It is clear that our gut microbes have far-reaching modulatory influences on most, if not all of our physiological processes, and learning how to harness these microbes will begin with a clearer understanding of complete host responses.

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