Mechanistic understanding of the effects of probiotics in the modulation of abdominal pain: one study at a time

The gastrointestinal tract in humans is host to 1 × 1013 to 1 × 1014 microorganisms amongst which commensal bacteria and pathogenic bacteria form a symbiotic environment (Frosali et al. 2015). This homeostatic state is key to the maintenance of the health of the host, and the scientific community is increasingly interested in investigating the effect of disruption of this balance, also called dysbiosis, in disease. In the recent years important findings have highlighted the influence of gut microbiota on the development and function of the nervous system and the state of the immune system, as seen in inflammatory bowel diseases (Maranduba et al. 2015). One of the greatest challenges in investigating the microbiome composition and function in human health and disease is to determine the causality between microbiome variation and pathophysiology. The gut microbiota and bacterial metabolites have recently been the focus of intense research looking at the molecular mechanisms underlying their role in the regulation of the neuroimmune system and physiological functions, and progress in the field has been facilitated by rapidly evolving bioanalytical techniques. Multiple clinical studies have focused on evaluating the composition and organization of gut microbiota and related metabolites in patients suffering from irritable bowel syndrome (IBS) compared with healthy controls. This research effort is driven by the need to shed light on the relationship between diet and the composition of the microbiome, and IBS symptoms, which include abdominal pain. Overall, the findings have been consistent in showing a shift in fecal microbial community composition in IBS (Rajilic-Stojanovic et al. 2015). What is less straightforward is the specificity, nature and direction of those microbial differences across the different studies, which seem to be affected by variables such as the analytical methods used, geography, diet, or homogeneity of the IBS groups (Mayer et al. 2014). However, based on several pre-clinical and clinical studies, it seems that treatments targeting the gut microbiome, using probiotics or antibiotics in adults, may offer benefits in terms of symptoms and, in particular, symptoms of visceral pain (Mayer et al. 2014). Studies in pediatric IBS populations have reported a beneficial effect of Lactobacillus rhamnosus on pain (Horvath et al. 2011), and Lactobacillus reuteri DSM 17938 (DSM) was found to be effective at reducing symptoms of infantile colic in breast-fed infants (Savino et al. 2010, Guandalini, 2014). Despite the increasing number of reports showing a modulatory effect of manipulating the gut microbiome on gastrointestinal function including pain, motility or permeability, the mechanisms by which the gut microbiota takes part in brain–gut activity, as in a microbiome–brain–gut system, remain unclear. With multiple mechanisms likely to be at play, preclinical studies have been instrumental in identifying the layers of those signalling mechanisms. In this issue of The Journal of Physiology, Perez-Burgos et al. (2015) examine the potential role of the transient receptor potential vanilloid 1 (TRPV1) channel in the mechanisms mediating an antinociceptive effect of L. reuteri DSM17938 (DSM) in a rat model of visceral pain induced by gastric distension. TRPV1 receptors are key in the transduction of pain signals in the gut (Blackshaw 2014) and constitute a rational target to look at when pursuing potential mechanisms of action of agents with a modulatory effect on visceral pain. This is further supported by previous evidence showing increased TRPV1 expression in rectal biopsies from IBS patients (Akbar et al. 2008). By testing the effect of DSM on capsaicin-evoked rise in intracellular Ca2+ in isolated DRG neurons from mice, Perez-Burgos et al. were able to show an inhibitory effect of DSM on TRPV1 channels in extrinsic primary sensory terminals. The fact that this effect was reproduced by conditioned medium but not gamma-irradiated dead DSM suggests that the effect of DSM may be related to a product derived from the bacterium, though this was not investigated in this study. This is an important consideration for the future as the identification of bacterium-derived products may help in characterizing the candidate signalling molecules mediating the effect of DSM on TRPV1 or, more generally, mediating the effect of gut bacteria on brain–gut communication. Another important observation from the current study is that a different probiotic bacterium, JB-1, previously shown to reduce pain-related pseudoaffective responses and spinal nerve single fibre firing induced by gut distension, failed to reduce the capsaicin evoked Ca2+ rise in DRG neurons seen with DSM treatment. These results indicate that different bacteria used in the context of preclinical models of gut distension most likely act via different signalling mechanisms to modulate pain response. One should also consider the role played by methodological differences in the contrasting results observed across the literature and reflect on the need to define new standards for the design of translational preclinical studies. This should also be applied to clinical studies for which methodological differences may account for the heterogeneity of findings on the efficacy of manipulating the gut microbiome on gastrointestinal symptoms. Despite these limitations, there is no doubt that mechanistic studies like the one presented in the paper from Perez-Burgos et al. have a great implication for the future development of new therapeutic tools targeting the gut microbiome for the treatment of gastrointestinal diseases.