Tilemachos Koutouratsas, Anastassios Philippou, George Kolios, Michael Koutsilieris, and Maria Gazouli
Abstract
Inflammatory bowel diseases (IBD) include a spectrum of chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is yet to be elucidated. The intestinal microbiome has been studied as a causal component, with certain microbiotic alterations having been observed in subtypes of IBD. Physical exercise is a modulator of the intestinal microbiome, causing shifts in its composition that are partially corrective of those observed in IBD; furthermore, physical exercise may be beneficial in patients with certain IBD subtypes. This review studies the effects of physical exercise on the human gut microbiome while investigating pathophysiologic mechanisms that could explain physical activity’s clinical effects on patients with IBD.
Core Tip: Inflammatory bowel diseases (IBD) are a spectrum of diseases that are characterized by their complex pathogenesis. The intestinal microbiome is thought to be a part of their pathogenesis, with certain alterations having been associated with IBD subtypes. Physical exercise is a modulator of the intestinal microbiome that has, furthermore, been associated with positive clinical outcomes in certain patients with IBD. Herein we discuss certain types of physical exercise, their effect on the intestinal microbiome, and its clinical effects on patients with IBD, as well as investigating underlying pathophysiologic mechanisms that could mediate the observed associations.
Introduction
Inflammatory bowel disease (IBD) comprises a spectrum of chronic inflammatory diseases that primarily but not exclusively affect the gastrointestinal tract, including ulcerative colitis (UC), Crohn’s disease (CD), and other related conditions. Their pathogenesis is classically thought to include interactions between genetic, immune-mediated, and environmental factors. Studies on the molecular epidemiology of IBD have shown that the gut microbiome composition is a biomarker of prognostic importance for CD and UC. Other molecular phenotypes include NOD2, MHC, and MST1 genotypes, which are correlated to disease location and activity, microRNA miR-215 levels, and DNA methylation, which are correlated to disease activity, FOXP3 haplotype, which is of prognostic importance, and oncostatin M and IL-1β levels, which predict response to anti-tumor necrosis factor therapy; furthermore, serum C-reactive protein levels correlate to disease activity but are generally nonspecific. Increased serum miR-595 and miR-1246 levels are associated with active IBD. Serum interleukin (IL)-2 and IL-6l and positivity for anti-bacterial flagellin, anti-outer membrane porin C, anti-A4-Fla2, and anti-Fla-X antibodies predict recurrence of disease. The heterogeneity of IBD phenotypes underlines the need for new markers that can subclassify, diagnose, inform prognosis, and guide IBD treatment; but owing to the low sensitivity or specificity of known molecular markers, current knowledge is far from adequate to support their use in everyday clinical practice, a limitation that includes the microbiome as biomarker.
Early studies on animal models have shown that immune cells could not cause inflammation in the absence of intestinal bacteria, therefore suggesting a putative role for the intestinal microbiome in the induction and/or maintenance of local inflammation and disease. This was further supported by the observation that intestinal inflammation in IBD was greatest in parts of the bowel richer in bacteria. Further studies have demonstrated that certain patterns of microbiotic alterations, including increases or reductions in the plethora of bacterial, fungal, and viral species, were likely linked to the risk for IBD.
Physical exercise is a possible modulator of intestinal microbiome composition, altering the functional activity of the gut ecosystem. Exercise is associated with increased biodiversity and a beneficial metabolic function, while exhaustive exercise training might be associated with dysbiosis of the gut microbiota, promoting negative metabolic effects and inflammation. Thus, physical activity/exercise has been studied as a significant modifier of the intestinal microbiome in animal and human studies. Specifically, more active individuals’ microbiomes tend to harbor a higher abundance in Akkermansia muciniphila, a health-promoting species, as well as decreased Bacteroidetes bacteria and increased bacterial diversity. Specific types of physical exercise have not only been associated with microbiotic signatures, but also with a reduction in endotoxemia and serum inflammatory markers. These alterations persist as statistically significant, even when normalizing for age, weight, body composition, and nutritional habits as confounding factors. Nevertheless, it should be noted that researchers have also reported a lack of correlation between a certain type of exercise and changes in the microbiome; moreover, some contradictions as to the observed patterns of microbiotic alterations associated with exercise are evident. This ambiguity is, however, expected to be partly clarified when common definitions and detailed description of exercise characteristics [i.e. frequency, intensity, type (mode), time (duration), and volume/dose (duration x intensity)] and methods of fecal sampling are utilized among the same study groups.
Given the established pathobiological role for the microbiome in IBD and taking into account the more recent data assessing patterns of microbiotic alterations associated with exercise, this review aims to summarize and clarify the important findings linking dysbiosis in IBD to physical activity, with a focus on preventative medicine and therapeutics.
Role of the microbiome in IBD
Patients with CD have a diminished diversity of the fecal intestinal microbiome, with Lachnospiraceae, Bacteroidetes, and the species Clostridium leptum being decreased, with Proteobacteria, Actinobacteria, and the genus Prevotella being increased. Patients with inflammatory bowel disease also have increased Fusobacterium, Pasturellaceae, Ruminococcus gnavus, Veillonellaceae, Candida albicans, Candida tropicalis, Clavispora lusitaniae, Cyberlindnera jadinii, Kluyveromyces marxianus, and Caudivirales in their gut microbiota, as well as decreased Bacteroides, Bifidobacterium, Clostridium XIVa, Clostridium IV, Faecalibacterium prausnitzii, Roseburia, Suturella, and Saccharomyces cerevisiae. Therefore, it can be argued that intestinal dysbiosis may be a component of IBD pathogenesis.
The involvement of the microbiome in the pathogenesis of IBD is further supported by the effectiveness of antibiotic therapy in the treatment of certain IBD phenotypes, such as perianal CD and pouchitis, and in the prevention of postoperative relapse in patients with CD.
Fecal microbiota transplantation involves the transfer of feces from a donor to the GI tract of a recipient, as an attempt to enrich the recipient’s gut microbiota and correct any dysbiosis. Fecal microbiota transplantation is currently systematically used in the treatment of Clostridium difficile colitis. Some researchers have also investigated its implementation in IBD therapeutics, with some promising findings having been reported, although no concrete conclusions can yet be drawn about its efficacy and safety, plausibly owing to the dissimilarities between the associated studies.
Conclusion
The findings of the present review imply that there exists a promising field of research regarding exercise-induced changes of the microbiome in IBD. What needs to be elucidated is whether the microbiome is a passive “bystander” in the systemic effects induced by physical activity, i.e. observing and reacting to activity-related systemic metabolic and endocrine signals by altering its composition, or whether it is a necessary physiological intermediate in the restoration of immune tolerance and normal gastrointestinal function in the context of IBD. Further research should also focus on disease determinants, such as age, sex, type, localization, histology, refractory phenotype, disease activity, molecular markers, and performance status, which could affect the disease’s response to certain types of physical exercise. Besides, considering that there is not only one optimal microbiota composition for the IBD patients, more studies are also needed to reveal how microorganisms interact with each other and with their host to identify different healthy microbiota schemes and an optimal, potentially personalized, dose of exercise for these patients. Lastly, an interesting field might exist for the microbiome as an index predictive or indicative of exercise-induced amelioration of IBD clinical symptoms, as part of current research on the molecular epidemiology of IBD.
