Physical Activity Shapes the Intestinal Microbiome and Immunity of Healthy Mice but Has No Protective Effects against Colitis in MUC2 ^−/− Mice

Abstract

The interactions among humans, their environment, and the trillions of microbes residing within the human intestinal tract form a tripartite relationship that is fundamental to the overall health of the host. Disruptions in the delicate balance between the intestinal microbiota and host immunity are implicated in various chronic diseases, including inflammatory bowel disease (IBD). There is no known cure for IBD; therefore, novel therapeutics targeting prevention and symptom management are of great interest. Recently, physical activity in healthy mice was shown to be protective against chemically induced colitis; however, the benefits of physical activity during or following disease onset are not known. In this study, we examine whether voluntary wheel running is protective against primary disease symptoms in a mucin 2-deficient (Muc2−/−) lifelong model of murine colitis. We show that 6 weeks of wheel running in healthy C57BL/6 mice leads to distinct changes in fecal bacteriome, increased butyrate production, and modulation in colonic gene expression of various cytokines, suggesting an overall primed anti-inflammatory state. However, these physical activity-derived benefits are not present in Muc2−/− mice harboring a dysfunctional mucosal layer from birth, ultimately showing no improvements in clinical signs. We extrapolate from our findings that while physical activity in healthy individuals may be an important preventative measure against IBD, for those with a compromised intestinal mucosa, a commonality in IBD patients, these benefits are lost. IMPORTANCE Perturbation in the gut microbial ecosystem has been associated with various diseases, including inflammatory bowel disease. Habitual physical activity, through its ability to modulate the gut microbiome, has recently been shown to prophylactically protect against chemically induced models of murine colitis. Here, we (i) confirm previous reports that physical activity has limited but significant effects on the gut microbiome of mice and (ii) show that such changes are associated with anti-inflammatory states in the gut, such as increased production of beneficial short-chain fatty acids and lower levels of proinflammatory immune markers implicated in human colitis; however, we also show that (iii) these physical activity-derived benefits are completely lost in the absence of a healthy intestinal mucus layer, a hallmark phenotype of human colitis.

The Combination of Intestinal Alkaline Phosphatase Treatment with Moderate Physical Activity Alleviates the Severity of Experimental Colitis in Obese Mice via Modulation of Gut Microbiota, Attenuation of Proinflammatory Cytokines, Oxidative Stress Biomarkers and DNA Oxidative Damage in Colonic Mucosa

“…Furthermore, the reduced running distance was paralleled by a decrease in the muscle strength assessed by the grip test in these mice compared with healthy mice. The running distance on the SW of healthy mice well corresponded with the similar range, 1.3 and 1.1 km/day, reported before in mice without colitis [38]. The access of mice to SW in all groups led to a reduction of their body weights, especially notable in those fed with diet-induced obesity.…”

Voluntary Wheel Running in Old C57BL/6 Mice Reduces Age-Related Inflammation in the Colon but Not in the Brain

“…By analyzing colonic tissue, we revealed a significant decrease in Ifng, ll10, Ccl2, S100b, and Iba1 (Figure 3B). Down-regulation of Ifng was also detected in colonic tissue of 2-3 months old mice after 6 weeks of VWR [51]. These mice were also characterized by a decrease in Tnf, which was not significantly changed in our aged mice, and an increase in the protective Il10 [51], which we found downregulated in the aged colon after running (Figure 3B).…”

“…Down-regulation of Ifng was also detected in colonic tissue of 2-3 months old mice after 6 weeks of VWR [51]. These mice were also characterized by a decrease in Tnf, which was not significantly changed in our aged mice, and an increase in the protective Il10 [51], which we found downregulated in the aged colon after running (Figure 3B). Mice with induced colitis were subjected to forced moderate exercise, which led to an increase in cytokines such as Tnf, Il1b, and Il10 in the colon and exacerbated colitis symptoms, whereas 30 days of VWR attenuated colitis in these mice and was associated with a decrease in Tnf [52].…”

Lactate in contemporary biology: a phoenix risen

“…The concentration of lactate in human feces is relatively low (< 5 mM) because of the presence of bacteria that convert lactate to butyrate (Duncan et al, 2004). More recently, we have learned that physical exercise and physical fitness encourage diversity of species including those that act to convert lactate to butyrate (Estaki et al, 2016;Estaki et al, 2020). Recently also, the presence of "performance-enhancing" gut microbes, members of the genus Veillonella, in the stools of marathon runners (Scheiman et al, 2019) have been found.…”