Diet and exercise modulate the gut microbiome with implications for health and disease

The gut is home to trillions of microbes, collectively called the gut microbiota, that play crucial roles in host health. In recent years, the gut microbiome has emerged as having a significant impact in preventing, exacerbating, and even causing disease. Fortunately, the gut microbiota is also highly malleable to interventions. Diet and exercise are two potential lifestyle factors that have a major impact on the gut microbiota. The primary purpose of the work presented in this dissertation was to determine the interplay between diet, exercise, and the gut microbiome in states of health and disease, and to elucidate some of the mechanisms by which exercise-induced changes in the gut microbiome confer protection against disease. \n\nThis dissertation is divided into three primary sections. First, we explored the ability of pectin, a soluble, fermentable fiber to enhance learning and memory in two cohorts of young mice. Despite identical treatment of the two cohorts, we observed stark differences in the behavioral outcomes of the two cohorts, along with distinct gut microbiotas. In one cohort, pectin-fed mice exhibited significantly improved cognitive performance compared to cellulose-fed mice; however, in the other cohort, there was no effect of diet. Microbiota analysis revealed significantly different bacterial communities between the two cohorts, and several genera that correlated with performance.\n\nIn the next section, we investigated the effects of six weeks of aerobic exercise training on markers of insulin sensitivity, inflammation, and metabolic endotoxemia in previously sedentary, lean and obese humans, and how these correlated with already published effects of the exercise intervention on the gut microbiota and microbial metabolites. We found that exercise training reduced insulin resistance and markers of metabolic endotoxemia, potentially due to improvements in gut barrier function. Several of these parameters correlated with baseline and exercise-induced changes in microbiota composition and microbial metabolites, suggesting that exercise may in part confer benefits on cardiovascular health and endotoxemia through modulating the gut microbiota.\n\nLastly, we investigated the effects of exercise-induced changes in the gut microbiota on host gene expression in the brain and colon. To do this, we analyzed tissues collected from a previous experiment in which we transplanted cecal contents from exercised or sedentary mice into two groups of germ-free mice. After five weeks of colonization, recipient mice were euthanized and whole transcriptome analysis was performed on RNA isolated from the distal colon and whole brain to assess global gene expression differences. The exercised microbiota increased expression of genes related to immune function in the distal colon, and cell-cell communication in the whole brain. This broad-scale approach to screen for potential genes and pathways that are influenced by an exercised microbiota will open up many new avenues for future discovery.\n\nIn summary, this dissertation provides evidence for a complex interplay of diet and exercise with the gut microbiome in states of health and disease. Altogether, these findings indicate that lifestyle interventions can be used to positively modulate the gut microbiota and host health, and that baseline gut microbiota characteristics may ultimately help predict the success of such interventions. Future research should further explore the mechanisms involved and examine the effects of diet and exercise on the gut microbiota in a variety of clinical populations.