The Impact of Diet and the Gut Microbiota on Small Intestinal Gut-Brain Signaling Mechanisms that Regulate Metabolic Homeostasis

Abstract

Over the last several decades, metabolic diseases, like obesity and diabetes, have emerged as a major public health crisis. In 2019 alone, 5 million deaths were attributed to obesity-related causes and 1.4 million to type II diabetes (T2D). This increasing prevalence and mortality rate highlights the need for alternative therapies to prevent and treat these diseases. Pharmacological and surgical interventions, while highly effective, are expensive and often produce negative side effects, making them unobtainable for a large portion of the population. Thus, alternative therapies and a better understanding of the mechanisms that control food intake and blood glucose, could provide more effective ways to reduce disease prevalence. Multiple pathways involving endocrine and neuroendocrine signals as well as neuronal gut-brain signaling via vagal and spinal afferents, control food intake and glucose homeostasis in response to a meal. Intestinal nutrients, like lipids, activate enteroendocrine cells, which release gut peptides that signal to vagal afferent neurons. This gut-brain signaling is influenced by the gut microbiota, which can be rapidly shifted by diet and interacts with the intestinal epithelium. High-fat feeding and metabolic disease negatively shift the microbiota, suggesting that targeting the microbiome could improve gut-brain signaling to restore energy and glucose homeostasis in individuals with obesity or diabetes.Chapter 1 highlights the link between the development of T2D and the gut microbiota and explores its role in both current and novel treatments for T2D, highlighting potential alternative therapies that directly target the gut microbiota including fecal microbiota transplant, prebiotics, probiotics, synbiotics, or xenobiotics. While previous research has established a role for the gut microbiota in metabolic disease, the extent to which it can be effectively targeted for treatment remains unclear. Thus, a better understanding of both the impact of the gut microbiota in the etiology of diabetes and its therapeutic potential for treating metabolic disease could usher a new approach to targeted treatment options to ameliorate the disease. Chapter 2 establishes (1) the ability of specific vagal afferents to regulate food intake in response to small intestinal lipids or the gut peptide cholecystokinin (CCK), and (2) that alterations to the small intestinal microbiota following oligofructose (OFS) treatment can restore this small intestinal lipid sensing and neuronal gut-brain signaling in high fat (HF)-fed rats to reduce food intake. Vagal afferents are necessary to control food intake, but the specific neuronal pathway through which nutrients signal to the brain has not been established. Furthermore, while diet and shifts in the gut microbiota alter gut-brain signaling, the role of the small intestinal microbiota has not been explored. These findings provide further insight into the role of vagal afferent signaling in the control of food intake and establishes a causal role for prebiotics and the small intestinal microbiota in improving energy homeostasis in HF-fed animals. In Chapter 3, we establish a glucoregulatory role of the small intestinal microbiota as it impacts small intestinal lipid sensing. Short-term OFS treatment in HF-fed animals improves whole body glucose homeostasis and decreases glucose production during a small intestinal lipid infusion, likely via shifts in the small intestinal microbiota. Glucagon-like peptide-2 (GLP-2) treatment produces similar improvements in HF-fed rats and may be necessary for the benefits of OFS on glucose production. We also developed an organoid model to study nutrient sensing changes in HF- and HF-OFS-fed mice. While previous research links OFS to improved glucose homeostasis via shifts in the distal gut microbiota, our study is the first to highlight the role of OFS-induced shifts in the small intestinal microbiota as they impact glucose production. These findings suggest that targeting the gut microbiota and gut-brain signaling pathways could lead to new therapies for reducing obesity and diabetes prevalence and improving metabolic outcomes.