The gut–brain axis: Identifying new therapeutic approaches for type 2 diabetes, obesity, and related disorders

Abstract

Background The gut-brain axis, which mediates bidirectional communication between the gastrointestinal system and central nervous system (CNS), plays a fundamental role in multiple areas of physiology including regulating appetite, metabolism, and gastrointestinal function. The biology of the gut-brain axis is central to the efficacy of glucagon-like peptide-1 (GLP-1)-based therapies, which are now leading treatments for type 2 diabetes (T2DM) and obesity. This success and research to suggest a much broader role of gut-brain circuits in physiology and disease has led to increasing interest in targeting such circuits to discover new therapeutics. However, our current knowledge of this biology is limited, largely because the scientific tools have not been available to enable a detailed mechanistic understanding of gut-brain communication. Scope of review In this review, we provide an overview of the current understanding of how sensory information from the gastrointestinal system is communicated to the central nervous system, with an emphasis on circuits involved in regulating feeding and metabolism. We then describe how recent technologies are enabling a better understanding of this system at a molecular level and how this information is leading to novel insights into gut-brain communication. We also discuss current therapeutic approaches that leverage the gut-brain axis to treat diabetes, obesity, and related disorders and describe potential novel approaches that have been enabled by recent advances in the field. Major conclusions The gut-brain axis is intimately involved in regulating glucose homeostasis and appetite, and this system plays a key role in mediating the efficacy of therapeutics that have had a major impact on treating T2DM and obesity. Research into the gut-brain axis has historically largely focused on studying individual components in this system, but new technologies are now enabling a better understanding of how signals from these components are orchestrated to regulate metabolism. While this work reveals a complexity of signaling even greater than previously appreciated, new insights are already being leveraged to explore fundamentally new approaches to treating metabolic diseases.

Glucose Stimulates Gut Motility in Fasted and Fed Conditions: Potential Involvement of a Nitric Oxide Pathway

“…The number of new patients suffering from type 2 diabetes (T2D) is still rising despite decades of extensive research on the causes of the disease. Among the most recent progresses, several recent advances have highlighted the role of the gut on this metabolic disorder [ 1 ]. In fact, T2D is associated with numerous intestinal dysfunctions strongly altering the gut-brain communication.…”

Hypothalamic neuroinflammation induced by obesity and the effect of Liraglutide ‎

“…It has been known that both hypothalamic-pituitary-adrenal (HPA) axis and the Gut-brain axis of glucagon-like peptide-1 (GLP-1) exchange signals via the vagal nerve, thereby regulating various physiological functions, including gastric motility and digestion, appetite, and energy metabolism. In contrast, any hypothalamic inflammation or dysregulation in these axes will be associated with metabolic dysfunctions, leptin plus insulin resistance, and upper-body obesity [19,22,23]. GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system, and GLP-1 protein may cross the blood-brain barrier [24].…”

Enteroendocrine cell lineages that differentially control feeding and gut motility

“…The gut-brain axis plays a critical role in animal physiology and behavior. Sensory pathways from the gut relay information about ingested nutrients, meal-induced tissue distension, osmolarity changes in the intestinal lumen, and cellular damage from toxins (Bai et al, 2019;Brookes et al, 2013;Prescott and Liberles, 2022;Richards et al, 2021;Williams et al, 2016).…”

“…Moreover, manipulations of the gut-brain axis have been harnessed clinically through gut hormone receptor agonism or bariatric surgery to provide powerful therapeutic approaches for obesity and diabetes intervention (Richards et al, 2021;Seeley et al, 2015).…”