“The Gut-Brain Axis: Identifying New Therapeutic Approaches for Type 2 Diabetes, Obesity, and Related Disorders”, 2021-04 ():
The gut-brain axis plays an essential role in regulating metabolism and leading therapeutics for T2DM and obesity harness this machinery.
Multiple components of the gut-brain axis are involved in an integrated response to sensory information to maintain whole-body homeostasis.
A systems biology approach using advanced technologies is enabling a detailed mechanistic understanding of gut-brain communication.
This understanding is leading to new approaches that may result in the next generation of therapeutics for metabolic diseases.
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.
[Keywords: gut-brain axis, diabetes, obesity, gut peptides, vagus]
…First-generation GLP-1 analogs are injectables that are dosed once daily or more frequently and are associated with relatively modest weight loss. Second-generation GLP-1 analogs, including once-weekly exenatide, semaglutide, dulaglutide, and oral semaglutide, which have been approved for T2DM have more convenient dosing regimens (1 weekly, oral) and high-dose semaglutide and dulaglutide have shown the potential for > 10% weight loss in clinical studies. All these analogs are associated with tolerability issues (nausea/vomiting). Next-generation approaches that are being investigated in the clinic include injectable agents that exploit dual pharmacology and oral small molecule GLP-1R agonists. Future approaches currently being explored include directly targeting gut EEC and vagal circuits with small molecule oral therapeutics.
…An oral formulation of semaglutide has also been approved for T2DM. In head-to-head studies, HbA1c decreases were superior those achieved with the DPP-4 inhibitor sitagliptin [135] and non-inferior to liraglutide [136]. Modest weight loss (up to 2.3 kg) was achieved with the oral formulation in a monotherapy study in patients with T2DM [137, 138]. Tolerability remains an issue, and the dosing regimen is relatively complex. It remains to be determined whether improved formulations can result in greater convenience and efficacy.