Mechanisms and clinical implications of gut-brain interactions
Zachary S. Lorsch, Rodger A. Liddle
Zachary S. Lorsch, Rodger A. Liddle
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Review

Mechanisms and clinical implications of gut-brain interactions

Abstract

Connections between the digestive system and the brain have been postulated for over 2000 years. Despite this, only recently have specific mechanisms of gut-brain interaction been identified. Due in large part to increased interest in the microbiome, the wide use of incretin-based therapies (i.e., glucagon-like peptide 1 [GLP-1] receptor agonists), technological advancements, increased understanding of neuroimmunology, and the identification of a direct enteroendocrine cell–neural circuit, research in the past 10 years has made it abundantly clear that the gut-brain connection plays a role both in clinical disease as well as the actions of therapeutics. In this Review, we describe mechanisms by which the gut and brain communicate and highlight human and animal studies that implicate changes in gut-brain communication in disease states in gastroenterology, neurology, psychiatry, and endocrinology. Furthermore, we define how GLP-1 receptor agonists for obesity and guanylyl cyclase C agonists for irritable bowel syndrome leverage gut-brain mechanisms to improve patient outcomes. This Review illustrates the critical nature of gut-brain communication in human disease and the potential to target gut-brain pathways for therapeutic benefit.

Authors

Zachary S. Lorsch, Rodger A. Liddle

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Figure 1

Mechanisms of signaling between the gut and the brain.

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Mechanisms of signaling between the gut and the brain. Information can b...
Information can be transmitted from the gut lumen to the brain in a variety of ways, but recent research has highlighted four distinct categories of signaling. (A) In hormonal signaling, hormones from the gut epithelium are either released into the bloodstream (endocrine) or locally (paracrine), where they act via receptors to exert an effect. Hormones act on receptors in the ENS and CNS (particularly the hypothalamus) to receive these signals. 5-HT, 5-hydroxytryptamine (serotonin). (B) In neuropod-mediated signaling, EECs form close connections that rapidly transmit information from the gut lumen to the CNS. In more proximal regions of the gut (i.e., stomach, small intestine), signals are typically transmitted via the vagus nerve and convey nutritive information. Neuropod signaling in more distal regions (i.e., colon) conveys information related to visceral pain and stretch, which are received by the brain via the dorsal root ganglia. (C) Gut microbiota produce local effects in the gut lumen that affect epithelial permeability and allow transmission of the microbiota or associated metabolites into the bloodstream. Some of these changes induce an inflammatory response. Alternatively, microbes or metabolites (such as short-chain fatty acids) act locally on receptors to modify cell function. (D) The gastrointestinal immune system surveils the gut lumen with resident T cells and neutrophils that are activated by microbes and their metabolites and convey signals to the brain. Responses can be modified via inflammation within the gastrointestinal tract, leading to increased permeability and allowing further immune interactions. Concurrently, top-down mechanisms have been described, including glucocorticoid-dependent activation of ENS microglia leading to inflammation within the gut epithelium.