Increased dysregulation of non-neuronal and neuronal cell types as a major contributor of visceral pain in gastrointestinal disease
Review by Prof. Cass Condray (USA)
Study Summary
The gut–brain axis and pain signaling mechanisms in the gastrointestinal tract by Kimberly A. Meerschaert and Isaac M. Chiu, in Nature Reviews Gastroenterology & Hepatology, explores the intricate communication pathways between the gut and the nervous system, emphasizing their role in visceral pain perception in gastrointestinal disease.
Visceral pain is a prevalent clinical issue prompting many individuals with gastrointestinal disorders to seek medical attention and is primarily detected by peripheral sensory neurons innervating the gut. These neurons identify harmful stimuli and relay signals to the central nervous system, culminating in the sensation of pain. The gut–brain axis facilitates this bidirectional communication, where sensory neurons respond to mechanical and chemical cues within the intestines and interact with immune cells, epithelial cells, and the gut microbiota. Such interactions can lead to peripheral sensitization, heightening visceral pain.
This review provides a comprehensive overview of the anatomical routes involved in gut pain processing and elucidates how intercellular communications are integrated within the gut–brain axis. They highlight that disruptions in these bidirectional interactions during gastrointestinal diseases can intensify visceral pain. By understanding these altered communications, the review suggests potential therapeutic targets for alleviating visceral pain, offering hope for improved treatments for those affected by such conditions.
Commentary
Major strengths include outlining signaling pathways behind the mechanism of linaclotide, shown preclinically to inhibit colonic nociceptors and reduce visceral hypersensitivity in mouse and rat models of colonic inflammation, as well as histamine-1 receptor antagonists and mast cell stabilizers, have some efficacy in reducing visceral pain in patients with IBS; as well as 5-HT receptor signaling through 5-HT antagonists. Activation of GABA receptors on colonic afferents decreases sensitivity in mice, and trials of pregabalin significantly reduced pain in IBS and functional dyspepsia.
However, in a trial of neurokinins, neurokinin receptor 3 antagonist, talnetant, decreased visceral hypersensitivity was observed rats, but failed to alter pain in human volunteers. Visceral pain is a substantial and clinically impactful issue associated with several visceral diseases and one of the primary reasons why patients with gastrointestinal disorders such as IBS and IBD seek medical assistance. This review found key signaling pathways and potential therapeutic targets to address this.
These findings are generalizable to an extent, but as different global regions have different diets with increased or decreased amounts of short-chain fatty acids, such as butyrate, acetate and propionate, increased or decreased use of dietary emulsifiers and other food additives associated with increased visceral pain, different regions may have different findings. Future directions should include gut-brain visceral pain studies in different microbiome models, such as SIBO, C. diff, and IBD patients on TPN, all of which create altered microbiomes and are associated with visceral abdominal pain.
Citation
Meerschaert, K.A., Chiu, I.M. The gut–brain axis and pain signalling mechanisms in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-01017-9
Link
https://www.nature.com/articles/s41575-024-01017-9
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