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The gut–brain axis and pain signalling mechanisms in the gastrointestinal tract

Nature Reviews Gastroenterology & Hepatology volume 22, pages 206–221 (2025)Cite this article

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Abstract

Visceral pain is a major clinical problem and one of the most common reasons patients with gastrointestinal disorders seek medical help. Peripheral sensory neurons that innervate the gut can detect noxious stimuli and send signals to the central nervous system that are perceived as pain. There is a bidirectional communication network between the gastrointestinal tract and the nervous system that mediates pain through the gut–brain axis. Sensory neurons detect mechanical and chemical stimuli within the intestinal tissues, and receive signals from immune cells, epithelial cells and the gut microbiota, which results in peripheral sensitization and visceral pain. This Review focuses on molecular communication between these non-neuronal cell types and neurons in visceral pain. These bidirectional interactions can be dysregulated during gastrointestinal diseases to exacerbate visceral pain. We outline the anatomical pathways involved in pain processing in the gut and how cell–cell communication is integrated into this gut–brain axis. Understanding how bidirectional communication between the gut and nervous system is altered during disease could provide new therapeutic targets for treating visceral pain.

Key Points

  • Visceral pain is a substantial clinical issue associated with several visceral diseases and one of the primary reasons why patients with gastrointestinal disorders seek medical assistance.

  • Sensory neurons originating from the dorsal root ganglia innervate the gut and are responsible for detecting noxious stimuli and transmitting signals to the central nervous system, which are perceived as pain.

  • The bidirectional communication network between the gastrointestinal tract and the nervous system is known as the gut–brain axis; this network has a crucial role in mediating pain in the context of visceral disorders.

  • Immune cells, epithelial cells and the gut microbiota all communicate with sensory neurons; this communication can lead to peripheral sensitization and modulation of visceral pain processing.

  • Dysregulation of the interactions between non-neuronal cell types and neurons can contribute to visceral hypersensitivity in gastrointestinal diseases, and understanding these alterations could open new therapeutic targets for the treatment of visceral pain.

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Fig. 1: Extrinsic neuronal innervation of the gastrointestinal tract.
Fig. 2: Neuroimmune interactions that modulate or induce visceral pain.
Fig. 3: Neuroepithelial interactions in visceral pain and gut barrier protection.
Fig. 4: Microbial direct and indirect interactions with sensory neurons in visceral pain.

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Acknowledgements

I.M.C. acknowledges funding from the Kenneth Rainin Foundation, NIH/NIDDK grant R01DK127257 and the Food Allergy Science Initiative. K.A.M. was supported by NIH fellowship F32DK137456.

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  1. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    Kimberly A. Meerschaert

  2. Department of Immunology, Harvard Medical School, Boston, MA, USA

    Isaac M. Chiu

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K.A.M. researched data for the article. Both authors contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Kimberly A. Meerschaert or Isaac M. Chiu.

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Competing interests

I.M.C. is on scientific advisory boards for GSK Pharmaceuticals and Nilo Therapeutics. He also consults for Panther Life Sciences and Fzata. His laboratory has received sponsored research support from GSK, Abbvie/Allergan and Moderna. K.A.M. declares no competing interests.

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Meerschaert, K.A., Chiu, I.M. The gut–brain axis and pain signalling mechanisms in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 22, 206–221 (2025). https://doi.org/10.1038/s41575-024-01017-9

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