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  • Review Article
  • Published:

Neuroplasticity and dysfunction after gastrointestinal inflammation

Nature Reviews Gastroenterology & Hepatology volume 11, pages 611–627 (2014)Cite this article

Subjects

Key Points

  • Gastrointestinal infection and inflammation are key risk factors for the development of numerous clinical gastrointestinal disorders that present with symptoms such as altered motility or secretion, abdominal discomfort and pain

  • Neuronal processing along the gut–brain axis is crucial for the function and modulation of key gastrointestinal processes; findings suggest that this processing can be altered by gut inflammation or infection

  • Inflammation or infection causes specific changes in enteric neuronal excitability, which can persist after inflammation has resolved; in some experimental models, inflammation also causes a rapid loss of myenteric neurons and viscerofugal neurons

  • Inflammation causes a specific hypersensitivity of visceromotor sympathetic neurons in prevertebral ganglia, which persists long after inflammation has resolved

  • Extrinsic gut sensory afferents express pronociceptive channels and receptors that can be activated in response to inflammatory and immune mediators, leading to acute neuronal hyperexcitability, visceral hypersensitivity and neurogenic inflammation

  • Inflammation causes lowering of mechanical activation thresholds of high-threshold or low-threshold afferents, which leads to hyperexcitability in afferent neuronal cell bodies, and increased activation of nociceptive pathways in the central nervous system

Abstract

The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.

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Figure 1: Neural innervation and multiple levels of reflex control of gastrointestinal function.
Figure 2: Neuroplasticity in enteric neurons during and after gut inflammation.
Figure 3: Neuroplasticity in sympathetic neurons during and after gut inflammation.
Figure 4: Inflammation-induced neuroplasticity: contribution of neuroactive signalling molecules and the channels/receptors they act on.
Figure 5: Neuroplasticity in extrinsic sensory afferent pathways during and after resolution of gut inflammation.

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Acknowledgements

The authors wish to thank J. Applequist at the Mayo Clinic College of Medicine and J. Maddern at the University of Adelaide, Australia, for their secretarial assistance. S.M.B. is supported by an NHMRC R.D. Wright Biomedical Fellowship and by NHMRC Australia Project grants (1008100, 1049682, 1049928 and 1063803). D.R.L. is supported by NIH grant DK76665.

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Authors and Affiliations

  1. Visceral Pain Group, Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, 5000, SA, Australia

    Stuart M. Brierley

  2. Department of Physiology and Biomedical Engineering and Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, 55905, MN, USA

    David R. Linden

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  1. Stuart M. Brierley
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S.M.B. and D.R.L. contributed equally to the discussion of content, writing and reviewing/editing the manuscript before submission.

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Correspondence to Stuart M. Brierley.

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Competing interests

S.M.B. receives research support from Ironwood Pharmaceuticals Inc. None of the details relating to this research support are discussed in this review. D.R.L. declares no competing interests.

Supplementary information

Supplementary Box 1

Other clinical gastrointestinal inflammatory disorders causing gut dysfunction (PDF 447 kb)

Supplementary Box 2

Non-neuronal influences on gastrointestinal function (PDF 287 kb)

Supplementary Table 1

Animal models of gastrointestinal infection/inflammation and the neuroplasticity and altered gut function they induce (PDF 198 kb)

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Brierley, S., Linden, D. Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat Rev Gastroenterol Hepatol 11, 611–627 (2014). https://doi.org/10.1038/nrgastro.2014.103

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