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  • Review Article
  • Published:

Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy

Nature Reviews Gastroenterology & Hepatology volume 12, pages 353–362 (2015)Cite this article

Subjects

Key Points

  • Neural reflex regulation of immune responses depends on the type and tissue compartment of the inflammatory response

  • Although immune cells respond to cholinergic receptor activation, immune organs such as the spleen and lymphoid organs are innervated by adrenergic pathways rather than cholinergic pathways

  • A variety of cholinergic, adrenergic and enteric neurotransmitters has strong immune-regulating potential, but only limited evidence exists for neural afferent–efferent reflex pathways in intestinal immune regulation

  • Clinical and preclinical studies using electrical (implanted devices) or nutritional (cholecystokinin-afferent activation) activation of vagal reflex are ongoing and suggest an anti-inflammatory potential of vagus nerve stimulation (afferent or efferent)

Abstract

Studies in neuroscience and immunology have clarified much of the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems. As with other organs, intestinal immune responses and the development of immunity seems to be modulated by neural reflexes. Sympathetic immune modulation and reflexes are well described, and in the past decade the parasympathetic efferent vagus nerve has been added to this immune-regulation network. This system, designated 'the inflammatory reflex', comprises an afferent arm that senses inflammation and an efferent arm that inhibits innate immune responses. Intervention in this system as an innovative principle is currently being tested in pioneering trials of vagus nerve stimulation using implantable devices to treat IBD. Patients benefit from this treatment, but some of the working mechanisms remain to be established, for instance, treatment is effective despite the vagus nerve not always directly innervating the inflamed tissue. In this Review, we will focus on the direct neuronal regulatory mechanisms of immunity in the intestine, taking into account current advances regarding the innervation of the spleen and lymphoid organs, with a focus on the potential for treatment in IBD and other gastrointestinal pathologies.

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Figure 1: A schematic of interactive parasympathetic and sympathetic innervation of lymphoid structures.
Figure 2: Intestinal innervation and immune cell regulation.

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Authors and Affiliations

  1. Department of Gastroenterology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Meibergdreef 69, 1105BK, Amsterdam, Netherlands

    Rose A. Willemze & Wouter J. de Jonge

  2. Department of Surgery, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ, Eindhoven, Netherlands

    Misha D. Luyer

  3. School for Mental Health and Neuroscience, Health and Nutrition, 6200 MD, Maastricht University, Netherlands

    Wim A. Buurman

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Correspondence to Wouter J. de Jonge.

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R.A.W. is funded by a research grant from GlaxoSmithKline. M.D.L. receives research funding and consultancy fees from Covidien, Fonds NutsOhra, Nutricia and ZonMw. W.J.J. has received research and consultancy grants from GlaxoSmithKline, Mead Johnson Nutrition Paediatric Institute, Schwabe Corporation and Setpoint Medical. W.A.B. declares no competing interests.

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Willemze, R., Luyer, M., Buurman, W. et al. Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy. Nat Rev Gastroenterol Hepatol 12, 353–362 (2015). https://doi.org/10.1038/nrgastro.2015.56

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