Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms

Abstract

The gastrointestinal tract has extensive, surgically accessible nerve connections with the central nervous system. This provides the opportunity to exploit rapidly advancing methods of nerve stimulation to treat gastrointestinal disorders. Bioelectric neuromodulation technology has considerably advanced in the past decade, but sacral nerve stimulation for faecal incontinence currently remains the only neuromodulation protocol in general use for a gastrointestinal disorder. Treatment of other conditions, such as IBD, obesity, nausea and gastroparesis, has had variable success. That nerves modulate inflammation in the intestine is well established, but the anti-inflammatory effects of vagal nerve stimulation have only recently been discovered, and positive effects of this approach were seen in only some patients with Crohn’s disease in a single trial. Pulses of high-frequency current applied to the vagus nerve have been used to block signalling from the stomach to the brain to reduce appetite with variable outcomes. Bioelectric neuromodulation has also been investigated for postoperative ileus, gastroparesis symptoms and constipation in animal models and some clinical trials. The clinical success of this bioelectric neuromodulation therapy might be enhanced through better knowledge of the targeted nerve pathways and their physiological and pathophysiological roles, optimizing stimulation protocols and determining which patients benefit most from this therapy.

Key points

  • The gastrointestinal tract has substantial two-way neural interactions with the central nervous system through the vagus nerve, thoracolumbar connections and sacral nerves, which provide opportunities for disease-modifying bioelectric neuromodulation therapy.

  • Sacral nerve stimulation (SNS) to treat faecal incontinence is the only neuromodulation protocol for a gastrointestinal disorder that is currently in general use; adapted SNS to selectively stimulate efferent pathways to treat constipation is not in general use.

  • Inhibition of gastrointestinal inflammation might be possible via vagal nerve stimulation (VNS) or sympathetic nerve stimulation, and limited clinical testing suggests effectiveness of cervical VNS.

  • The vagus nerve carries signals for feeding, whose block might reduce appetite and treat obesity; however, electrical block of vagal afferents had variable clinical success, whereas direct stimulation of afferent endings at the gastric surface reduced satiety in some studies.

  • Gastric electrical stimulation stimulates afferent endings at the gastric surface, which, in some studies, reduced postprandial nausea in patients with gastroparesis and reduced weight gain in patients with obesity.

  • Bioelectric neuromodulation might be a valuable treatment for several gastrointestinal disorders but further investigations into the underlying mechanisms, placement of stimulating electrodes, stimulus parameters and patient populations to optimize effectiveness are still required.

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Fig. 1: Sites of bioelectric neuromodulation to change gastrointestinal functions.
Fig. 2: The extrinsic innervation of the gastrointestinal tract.
Fig. 3: Gastric sites of bioelectric neuromodulation.
Fig. 4: Nerve pathways for voluntary control of defecation and faecal continence.

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Acknowledgements

Work on bioelectric modulation for inflammatory bowel disease is supported by the Defense Advanced Research Projects Agency (DARPA) BTO through the Space and Naval Warfare Systems Center Contract No. N66001-15-2-4060 to J.B.F., and work on gastric disorders by NIH (SPARC) grant ID# OT2OD023847 to J.B.F., the National Institutes of Health (NIH) and the National Health and Medical Research Council of Australia. Billie Hunne is thanked for assistance in the preparation of illustrations.

Review criteria

Literature searches included publications in the past 10 years. Earlier publications have been sought if they were referenced in contemporary papers. Combinations of the following search terms were used: “vagus nerve”, “vagus nerve stimulation”, “gastric electrical stimulation”, “inflammatory bowel disease”, “sacral nerve stimulation”, “ileus”, “gastroparesis”, “faecal incontinence”, “constipation”, “appetite”, “satiety”, “nausea”. Searches were conducted in Google Scholar and PubMed.

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All authors researched data for the article, made substantial contributions to discussion of the article content, wrote and reviewed/edited the manuscript before submission.

Correspondence to Sophie C. Payne.

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Glossary

Central nervous system

(CNS). The nervous system consisting of the brain and spinal cord.

Enteric nervous system

(ENS). The nervous system embedded in the wall of the gastrointestinal tract, in the gallbladder and the pancreas.

Efferent

Refers to nerve pathways from the CNS and ENS to muscle, gland and epithelia.

Afferent

Refers to nerve pathways that carry sensory information from tissues to the CNS and ENS.

Sympathetic postganglionic neurons

Neurons of sympathetic pathways whose cell bodies reside in ganglia outside the CNS and ENS.

Cervical sympathetic chain

The part of the chain of sympathetic ganglia in the neck.

Ganglia

Collections of the cell bodies of autonomic neurons.

C fibres

Axons that conduct at low speeds (approximately 1 m/s).

Enteroendocrine cells

Endocrine cells that are found in the lining of the gastrointestinal tract.

Autonomic and somatic efferents

Efferent neurons that belong to the autonomic nervous system and efferent neurons that are involved in somatic (skeletal muscle) control.

Superantigens

Antigens that cause nonspecific activation of T cells resulting in polyclonal T cell activation and massive cytokine release.

Oxidative burst

The rapid release of reactive oxygen species (superoxide radicals and hydrogen peroxide).

Cholinergic agents

Drugs whose action relies on the neurotransmitter acetylcholine.

Pathogen-associated molecular patterns

(PAMPs). Molecular motifs conserved within microorganisms that are recognized by cells of the innate immune system.

Capsaicin-sensitive

Refers to neurons that are activated by the capsaicin compound from red peppers, which in high enough concentrations causes the neurons to degenerate.

Myenteric plexus

A plexus of nerves and ganglia of the enteric nervous system, located within the external muscle of the gastrointestinal tract.

Tyrosine-hydroxylase-immunoreactive nerve endings

The endings of neurons that contain the enzyme tyrosine hydroxylase, which is necessary for the synthesis of adrenaline, dopamine and noradrenaline.

Colonic histological score

The score given by a histopathologist that quantifies damage to the colon.

Nicotinic receptors

A class of cell surface receptors that bind and mediate cellular effects of acetylcholine.

Excess weight loss

(EWL). A common metric for reporting loss of excess body weight, calculated as 100% × (weight loss / excess weight at beginning of treatment); excess weight is defined as the difference between the patient’s weight and the body weight if BMI were 25.

Hedonic eating

Eating for pleasure that is not necessarily associated with need for nutrient.

Slow waves

Slow oscillation in the membrane potentials of muscle cells that can lead to regular contractile activity.

Chagas disease

A disease caused by infection with the protist Trypanosoma cruzi that can result in degeneration of colonic enteric neurons.

Onuf’s nucleus

A gathering of nerve cells in the sacral spinal cord that innervate the pelvic floor, including the external anal sphincter.

Spinal cord injury

Injury to the spinal cord sufficient to cause clinically recognizable deficits of sensory or motor functions.

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Payne, S.C., Furness, J.B. & Stebbing, M.J. Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms. Nat Rev Gastroenterol Hepatol 16, 89–105 (2019). https://doi.org/10.1038/s41575-018-0078-6

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