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Hormones of the gut–brain axis as targets for the treatment of upper gastrointestinal disorders

Key Points

  • The gut is at the centre of an integrated gut–brain–energy axis, modulating appetite, metabolism and digestion.

  • During fasting, hormones contribute to the fasting pattern of gut motility (for example, motilin), the re-establishment of appetite (for example, orexin, ghrelin) and drive marked changes in these and other functions (for example, ghrelin), possibly to prepare for eating.

  • During eating and digestion, hormones (for example, gastrin, cholecystokinin (CCK), pancreatic polypeptide) contribute to satiety and regulate gastric emptying. Others (for example, peptide YY) are released from the intestine in response to poorly digested material, slowing down gastrointestinal motility and increasing satiety ('ileal break').

  • Upper gut disorders can disturb gastric movements and influence food preference, appetite or eating behaviours, in part by mechanisms by which the gut defends itself against ingestion of toxic material (for example, nausea, vomiting). Emesis, hunger, satiety and nausea are points on the same physiological spectrum; each can be regulated by hormones normally released during fasting, eating and digestion.

  • In the development of drugs to modulate the hormonal gut–brain axis, areas currently receiving attention are motilin receptor agonists (gastric prokinetics), and ghrelin and CCK1 receptor agonists. The latter exert multiple activities and possibly represent a more complete treatment of complex disorders such as functional dyspepsia.

  • Eating and digestion rely on an integrated gut–brain–energy axis. The recognition of complex hormonal links is creating a paradigm shift in how drug targets are identified to deliver more effective treatments for complex disorders. For example, drugs that modulate gastric motility can also represent targets for gastric prokinetc drugs. Those that modify eating behaviours can also represent targets for treatment of nausea, currently a serious clinical problem.

Abstract

The concept of the gut forming the centre of an integrated gut–brain–energy axis — modulating appetite, metabolism and digestion — opens up new paradigms for drugs that can tackle multiple symptoms in complex upper gastrointestinal disorders. These include eating disorders, nausea and vomiting, gastroesophageal reflux disease, gastroparesis, dyspepsia and irritable bowel syndrome. The hormones that modulate gastric motility represent targets for gastric prokinetic drugs, and peptides that modify eating behaviours may be targeted to develop drugs that reduce nausea, a currently poorly treated condition. The gut–brain axis may therefore provide a range of therapeutic opportunities that deliver a more holistic treatment of upper gastrointestinal disorders.

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Figure 1: Illustration of the main features of the enteric nervous system (ENS).

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Acknowledgements

The authors gratefully acknowledge the many contributions made by colleagues and collaborators, which have helped to shape the ideas expressed in this review.

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Correspondence to Gareth J. Sanger.

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DATABASES

OMIM

Anorexia

bulimia

cyclic vomiting syndrome

GERD

Glossary

Upper GI disorders

These are disorders that involve the oesophageal, stomach and upper small intestinal regions and are manifested as changes in appetite, satiety, nausea, abdominal pain or discomfort, bloating and other symptoms. Examples include, eating disorders, nausea and vomiting, gastroesophageal reflux, dyspepsia and gastroparesis.

Crural diaphragm

The lower oesophageal sphincter is anchored by ligaments to the skeletal muscle of the crural diaphragm.

Intrinsic primary afferent neurons

Specialized nerves within the enteric nervous system that act as enteric sensory neurons, that are characterized by morphology, location, electrophysiological properties and sensitivity to luminal chemicals or mechanical distortion.

Vago–vagal reflexes

Reflexes that use both vagal afferent nerves (to signal a response) and vagal efferent nerves (to effect a response). Includes, for example, the transient lower oesophageal sphincter relaxations evoked by gastric fundus distension.

Gastric accommodation

Relaxation of the upper regions of the stomach during eating to make room for the ingested food. Impairment of accommodation can, for example, lead to early satiety.

Orexigenic

Increasing or stimulating appetite.

Arcuate nucleus

The hypothalamic nucleus associated with feeding behaviours.

Capsaicin

This pungent chemical is contained within chillies and is now known to activate vanilloid receptors.

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Sanger, G., Lee, K. Hormones of the gut–brain axis as targets for the treatment of upper gastrointestinal disorders. Nat Rev Drug Discov 7, 241–254 (2008). https://doi.org/10.1038/nrd2444

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