How the Brain and Gut Communicate to Control Bowel Movements — and Where Peptide Receptors Offer Treatment Targets | Research

The takeaway

A comprehensive review identifies four levels of neural control governing colorectal motility and defecation, with peptide receptors (including ghrelin) on key connector neurons emerging as promising therapeutic targets for constipation.

4 levels of neural control
Colorectal motility is governed by four hierarchical neural control levels — from cortex to enteric nervous system — connected by parasympathetic preganglionic neurons that carry peptide receptors now being identified as drug targets.

What the researchers found

The review integrates foundational and recent research to describe four hierarchical levels of neural control over colorectal motility and defecation:

1. Cortical and hypothalamic centers in the brain

2. Pontomedullary cell groups in the brainstem

3. Lumbosacral defecation centers in the spinal cord

4. The enteric nervous system (ENS) within the gut wall

The critical link between the central nervous system (CNS) and ENS is provided by parasympathetic preganglionic (PPG) neurons, which express a wide range of amine and peptide receptors. These receptors — including those for ghrelin, dopamine, and serotonin — are identified as potential therapeutic targets for constipation. The importance of CNS-ENS coordination is demonstrated by the severe constipation that follows spinal cord injury or occurs in Parkinson's disease, and by the failed defecation seen in Hirschsprung and Chagas diseases when the ENS is absent.

Why it matters

Constipation affects hundreds of millions of people worldwide and is a debilitating symptom of spinal cord injury, Parkinson's disease, and other neurological conditions. Current treatments are often inadequate. By mapping the neural circuits in detail and identifying peptide receptors on key connector neurons, this review provides a roadmap for developing more targeted and effective therapies for bowel dysfunction.

How the study worked

This is a comprehensive narrative review that integrates foundational neuroscience knowledge with recent advances in gut-brain signaling research. The authors synthesized evidence from clinical observations (spinal cord injury, Parkinson's disease, Hirschsprung disease, Chagas disease) and preclinical studies to map the neural circuits controlling colorectal motility.

What this study cannot tell us

As a narrative review, this paper synthesizes existing evidence without presenting new experimental data. The therapeutic targets identified are based on receptor expression patterns and have not been clinically validated for constipation treatment. The complexity of the four-level neural control system means that targeting a single receptor may have limited efficacy. Much of the understanding comes from animal models and disease observations rather than controlled human studies.

How to read the evidence

This is a comprehensive narrative review synthesizing foundational knowledge and recent advances. It integrates clinical observations and preclinical research to propose a framework and identify therapeutic targets, but does not present new experimental data or follow systematic review methodology.

When this study was published

Published in 2025, this is a very recent review that integrates both historical foundational neuroscience and the latest research on gut-brain communication, making it a current and authoritative reference.

The bigger picture

The gut-brain axis is one of the most active areas in biomedical research, with implications for conditions ranging from irritable bowel syndrome to Parkinson's disease. This review provides a detailed structural framework for understanding how brain signals reach the gut, and vice versa. The identification of peptide receptors on PPG neurons as therapeutic targets could open new avenues for treating not just constipation, but potentially other gut-brain disorders.

Questions still open

Can drugs targeting ghrelin receptors on PPG neurons effectively treat constipation in spinal cord injury patients?
How do the peptide receptor profiles on PPG neurons change in Parkinson's disease, and could this inform targeted therapies?
Would combination therapies targeting multiple peptide and amine receptors on PPG neurons be more effective than single-target approaches?

Common questions

Why does constipation occur after spinal cord injury or in Parkinson's disease?

The gut has its own nervous system (enteric nervous system) that can generate basic contractions, but it needs signals from the brain and spinal cord to coordinate the powerful propulsive movements required for defecation. Spinal cord injury cuts the connection between brain and gut, while Parkinson's disease damages the brain circuits that send these coordinating signals. In both cases, the gut's own nervous system alone cannot maintain normal bowel function.

How could peptide receptors help treat constipation?

The neurons that connect the brain to the gut's nervous system carry receptors for peptides like ghrelin. Drugs that activate these receptors could potentially boost the signaling between brain and gut, restoring the coordinated bowel movements needed for normal defecation. This approach could be particularly valuable for patients with neurological conditions where the brain-gut connection is impaired.

Read the original research

Gut-brain communication: nerve circuits and chemical messengers of colorectal motility and defecation control.

American journal of physiology. Regulatory, integrative and comparative physiology, 329(6), R931-R945

View on PubMed ↗Publisher’s paper ↗

Citation

Han, Myat Noe; Furness, John B; Ringuet, Mitchell T; Montenegro, Ella; Wu, Hongkang; Hossain, Mohammed Akhter; Diwakarla, Shanti; Dehkhoda, Farhad; Furness, Sebastian G B. (2025). Gut-brain communication: nerve circuits and chemical messengers of colorectal motility and defecation control.. American journal of physiology. Regulatory, integrative and comparative physiology, 329(6), R931-R945. https://doi.org/10.1152/ajpregu.00212.2025