Evaluating the molecular and genetic mechanisms underlying gut motility disorders

ABSTRACT

Introduction

Gastrointestinal (GI) motility disorders comprise a wide range of different diseases affecting the structural or functional integrity of the GI neuromusculature. Their clinical presentation and burden of disease depends on the predominant location and extent of gut involvement as well as the component of the gut neuromusculature affected.

Areas covered

A comprehensive literature review was conducted using the PubMed and Medline databases to identify articles related to GI motility and functional disorders, published between 2016 and 2023. In this article, we highlight the current knowledge of molecular and genetic mechanisms underlying GI dysmotility, including disorders of gut–brain interaction, which involve both GI motor and sensory disturbance.

Expert opinion

Although the pathophysiology and molecular mechanisms underlying many such disorders remain unclear, recent advances in the assessment of intestinal tissue samples, genetic testing with the application of ‘omics’ technologies and the use of animal models will provide better insights into disease pathogenesis as well as opportunities to improve therapy.

KEYWORDS:

• Intestinal motility disorders
• genetics
• molecular analysis
• dysmotility
• disorders of gut–brain interaction

Article highlights

• With the rapid advancement in molecular genetics, there is a possibility that GI disorders previosusly labeled as ‘functional,’ like DGBI, may eventually be identified as subtypes of enteric neuropathies.

• Esophageal achalasia, characterized by esophageal outflow obstruction due to impaired lower sphincter relaxation, has an etiology predominantly related to immunological disturbance, perhaps potentiated by infection.

• In infantile hypertrophic pyloric stenosis genetic and molecular studies suggest a significant association with NOS1a and many other susceptibility loci.

• In patients with gastroparesis, cellular-based analyses involving proteomics and transcriptomic studies of full-thickness gastric biopsies reveal that the most affected pathways are involved in macrophage-based immune dysregulation.

• PIPO and CIPO are complex, heterogeneous disorders in which either enteric nerves, smooth muscle cells or ICCs are affected. Molecular analyses may aid in the differentiation of subtypes and elucidation of the underlying etiopathogenesis or pathophysiology, which may inform a specific course of treatment for a certain patient.

• Although, genetic testing in HSCR may not be able to replace the gold-standard rectal biopsy, it may identify variants at highest risk for the condition, and direct both the application of diagnostic tools as well as treatment.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.