Age-related changes in the functional role of the mucosa in the murine anorectum

Abstract

Age-related lower bowel dysfunction is a major healthcare concern, affecting approximately 1 in 10 older adults in the UK and contributing to significant morbidity, reduced quality of life, and an estimated ￡1.7 billion annual healthcare burden. Conditions such as chronic constipation and faecal incontinence are highly prevalent in elderly populations and are leading causes of hospital admission and placement in long-term care. Current treatment strategies focus on symptom management rather than prevention, meaning that interventions are typically introduced only after irreversible changes to bowel function have occurred. Despite this, the mechanisms underlying age-related anorectal dysfunction remain poorly understood. While previous research has explored the role of the mucosa in regulating gastrointestinal motility, the impact of ageing on this role has not been investigated, and although serotonin signalling has been studied in the gut more broadly, its functional role in the anorectum and whether this changes with age remains unexplored.
This thesis employs a murine model to provide evidence on the mucosa’s contribution to anorectal function and its age-related changes. Mice provide a robust model for studying gut physiology, with age ranges of 3-24 months approximating key stages of the human lifespan. The use of well-characterised organ bath pharmacology, electrochemical sensing, faecal analysis, and quantitative proteomics enables a multilayered investigation into mucosal regulation and its alterations with ageing.
Chapter one establishes a framework for understanding age-related bowel dysfunction and mucosal physiology. Chapter two provides evidence of an age-related increase in both contraction and relaxation responses to electrical field stimulation (EFS) and pharmacological agonists, suggesting changes in coordinated neuromuscular modulation and potential compensatory adaptations with age. Chapter three offers further evidence that the mucosa plays a functional role in modulating anorectal motility, demonstrating that its suppressive influence on contraction and relaxation response diminishes with ageing, and hypothesising that altered mucosal mediators, including melatonin and serotonin, contribute to this change. Chapter four provides evidence from in vivo electrochemical sensing that serotonin overflow increases with age in the anorectal mucosa, alongside reductions in faecal output and water content, strengthening the link between altered mucosal signalling and functional decline. Chapter five uses advanced quantitative proteomics to show that most age-related changes in the anorectum occur within the mucosa rather than the muscle. Bioinformatic analysis identifies widespread changes in RNA splicing, a relatively new hallmark of ageing, and links these changes to cellular senescence, stress responses, and inflammation. Together, these findings provide compelling evidence that the mucosa plays a dynamic role in regulating anorectal motility and that ageing is characterised by a loss of mucosal inhibitory control, dysregulated serotonergic signalling, and molecular reprogramming involving RNA processing pathways. This work highlights the mucosa as a critical driver of age-related bowel dysfunction and identifies potential molecular targets for interventions aimed at preserving or restoring anorectal function in ageing populations.

Date of Award	Feb 2026
Original language	English
Awarding Institution	University of Brighton
Supervisor	Mark Yeoman (Supervisor) & Bhavik Patel (Supervisor)