Integrated analysis of the impact of age-associated neuronal and enteroendocrine changes on normal bowel functions

Lead Research Organisation: Open University
Department Name: Life, Health & Chemical Sciences

Abstract

In the ageing population, terminal bowel dysfunction, manifest as faecal incontinence, which is often linked with faecal impaction, is very common and a significant cause of illness. Normal bowel function and defecaetion depend upon a combination of voluntary and involuntary actions of the muscles regulating bowel function. These processes, in turn, depend upon the structural integrity and the normal molecular and physiological properties of the complex system of nerves, muscles and secretory cells that together make up this part of the digestive tract. Many cells and tissues are known to undergo structural and molecular changes during ageing that result in changes to their functional properties. Little is known however, of the changes that occur in the cells of the terminal bowel during ageing. The aim of the proposed project is therefore to use a multi-disciplinary approach, bringing together expertise from four academics, to fully characterise the physiological, molecular and structural age-associated changes in the cells of the terminal colon, rectum and anal sphincters. The work will be performed in mice, for a number of reasons; mice have a life-span amenable to studies on ageing; many of the variables associated with studies on humans can be avoided; mouse gastrointestinal physiology is well-understood and readily analysed and in future, research based on the data obtained from this project will be able to employ the powerful tool of mouse genetics to further analyse the changes that occur in ageing terminal bowel. The results of this work will allow more effective therapies for the treatment of age-associated incontinence and faecal impaction to be developed

Technical Summary

In the ageing population, terminal bowel dysfunction, manifest as faecal incontinence, often linked with faecal impaction, is very common and a significant cause of morbidity. Normal bowel function and defecaetion depend upon autonomic and sensory reflexes in the terminal colon, rectum and internal anal sphincter, and voluntary control of the external anal sphincter and pelvic floor muscles. These processes, in turn, depend upon the structural integrity and the normal molecular, neurochemical and physiological properties of the nervous, enteroendocrine and muscular systems. The aim of the proposed project is to use a multi-disciplinary approach, bringing together expertise from four academics, to fully characterise the physiological, molecular, neurochemical and ultrastructural age-associated changes in the smooth and striated sphincteric muscles, intrinsic autonomic innervation and enteroendocrine systems of the terminal colon, rectum and anal sphincters. The work will be performed in mice because mouse gastrointestinal physiology is well-understood and readily analysed and in future, research based on the data obtained from this project will be able to employ the powerful tool of mouse genetics to further analyse the changes that occur in ageing terminal bowel. The results of this work will allow more effective therapies for the treatment of incontinence and faecal impaction to be developed.

Publications

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Description Consitpation, faecal impaction and incontinence are common disorders among the elderly population. This project analysed age-related changes in the cells in the mouse terminal bowel, in order to gain an understanding of how cellular changes might contribute to bowel dysfunction.

We have analysed changes in the nerve cells and fibres that regulate the contraction of the muscle that moves gut contents along the bowel, and also defaecation. We have also studied changes in two other cell types, that play a role in the regulation of the function of the gut, these are known as Interstitial cells and enteroendocrine cells.

We found that the number of different types of nerve cells is maintained in the ageing mouse colon, but some nerve cells displayed markers of cellular senescence and some degenerative changes were observed in nerve cells and in nerve fibres.

The density of some types of nerve fibres was reduced in the internal anal sphincter muscle of ageing animals, but other types were unaffected. There was also a reduction in the density of Interstitial cells in both the ano-rectum and colon of the ageing gut.

Changes in the patterns of defaecation and physiological properties of the terminal bowel of these ageing mice was also measured. Thus the cellular changes detected may have contributed to the observed functional changes, and suggest further areas for future study and provide a basis for development of possible therapeutic strategies.
Exploitation Route Possible use in public awareness of conditions associated with ageing These results could form the basis for future work on development of therapies to alleviate terminal bowel dysfunction in the elderly.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Our findings have provided information that will inform development of pharmacological and lifestyle strategies to improve continence in the elderly population.
First Year Of Impact 2014
Sector Communities and Social Services/Policy,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Policy & public services

 
Description Co-Investigator on Project grant
Amount £386,756 (GBP)
Funding ID BB/K009184/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2013 
End 03/2016
 
Description Analysis of cellular senescence in postmitotoic cells 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution We performed some analysis of senescence markers in our laboratory at the Open University
Collaborator Contribution They led the project and provided samples and some reagents for analysis
Impact Publication: Jurk D., Wang C., Miwa S., Maddick M., Korolchuk V., Tsolou A., Gonos E.S., Thrasivoulou C., Saffrey M.J., Cameron K., von Zglinicki T. (2012). Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11(6):996-1004
Start Year 2011
 
Description UCHL1 and enteric nervous system ageing 
Organisation Ottawa Hospital Research Institute
Country Canada 
Sector Academic/University 
PI Contribution My PhD student analysed enteric neurons in samples from transgenic and control mice provided by our collaborators
Collaborator Contribution They provided the samples from transgenic and control mice
Impact Coulombe J, Gamage P, Gray MT, Zhang M, Tang MY, Wolfe J, Saffrey MJ, Gray DA (2014), Loss of UCHL1 promotes age-related degenerative changes in the enteric nervous system. Front. Aging Neurosci.,19 June 2014 doi: 10.3389/fnagi.2014.00129
Start Year 2011
 
Description Is neuronal loss in the ageing gut the cause of age-asscociated functional decline? 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Poster at SET for Britain 2012

no actual impacts realised to date
Year(s) Of Engagement Activity 2012