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

Lead Research Organisation: University of Brighton
Department Name: Sch of Pharmacy & Biomolecular 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 morbidity. Normal bowel function and defecation depend upon involuntary actions of 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 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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Patel BA (2010) Inhibitory neuromuscular transmission to ileal longitudinal muscle predominates in neonatal guinea pigs. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Patel BA (2011) Electroanalytical approaches to study signaling mechanisms in the gastrointestinal tract. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Wang C (2013) Changes in the innervation of the mouse internal anal sphincter during aging. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Yeoman M (2012) Insights into CNS ageing from animal models of senescence. in Nature reviews. Neuroscience

 
Description Chronic constipation/faecal impaction are common conditions of older people and are a major risk factor for overflow incontinence, which can lead to a loss of independence and institutionalisation. The results from this project provide the very first detailed study of the effects of age on the function of the lower bowel. Using a mouse model we have demonstrated that ageing is associated with a decrease in the size, number and water content of faecal pellets, consistent with a model of chronic constipation. Age also increased the proportion of the lower bowel that was impacted with faecal mass further supporting this model. Studies of the motility of the bowel using either native or artificial faecal pellets showed that motility decreased with age and these effects occurred solely in the distal colon.



An examination of the potential mechanism underlying these changes showed that ageing was associated with a decrease in the amplitude and frequency of key motor programs responsible for the movement of the faecal pellets. These changes were due to an increase in serotonin (5-HT) availability due to decreases in the expression of a key protein, the serotonin transporter (SERT), responsible for the uptake of 5-HT from the extracellular space. This alteration in 5-HT signalling causes a consequential reduction in the release of key excitatory neurotransmitters known as tachykinins. Both the changes in 5-HT signalling and the motor activity were initiated at 18 months of age. In a recent publication we have shown that the change in SERT expression was due to an increase in mucosal TNF-alpha and the deficit in both SERT expression and faecal output could be reversed following a short treatment with the anti-TNF drug etanercept.

Similar changes in 5-HT signalling were seen in the rectum although in this case they were not significant until 24 months. In the rectum, increase in 5-HT potentiated the release of the relaxant, nitric oxide, reducing motility and exacerbating the state of constipation/impaction (paper under preparation)

Finally, we have examined the internal anal sphincter, a ring of smooth muscle that is important in maintaining continence. A functional analysis demonstrated impairment in the ability of the sphincter to relax with age, both in response to electrical stimulation and also to the application of key neurochemicals known to drive relaxation in vivo. Specifically, ageing was associated with an impairment of relaxation due to a deficit in nitric oxide signalling. No significant change was seen in the motor neuron that drive contraction and maintain continence. We propose that the deficit in relaxation may act as a partial outlet obstruction impairing faecal output and leading to impaction. Taken together these data provide the first detailed study of the effects of age on the function of the lower bowel.
Exploitation Route Until now it has been difficult to determine the contribution that changes in the physiology of the gastrointestinal (GI) tract play in age-related disorders of the bowel. Specifically, it has been difficult to dissect out the consequences of these changes from those associated with the increased intake of medicines observed in older people, changes to their diet or reduced motility. These data will therefore be useful to gastroenterologists, with responsibility for care of the elderly and may provide some aid to treat age-related constipation/faecal impaction. It is perceived that the main non-academic users of these data will be the pharmaceutical industry. The data generated from the current study has indicated signalling systems that are sensitive to the effects of age and recent work has inferred that these chnages are due to chronic low level inflammation and the effects can be reversed using an anti-TNF drug. We have recently been awarded a pathfinder grant to enable us to explore the possibilityof using anti-TNF drugs for the treatment of age-related constipation.
The project to date has identified and number of changes in the lower bowel which contribute to age-related chronic constipation and faecal impaction both of which can predispose the sufferer to overflow incontinence. It therefore provides important new information about how the gastrointestinal (GI) tract changes with age and the consequences these changes have on function. As such these findings would be useful for academics interested in the fields of GI physiology or ageing and also to gastroenterologists interested in age-related clinical disorders of the bowel.



However, the main aim of this project was to provide the first detailed examination of the effects of age on the lower bowel and to hopefully utilise these data in collaboration with the pharmaceutical industry to drive future drug therapies for these debilitating conditions and so improve the quality of life for older people. In terms of potential targets for drug therapy, we have described alterations in serotonin signalling, and the release of key tachykinins which reduce motility in the distal colon and rectum, while decreases in nitric oxide release in the internal anal sphincter inhibits normal defaecation. However, the observation for at least one molecule, nitric oxide, that signalling was increased in the rectum yet decreased in the internal anal sphincter provides issues over whether a simple drug treatment targeting nitric oxide would be effective.



Recent work has demonstrated that ageing is associated with increases in the levels of inflammatory markers in the lower bowel and as part of a recent BBRSC grant application we have asked for funding to examine whether treatments that alleviate the inflammation also restore normal function. The resolution of this problem would then potentially provide a suitable treatment for alleviating age-related lower bowel dysmotility.
Sectors Communities and Social Services/Policy,Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://www.brighton.ac.uk/strand/what-we-do/research-projects/effects-of-age-on-signalling-and-function-in-the-lower-bowel.aspx
 
Description Development of novel tools to study the physiology and pharmacology of the ageing gastrointestinal tract
Amount £26,000 (GBP)
Funding ID BB/I025409/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2011 
End 07/2014
 
Description Development of novel tools to study the physiology and pharmacology of the ageing gastrointestinal tract 
Organisation Michigan State University
Country United States 
Sector Academic/University 
PI Contribution BBSRC ISIS award (BB/IO25409/1)
Start Year 2011
 
Description STEM Sussex event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Schools
Results and Impact We have a stand booked at STEM Sussex, Crawley for the 6th July to disseminate some of our findings on the ageing bowel to an audience of school, children aged 7-11 years old. This is a one day event designed to familiarise school children with the workings of the GI tract and the effects that age has on the function of the GI tract Large model of GI tract that school children can walk though and examine. Lab test to look at taste and how taste regulates physiological functions.

No recordable impacts
Year(s) Of Engagement Activity 2012
 
Description STEM Sussex event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Stimulated thought and increased knowledge in a group of school children aged 11-19 years ol

Stand was one of the most highly rated by the students in the show. Interactive and engaging.
Year(s) Of Engagement Activity 2013
 
Description STEM Sussex event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Workshop highlighting the role played by the senses in nutrition and the function of the gastrointestinal tract and how it changes with age
Year(s) Of Engagement Activity 2014
 
Description STEM Sussex event at the South of England show ground 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Demonstration and participation in events stimulated lots of talk with the school children about their aims and aspirations and potential future ewmployment

Stand was voted the best in show and we have been asked to return next year, with a bigger interactive stand
Year(s) Of Engagement Activity 2014