A multidisciplinary approach to studying crypt-villus homeostasis and regeneration in the intestinal epithelium

Lead Research Organisation: University of East Anglia
Department Name: Norwich Medical School


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Technical Summary

Using a combination of computational modelling and experimental measurements, we aim to understand the tight coordination between villi and crypts during the continuous renewal of the small intestinal epithelium and how the equilibrium is recovered after perturbations.

Experimental measurements will be gathered from healthy, altered and injured intestine. Counts and morphometric measurements of crypts and villi, cell proliferation, migration and shedding rates, cell size and cell density will be experimentally determined along the much studied murine small intestine in control conditions as well as after blocking cell proliferation by cytosine arabinoside, enhancing cell proliferation by glucagon-like peptide-2 and injuring the epithelium by bacterial lipopolysaccharide.

The spatio-temporal modelling of cell dynamics in the crypt-villus unit will be modelled by building on the individual cell models (IBMs) for the crypt already developed by the applicants. While it is feasible to simulate an IBM of one crypt-villus unit in a reasonable time, simulations comprising large populations of villi and crypts are likely to become computationally intractable. We will therefore investigate the relationship between populations of crypts and villi at the macroscopic level using 'mean-field' models. We will use the existing resources of Chaste, a software library for modelling soft tissues, to implement models and as a simulation suite.

Importantly, theory and experiments will be intertwined through the "predict-test-refine-predict" cycle to develop and test hypotheses regarding the regulation of cellular proliferation and migration along the crypt-villus axis, the mechanism of intestinal cell shedding and apoptosis and the relationship between these cellular phenomena and the maintenance of crypts and villi. Model simulations will be used to generate predictions on epithelium recovery after injury that will be tested experimentally, leading to refinement of the mode.

Planned Impact

This project proposal is targeting gut health to improve health and well-being across the life span by a multidisciplinary approach that integrates theoretical and experimental approaches. This is specifically targeted by the "Systems approaches to the bioscience" theme of the BBSRC research strategy priority "Exploiting new ways of working". Our project, specifically responds to the cross-council priority "Lifelong health and well-being" and the theme "Ageing research: lifelong health and well-being" of the priority "Basic bioscience underpinning health". BBSRC strategic priorities are devised to increase the impact of the BBSRC science on worldwide (and specifically on the UK) society and economy.

Our research focuses on understanding the basic mechanisms of regulation between intestinal villi and crypts and how their balance is recovered after injury and damage. As a result, we expect to gain continued and greater understanding of the fundamental aspects of this biological system. Our beneficiaries in the short term will be mainly those in the academic community while there is number of potential applications with economic and societal impacts in the long term.

Impact on Society

The public will be the first long term beneficiary of our research through enhanced gut health, gut tolerance to perturbations and recovery after injury, and the early detection of risk factors for GI-tract disease, leading to improved lifelong wellbeing and quality of life.
NHS and specialist services (e.g. gastroenterologists) will benefit from science-based advice and evidence to support improved strategies for a healthier gut. The output of our research may lead to develop novel prevention practices for intestinal tumourigenesis, chronic or inflammatory processes, intestinal ulcers and coeliac disease.
Enhancing the professional skills base. The staff working on the project and the participants in the workshops will be trained in a highly interdisciplinary area of knowledge. Knowledge in developing computing and modelling tools for Medicine and Biology is increasingly relevant to the public and private employment sector.

Inspiring young people. The integration of theoretical and experimental approaches that we propose, provides excellent opportunities for school and undergraduate science students to understand how biological systems work as a whole and to grasp the importance of multi disciplinary approaches to address unanswered scientific questions, contributing to the BBSRC public engagement priority by addressing young people in mathematics for biology.

Public opinion and policy makers. The generation of robust computing tools for in silico simulation of gut behaviour may provide an alternative platform to minimise the use of animals in research. Potentially, this will help policy makers address some public opinion concerns about animal testing.

Impact on Economy

A decreased UK Public spend might be envisaged from the reduced pressure on Health and Social care systems resulting from an improved gut health and wellbeing.

Industry, such as Biomedical industries and Biopharmaceutical companies, may benefit from strong evidence-based advice that may lead to the development of novel therapies and early markers for intestinal tumourigenesis, chronic inflammatory processes and coeliac disease. The output of this research on the kinetics of the intestinal epithelium renewal and regeneration might provide information to develop strategies to reduce the intestinal side effects of drugs treatments such as the highly used non-steroidal anti-inflammatory drugs. The small and large intestine account for 20-40% of all drug side effects [Best Pract Res Cl Ga 2010 24:133-141]. Thus, there is great potential to translate new ideas and results into exploitable outcomes and further strategic developmental proposals (EC, Human Frontiers programme) as well as attracting R&D investment from Global business into the UK economy.


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Muraro D (2018) Chronic TNFa-driven injury delays cell migration to villi in the intestinal epithelium. in Journal of the Royal Society, Interface

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Parker A (2017) Cell proliferation within small intestinal crypts is the principal driving force for cell migration on villi. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Parker A (2018) Host-microbe interaction in the gastrointestinal tract. in Environmental microbiology

Description The epithelial cell monolayer lining the small intestine has a complex architecture, with invaginations into the intestinal wall called crypts located between finger-like projections into the lumen called villi. Intestinal stem cells located at the base of each crypt proliferate and give rise to epithelial cells, which migrate to the tip of the neighbouring villi, from where they are shed into the gut lumen. Despite great interest in intestinal crypts as a model stem cell system, the forces responsible for epithelial cell migration along intestinal villi remain under debate. We have combined experimental and mathematical modelling approaches to address this outstanding question. Proliferation of crypt stem cells provides a likely source of upward migration pressure, yet some reports suggest active migration processes or whole villus contraction-relaxation may be necessary to explain apparent uncoupling between epithelial migration rates in crypts and villi. We have addressed this issue by developing mathematical models to describe in vivo epithelial dynamics along the entire crypt-villus axis, and compare it both under healthy homeostatic conditions and during perturbation and recovery. By comparing healthy mice with mouse models of genetically-impaired or chemically arrested cell proliferation, we find crypt cell proliferation and villus epithelial cell migration are tightly coupled under all conditions, and that alterations in crypt proliferative output result in synchronous changes in epithelial dynamics on the villi. Thus, we conclude that cell proliferation within small intestinal crypts is the principal driving force for epithelial cell migration on villi.
Exploitation Route Our approach is tailored to in vivo cell labelling/tracing data in animal models. It can be applied to any disease model or pharmacological treatment and used to interrogate intestinal epithelial dynamics and detect situations in which cell production and migration become uncoupled leading to loss of homeostasis.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://decryptingvillus.ifr.ac.uk/
Description How the gut reacts to stress: changes in intestinal stem cell behaviour in response to perturbation of the enteric nervous system.
Amount £2,200 (GBP)
Funding ID BB/N014030/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2015 
End 12/2015
Description IFR in the City Event (Science in Norwich day) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Exhibition at public science day. Project-specific display stand with interactive exhibits and discussion with the public.
Year(s) Of Engagement Activity 2015
Description School Visit (to IFR) for Inside Science 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact "Mathematics In the Gut...Really" Presentations and discussion with Year 10-11 students from local school. Part of Inside Science.
Year(s) Of Engagement Activity 2014
Description Science Festival Norwich 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Science Festival 2016 at Norwich Cathedral, discussion with general public
Year(s) Of Engagement Activity 2014,2016
Description Sixth Form College Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Science talk and careers session (part of STEM Ambassador materials) delivered to VI Form College in Norwich.
Year(s) Of Engagement Activity 2016