Gut Signalling and Metabolism

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

We aim to understand how the digestive system listens and responds to signals sent by other organs, and why this matters.
We have tackled this question in the Drosophila fly; a simpler organism with which we share over 60% of our genes. Like us, flies have a gut populated by nerve cells, get fat and suffer from diabetes. Importantly, the fly allows us to do something very challenging: turning genes on and off in specific cells at specific times in order to learn about how these genes affect metabolism.
Using such genetic approaches, we recently found that the intestine can adapt to challenges in striking and unexpected ways. For example, during reproduction, the intestine grows dramatically and changes the way the mother handles nutrients to ensure reproductive success. Even before reproduction, the intestines of males and females are very different. The fact that female gut stem cells are more active than their male counterparts helps the female gut grow during reproduction, but also makes it more vulnerable to tumorigenic insults.
Informed by our findings in flies, we will now investigate whether similar mechanisms and intestinal sex differences can affect the human ability to reproduce, handle nutrient overload/scarcity, resist certain diseases and respond to their treatment. If they do, they will inform the development of genetic or drug treatments in the areas of fertility, weight gain/loss and cancer.

Technical Summary

We are investigating how the intestine controls energy homeostasis and nutritional decisions.
The digestive system is emerging as a key regulator of appetite and metabolism. It is now recognised that signals emanating from the gastrointestinal tract and its neurons can contribute to increasingly prevalent conditions such as diabetes and metabolic syndrome. In addition to signalling, the digestive tract can also undergo dramatic functional remodelling in response to environmental or internal change – for example, during reproduction.
Our lab has been exploring the mechanisms underlying intestinal plasticity and their functional significance. We recently identify a sex hormone required for intestinal remodelling during reproduction and, using targeted genetic experiments, demonstrated that such remodelling was required to sustain reproductive output (Reiff et al (2015) eLife). We also described extensive differences between the intestine of males and females, and showed that the intrinsic sexual identity of intestinal somatic stem cells played key roles during reproduction, but also increased gut tumour susceptibility in females (Hudry et al (2016) Nature). Finally, we described a new mechanism, key during malnutrition, by which enteric neurons sense lack of lack of specific nutrients (Linneweber et al (2014) Cell).
Most of our work has taken advantage of the genetic amenability of Drosophila. Over 60% of our genes have equivalent counterparts in Drosophila. Fruit flies also offer two key advantages to investigate the genetic control of physiology and metabolic adaptations: 1) they allow rapid mutation or misexpression of large numbers if genes (allowing for rapid identification of metabolically significant genes) and 2) they allow temporal and spatial control of gene expression (key to establishing directionality of signalling when investigating organ crosstalk).

While flies continue to be our primary discovery tool, we are also investigating whether the mechanisms of intestinal plasticity that the fly has revealed are evolutionarily conserved; are our organs sexually dimorphic and capable of similar remodelling? We are using mouse models and human cells to explore these questions.

Conservation of these mechanisms and sex differences may have important implications for our ability to reproduce, handle nutrient overload/scarcity, resist certain diseases and respond to their treatment. Genetic or pharmacological interventions aimed at modulating similar pathways in humans may be advantageous in the contexts of fertility, weight gain/loss and preventing tumour formation.
 
Title BBC Radio 4 interview 
Description BBC Radio 4 interview 
Type Of Art Performance (Music, Dance, Drama, etc) 
Year Produced 2016 
Impact n/a 
URL http://www.bbc.co.uk/programmes/b0713p30
 
Title BBC audio slideshow 
Description BBC audio slideshow 
Type Of Art Image 
Year Produced 2011 
Impact n/a 
URL http://www.bbc.co.uk/news/science-environment-12686745
 
Title Contributed images to "The Cell: An Image Library" 
Description Contributed images to "The Cell: An Image Library" 
Type Of Art Image 
Year Produced 2012 
Impact n/a 
URL http://www.cellimagelibrary.org/
 
Title Contributed images to the University of Cambridge's 800th anniversary light show. One of them was also the exclusive image used for the posters and flyers advertising the event 
Description Contributed images to the University of Cambridge's 800th anniversary light show. One of them was also the exclusive image used for the posters and flyers advertising the event 
Type Of Art Image 
Year Produced 2010 
Impact n/a 
 
Title Contributed video to Imagine Science Films Festival 
Description Contributed video to Imagine Science Films Festival 
Type Of Art Image 
Year Produced 2014 
Impact n/a 
URL http://old.imaginesciencefilms.org/events/neural-imagining-the-brain-seen-on-film/
 
Title My lab contributed a video to the University of Cambridge "Under the microscope" series, accessible on YouTube 
Description My lab contributed a video to the University of Cambridge "Under the microscope" series, accessible on YouTube 
Type Of Art Film/Video/Animation 
Year Produced 2012 
Impact n/a 
URL http://www.youtube.com/watch?v=CDg2Keu3HT8
 
Description CSC Institute Planning and Operations Team member
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Imporvements in research budget expenditure
 
Description Deputy Chair of Athena Swan Opportunities committee
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guideline committee
Impact Maximise opportunity for women and otehr minorities
 
Description Member of BBSRC Pool of Experts
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact How research budget is allocated - optimised value for money
 
Description Member of Wellcome Trust Pool of Prospective Committee Members
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Research budget allocation - imporved value for money
 
Description Member of promotion panel, Institut Curie, Paris, France
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description Scientific Advisory Board member, Institute of Functional Genomics of Lyon (IGFL), France
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Bruno Hudry EMBO Advanced Fellowship
Amount £82,096 (GBP)
Organisation European Molecular Biology Organisation (EMBO) 
Sector Learned Society
Country European Union (EU)
Start 01/2016 
End 01/2018
 
Description DFG Postdoctoral Fellowship
Amount £40,460 (GBP)
Organisation German Research Foundation (DFG) 
Sector Public
Country Germany, Federal Republic of
Start 04/2014 
End 12/2015
 
Description EMBO Long Term Postdoctoral Fellowship
Amount £50,421 (GBP)
Organisation European Molecular Biology Organisation (EMBO) 
Sector Learned Society
Country European Union (EU)
Start 01/2013 
End 12/2015
 
Description EMBO: The Crosstalk Between the Brain and Gut
Amount £37,570 (GBP)
Organisation European Molecular Biology Organisation (EMBO) 
Sector Learned Society
Country European Union (EU)
Start 04/2012 
End 03/2015
 
Description ERC Starting Grant BrainGutTalk"
Amount £1,071,243 (GBP)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 02/2013 
End 01/2018
 
Description Fellowship Spanish Ministry of Science
Amount £42,078 (GBP)
Organisation Spanish Ministry of Science and Innovation 
Sector Public
Country Spain, Kingdom of
Start 03/2011 
End 02/2013
 
Description New Investigator Award
Amount £201,134 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2013 
End 01/2015
 
Description Wellcome Trust Research Career Development Fellowship
Amount £637,016 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 06/2008 
End 01/2014
 
Title Transgenic Drosophila 
Description Generation of ca. 50 transgenic Drosophila stocks 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact Publications by both my and other groups 
 
Title antibodies 
Description Two antibodies against Drosophila proteins 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Publications by both my and other groups 
 
Title Collection of Data: Transcriptional datasets in Hudry et al 2016 Nature 
Description Hudry, B., Khadayate, S., Miguel-Aliaga, I. (2016) The sexual identity of adult intestinal stem cells controls organ size and plasticity. Nature 530:344-8. Recommended in F1000 and highlighted by Cell Stem Cell Preview, Curr Biol Dispatch and Nature News and Views 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact n/a 
 
Description Andreu Casali 
Organisation Institute for Research in Biomedicine (IRB)
Country Spain, Kingdom of 
Sector Academic/University 
PI Contribution Exchanged scientific data and conducted experiments.
Collaborator Contribution Exchanged scientific data and conducted experiments.
Impact Martorell et al. PLoS One. 2014 Feb 6;9(2)
Start Year 2012
 
Description Bimonthly Fly Meeting with LMCB researchers 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution present unpublished work and discuss other people's unpublished data, host meeting once a month
Collaborator Contribution present unpublished work and discuss other people's unpublished data, host meeting once a month
Impact We expect it to lead to future collaborations and publications
Start Year 2013
 
Description Bimonthly Fly Meeting with LRI researchers 
Organisation Cancer Research UK (CRUK)
Department London Research Institute (LRI)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution present unpublished work and discuss other people's unpublished data, host meeting once a month
Collaborator Contribution present unpublished work and discuss other people's unpublished data, host meeting once a month
Impact Expect it to result in publications and collaboration
Start Year 2013
 
Description Christian Wegener 
Organisation University of Würzburg
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution Exchanged scientific data and conducted experiments.
Collaborator Contribution Exchanged scientific data and conducted experiments.
Impact N/A
Start Year 2012
 
Description Elisabeth Knust 
Organisation Max Planck Society
Department Max Planck Institute for Molecular Cell Biology and Genetics
Country Germany, Federal Republic of 
Sector Public 
PI Contribution Provided scientific expertise Hosted one of their PhD students Trip of my PhD student to MPI in Dresden to carry out experiments there
Collaborator Contribution Provided scientific expertise Hosted one of my PhD students Sent one PhD student for training in my lab
Impact Linneweber et al (2014) Cell. In press
Start Year 2009
 
Description Maria Dominguez 
Organisation Miguel Hernández University of Elche (UMH)
Department Institute of Neurosciences
Country Spain, Kingdom of 
Sector Academic/University 
PI Contribution Exchanged scientific data and conducted experiments.
Collaborator Contribution Exchanged scientific data and conducted experiments.
Impact N/A
Start Year 2012
 
Description Mario de Bono 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution My PhD student conducted experiments in their lab
Collaborator Contribution Provided access to specialized equipment to my student and expertise
Impact Linneweber et al (2014). Cell. In press
Start Year 2012
 
Description Matt Wayland 
Organisation University of Cambridge
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Exchanged scientific data and conducted experiments.
Collaborator Contribution Exchanged scientific data and conducted experiments.
Impact Wayland et al. J Insect Physiol. 2014 Jun 4.
Start Year 2012
 
Description Nikolai Windbichler 
Organisation Imperial College London (ICL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Exchanged scientific data and conducted experiments.
Collaborator Contribution Cultural, societal
Impact n/a
Start Year 2015
 
Description Orie Shafer 
Organisation University of Michigan
Department Department of Molecular, Cellular and Developmental Biology
Country United States of America 
Sector Academic/University 
PI Contribution Exchanged scientific data and conducted experiments
Collaborator Contribution Exchanged scientific data and conducted experiments
Impact Talsma et al 2012 PNAS
Start Year 2010
 
Description Richard Baines 
Organisation University of Manchester
Department University of Manchester Innovation Group (UMI3)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution Exchanged scientific data and conducted experiments.
Collaborator Contribution Exchanged scientific data and conducted experiments.
Impact N/A
Start Year 2012
 
Title Software to monitor and quantify intestinal physiology in Drosophila 
Description The intestinal physiology of Drosophila melanogaster can be monitored in an integrative, non-invasive manner by analysing graphical features of the excreta produced by flies fed on a dye-supplemented diet. This assay has been used by various labs to explore gut function and its regulation. We have developed software that offers a flexible environment for a wide range of experimental designs, with special attention to automation and high-throughput processing. This software detects the distinctive changes in acid-base and water balance previously reported to occur in response to dietary challenges and mating. We have used this software to test the contribution of the bacterial environment of the flies to various intestinal parameters including the established diet- and mating-triggered responses. To this end, we have analysed the faecal patterns of flies reared in germ-free conditions, upon re-association with controlled microbiota and subjected to food-borne or systemic, non-lethal bacterial infections. We find that the tested faecal outputs are unchanged in all these conditions, suggesting that the impact of the bacterial environment on the intestinal features highlighted by faecal deposit analysis is minimal. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact This software is currently in use by several labs in different countries 
URL http://the-ultimate-reader-of-dung.sourceforge.net/
 
Description BBC Radio 4 and World Service interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Radio interview about our recent Nature paper
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b0713p30
 
Description Contributed images 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Contributed images to "The cell: An Image Library".

N/A
Year(s) Of Engagement Activity 2012
URL http://www.cellimagelibrary.org
 
Description Fabrics of Life Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact n/a
Year(s) Of Engagement Activity 2014
 
Description Fly Gut and brain video used for film festival (New York) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact n/a
Year(s) Of Engagement Activity 2014
 
Description Imperial Fringe: Food of Tomorrow event 
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 An evening on the future of food and how we will feed the next generation. Food of tomorrow was the latest in Imperial College's Fringe series of public evening events exploring the livelier side of science. Based on the College's ground-breaking research, the Fringe programme runs throughout the year to give our friends and supporters an opportunity to meet our researchers and find out more about our work.
Year(s) Of Engagement Activity 2016
 
Description Lecturer, "Human Culture: the human experience of materials applied to eating food" post-graduate student project, Design Products (Royal College of Art). 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact n/a
Year(s) Of Engagement Activity 2016
 
Description My lab contributed a talk to the University of the Third Age visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact n/a
Year(s) Of Engagement Activity 2016
 
Description Nature paper press coverage 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Wide press coverage for our 2016 Nature paper. Achieved an Altmetric = 270.
Daily Telegraph - p7
i (the paper for today) - p2
Press and Journal (Scotland) - p15
Daily Mail (online only) - http://www.dailymail.co.uk/sciencetech/article-3451482/Organs-know-male-female.html
Medical News Today - http://www.medicalnewstoday.com/articles/306695.php
Medical Xpress - http://medicalxpress.com/news/2016-02-deeper-sexual-nature.html
Yahoo! News - https://uk.news.yahoo.com/organ-stem-cells-sexual-identity-181117114.html
BT.com - http://home.bt.com/news/science-news/organ-stem-cells-have-sexual-identity-11364040903895
Irish Examiner - http://www.irishexaminer.com/examviral/science-world/organ-stem-cells-have-sexual-identity-382540.html
CBS Radio News
Internaitonal press
Year(s) Of Engagement Activity 2016
 
Description Neuroscience Program for Columbia University 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact My Lab's contribution to "Under the microscope" is used in "Fruit-Fly Gut and Brain" a video for a Neuroscience film program for Columbia University.

N/A
Year(s) Of Engagement Activity 2014
 
Description School Visits 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Microscopy demonstrations (Drosphila life cycle) to school children.

n/a
Year(s) Of Engagement Activity 2013
 
Description Workshop co-organiser. Brainy Tongue: The Sensory Logic of the Gastronomic Brain, San Sebastian, Spain, featuring world-renowned chefs and neurobiologists. Included open session featured by media worldwide 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact n/a
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/news/business-37800097