The gut microbiota as a modulator of behaviour - A role for nutritional and immune deficiencies
Lead Research Organisation:
Imperial College London
Department Name: Surgery and Cancer
Abstract
Both nutritional and immune deficiencies can have striking consequences on mental health. In a rodent model of early protein malnutrition, malnourished mice exhibited altered gene expression patterns in the brain and enhanced anxiety and depression-related behaviours. Similarly, the lack of a fully developed adaptive immune system was also reported in association with changes in the volume of several brain areas and an altered anxiety phenotype.
Mood and emotions are under the control of the gut microbiota-gut-brain axis. Research has shown that the composition of the gut microbiota is responsive to both nutritional state and immune function. Severe malnutrition is associated with an immature microbiome, characterised by a depletion in several anaerobic Firmicutes, Bacteroidetes and lactic acid bacteria, and by the overgrowth of enteric pathogens. Similarly, the depletion of peripherally-induced regulatory T cells results in a reduction in border-dwelling bacteria such as Mucispirillum schaedleri, Lactobacillus johnsonii and Helicobacter hepaticus and in an 80% reduction in the number of metabolic pathways measured in the intestinal lumen and in the serum.
In summary, the notion that nutritional and immune deficiencies (i) are linked to dysfunctional emotional behaviour and (ii) affect gut microbial composition, point to the possibility that the gut microbiota-gut-brain axis may contribute to the emotional disturbances associated with nutritional and immune deficiencies. In this PhD, the behavioural and metabolic effects of a protein-deficient diet (PROJECT 1) and of T cell deficiency (PROJECT 2) will be investigated, to understand the role played by the gut microbiota in this interaction. In addition, this PhD will test the hypothesis that peripheral metabolic markers of psychopathological states (i.e. major depressive disorder, or MDD) may be detectable in urine and blood in a human cohort (PROJECT 3). Supported by the notion that gut microbial function may affect the likelihood of treatment efficacy, the possibility of identifying early metabolic markers of treatment response will also be investigated.
Mood and emotions are under the control of the gut microbiota-gut-brain axis. Research has shown that the composition of the gut microbiota is responsive to both nutritional state and immune function. Severe malnutrition is associated with an immature microbiome, characterised by a depletion in several anaerobic Firmicutes, Bacteroidetes and lactic acid bacteria, and by the overgrowth of enteric pathogens. Similarly, the depletion of peripherally-induced regulatory T cells results in a reduction in border-dwelling bacteria such as Mucispirillum schaedleri, Lactobacillus johnsonii and Helicobacter hepaticus and in an 80% reduction in the number of metabolic pathways measured in the intestinal lumen and in the serum.
In summary, the notion that nutritional and immune deficiencies (i) are linked to dysfunctional emotional behaviour and (ii) affect gut microbial composition, point to the possibility that the gut microbiota-gut-brain axis may contribute to the emotional disturbances associated with nutritional and immune deficiencies. In this PhD, the behavioural and metabolic effects of a protein-deficient diet (PROJECT 1) and of T cell deficiency (PROJECT 2) will be investigated, to understand the role played by the gut microbiota in this interaction. In addition, this PhD will test the hypothesis that peripheral metabolic markers of psychopathological states (i.e. major depressive disorder, or MDD) may be detectable in urine and blood in a human cohort (PROJECT 3). Supported by the notion that gut microbial function may affect the likelihood of treatment efficacy, the possibility of identifying early metabolic markers of treatment response will also be investigated.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N014103/1 | 01/10/2016 | 30/09/2025 | |||
| 1770810 | Studentship | MR/N014103/1 | 01/10/2016 | 30/06/2021 |
| Description | Collaboration with University College Cork |
| Organisation | University College Cork |
| Country | Ireland |
| Sector | Academic/University |
| PI Contribution | Due to the published work arising from this PhD studentship a collaboration has developed with Professor John Cryan and Dr Gerard Clarke from University College Cork. My research group has analysed brain samples from rodent models generated in Cork to study the effects of Caesarean section on the blood-brain-barrier and the microbiota-gut-brain axis. |
| Collaborator Contribution | These partners provided the brain samples necessary to study the impact of C-section birth on the blood-brain-barrier and the microbiota-gut-brain axis. |
| Impact | This collaboration is multidisciplinary. My research group provides metabolomics expertise and the Cork teams provide expertise in neuroscience, neuropharmacology, and animal models. Due to the infancy of this collaborations there are no notable outputs to date. |
| Start Year | 2020 |
| Description | Investigating the effects of a deficient immune system on the gut-brain axis |
| Organisation | McMaster University |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | My role was to investigate the metabolic changes in the brain and in the gut of a T cell-deficient mouse model (developed by my collaborating partner) using NMR spectroscopy at the National Phenome Centre, Imperial College London. My research found that the concentrations of several neurotransmitters and other metabolites were altered in both the brain and the gut of T cell-deficient mice, which may explain the behavioural phenotype previously observed in these mice. |
| Collaborator Contribution | My collaborating partner (Prof Jane Foster, McMaster university) developed a T cell-deficient mouse model, in which depletion of functional T cells was achieved by genetic knockout of both ß and d chains of the T cell receptor (TCRß-/-d-). Prof Foster generated some data on the behavioural and gut microbial effect of T cell deficiency, and proved that T cell deficiency causes changes in emotional behaviour (reduced anxiety-like phenotype) and an altered faecal microbial composition. Finally, she provided me the samples from T cell-deficient mouse model for me to analyse at Imperial College London using 1H NMR spectroscopy. |
| Impact | This collaboration is multi-disciplinary, touching the fields of neuroscience, immunology, genomics and metabolomics. |
| Start Year | 2019 |
| Description | Investigating the impact of early-life protein malnutrition on the gut-brain axis |
| Organisation | St George's University of London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My research team covered the cost of the experiments (mice, behavioural rooms, etc.) that was not provided by the collaborators. We were responsible for the design of the animal study and for the metabolomic analysis. |
| Collaborator Contribution | Dr Alexis Bailey from St George's University of London has offered access to the the facility, equipment and materials to carry out a behavioural and molecular (quantitative receptor autoradiography) study of the impact of early life malnutrition on the gut-brain axis. Dr Bailey and the collaborating institution also took care of my animal training, and participated in designing the experiment. |
| Impact | Paper to be written up once all data have been collected and analysed. |
| Start Year | 2019 |
| Description | Shimadzu |
| Organisation | Shimadzu Corporation |
| Country | Japan |
| Sector | Private |
| PI Contribution | Working with a team from Cork we are exploring the impact of Caesarean section on the blood-brain-barrier and the microbiota-gut-brain axis. The team from Cork provide brain samples from rodents models and study their behaviour. The team from Shimadzu has been developing novel analytical approaches to measure the metabolites in these samples. My research team has been analysing the data to understand the impact of delivery mode on these profiles. |
| Collaborator Contribution | Shimadzu has analysed the metabolic profiles of brain samples (n = 50) from rodent models of C-section and natural birth. This has been achieved through the development of novel LC-MS-based methods. |
| Impact | No outputs to date. |
| Start Year | 2021 |
| Description | Member of the Organising and Programme Committee for Mind, Mood and Microbes - the international conference on the microbiota-gut-brain axis |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Part of the organising (1/4) and programme (1/14) committee for 'Mind, Mood and Microbes' - the international conference on the microbiota-gut-brain axis. Responsible for deciding the scientific direction of the conference and selecting and inviting speakers. |
| Year(s) Of Engagement Activity | 2020,2021 |
| URL | https://www.mindmoodmicrobes.org |
| Description | Oral presentation at ISNPR2019 conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | I presented the latest results of my CAN-BIND study, aimed at identifying early metabolic markers of depression and antidepressant response, in an talk hosted by the International Society for Nutritional Psychiatry Research (ISNPR). This international event was attended by ~500 people, mostly clinical psychiatrists, dietitians, and researchers in the field of nutrition and mental health. My talk was received with interest, and several questions were asked by the audience in relation to my human study and its implications for personalised medicine and clinical practice. |
| Year(s) Of Engagement Activity | 2019 |
| URL | http://isnprconf.org/ |
| Description | Panel member for a Q&A event for Mind, Mood & Microbes - the International conference on the microbiota-gut-brain axis |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | One of 8 experts on the microbiota-gut-brain axis that sat on the Q&A panel discussing emerging mechanisms and translational challenges and innovations in this area. Over 1000 individuals registered for this event from 48 countries. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.mindmoodmicrobes.org/mmm-expert-qa |
| Description | PhD Summer Showcase |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | I have taken part in the PhD Summer Showcase at Imperial College, which consisted of creating a short (3-minute) presentation on my research field for a lay audience. My presentation is available on the Youtube channel of the Imperial Graduate School and it currently has 163 views form the UK and other countries. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://www.youtube.com/watch?v=23niZSpBDsM&ab_channel=ImperialCollegeGraduateSchool |
| Description | Scientific Advisory Board for the RENEW project on the Gut-Bone Axis led by Prof Hanne Bertram (Aarhus University) |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A member of the Scientific Advisory Board for the RENEW project on the role of calcium absorption on the Gut-Bone axis funded by Innovation Fund Denmark. Providing expertise on the application of metabolomics and the gut microbiota. |
| Year(s) Of Engagement Activity | 2020,2021 |
| URL | https://pure.au.dk/portal/en/projects/renew--valorisering-af-sidestroemme-fra-mejeriindustrien-til-f... |
| Description | Sectional Nutrition Meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | The talk was given at a sectional meeting at Hammersmith campus, Imperial College London. The event was organised with the goal of allowing PhD students and post docs from different areas to present their research, generate points for discussion, and meet each other. The talks were streamed live and available on Panopto to all Imperial College students. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Talk delivered at the Medica Labmed Forum 2020 virtual conference on the biochemical language of the microbiota-gut-brain axis |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A talk titled 'The biochemical language of the microbiota-gut-brain axis' was delivered at the virtual event of the MEDICA LABMED FORUM 2020 as part of the 'Progress in microbiome and infection diagnostics' session. This was largely targeted towards a clinical audience |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://www.medica-tradefair.com/en/Forums_Conferences/Forums/MEDICA_LABMED_FORUM/MEDICA_LABMED_FORU... |
| Description | Talk on the Gut-Brain-axis at the European Behavioural Pharmacology Society / Canadian Biomarker Integration Network in Depression (CAN-BIND) - Behaviour to Biomarkers virtual workshop |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A talk was delivered at the European Behavioural Pharmacology Society (EBPS) / Canadian Biomarker Integration Network in Depression (CAN-BIND) - Behaviour to Biomarkers virtual workshop. This was a 20 minute talk on the application of metabolomics to study the metabolic components of the gut-brain axis. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.canbind.ca/canbindwebsitetest/ebps/ |