NDORMS DPhil & MSc by Research
Are metabolites generated by the microbiota key to a young immune system?
By 2050, the world’s population aged >60 years is expected to be 2 billion, up from 900 million in 2015, which is a major concern for the individual and for society generally. One of the contributing factors is ageing of the immune system. Aged individuals are less efficient at fighting infections and malignancies, have reduced capacity to respond to vaccinations, and moreover have low-grade chronic inflammation contributing to various age-related diseases such as neurodegeneration and cardiovascular disease. The mission of our ageing research is not to improve life span but health span, ie to reduce the burden of age-related diseases. Evidence is emerging that just a handful of cellular processes malfunctioning with age underlie these diseases. One of these processes is autophagy, the main mechanism by which cells remove cellular waste. Over the years, we have demonstrated a role for autophagy in different types of immune cells 1 2.
We found that autophagy declines with age in immune cells 3. Cells start to accumulate material that cannot be digested, which stops the cell from executing its functions and produce inflammatory cytokines in excess 4. When we re-introduced autophagy with the polyamine spermidine, immune cells were rejuvenated, in particular memory CD8+ T cells 5. Subsequently we uncovered a novel molecular pathway that controls autophagy downstream of the polyamines (Zhang et al, 2018 biorXiv).
While young cells are able to generate polyamines, they can also take it up from the environment. A major source of polyamines is the microbiota, the bacteria living in our gut. It is known that the gut microbiota is able to modulate host metabolism and immunity, mainly through the release of metabolites. In humans, the core microbiome is significantly different between old and young but the key metabolites maintaining a healthy lifespan have not been identified. It is possible that bacteria in the elderly gut no longer provide the metabolites necessary to maintain a healthy level of autophagy and thereby immune response. In this DPhil project, we will address if autophagy is maintained by the metabolites produced by gut bacteria. We will test if the novel molecular pathway that is key to immune rejuvenation can be recovered with microbiotic bacteria genetically engineered with state-of–the-art techniques to produce these metabolites in excess.
There is an increasing interest in using microorganisms as probiotics, either in fermented dairy products or formulated as tablets. However, convincing scientific data supporting their health claims are scarce. This study will help to understand at the metabolite level how the microbiome contributes to ageing.
- Riffelmacher, T. et al. Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity 47, 466-480, doi:10.1016/j.immuni.2017.08.005 (2017).
- Clarke, A. J., Riffelmacher, T., Braas, D., Cornall, R. J. & Simon, A. K. B1a B cells require autophagy for metabolic homeostasis and self-renewal. J Exp Med 215, 399-413, doi:10.1084/jem.20170771 (2018).
- Phadwal, K. et al. A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells. Autophagy 8, 677-689, doi:10.4161/auto.18935 (2012).
- Zhang, H., Puleston, D. J. & Simon, A. K. Autophagy and Immune Senescence. Trends Mol Med 22, 671-686, doi:10.1016/j.molmed.2016.06.001 (2016).
- Puleston, D. J. et al. Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife 3, doi:10.7554/eLife.03706 (2014).
The Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility at the University of Oxford.
The Simon lab consists currently of 4 postdocs, 2 DPhil students (both in their second year) and 2 graduate students and is well funded by the Wellcome Trust. It is a small, friendly and very international lab. While lab members are ambitious, the general attitude is not competitive and team spirit is very much encouraged. Every DPhil student (8 so far) has had the opportunity to write a review, and has published a first author paper. We collaborate locally, nationally and internationally. The presentation of data at national and international conferences is encouraged. We regularly welcome MSc students and other short-term students in the lab, so there will be opportunities to train your supervision skills.
Training will be provided in techniques including genetically engineering of gut microbiota, defining the metabolome, transcriptome and translatome (and related bioinformatics), read-outs for immunity such as multi parameter flow cytometry, histochemistry, confocal miscroscopy, Image Stream and Elispot.
Students will attend regular seminars within the department and those relevant in the wider University. Students will be expected to present data regularly in lab meetings, the departmental progress report seminars. Students will also have the opportunity to work closely with collaborating groups interested in the microbiome (Fiona Powrie, KIR and Justin and Erica Sonnenburg, Stanford).
A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome.
Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other departments. All students are required to attend a 2 - day Statistical and Experimental Design course at NDORMS.
How to Apply
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisors or the Graduate Studies Officer, Sam Burnell (Samuel.firstname.lastname@example.org), who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.
For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.