Thursday, 5 September 2013
I am delighted to report the results of a joint study with Harvard University, which reveal key signalling pathways of the intestinal adaptive immune system following infection or autoimmune disease, and I am especially proud that these findings have recently been published in the highly regarded academic journal, Science.
Given my background in physiology and my current role in transgenic-RAD, Discovery Science at AstraZeneca I was delighted to be approached by Professor Wendy Garrett from Harvard University to collaborate on this project. Her research group is one of the world leaders in the dynamic interactions between the immune system and microbial gut flora. They were interested in a transgenic line characterized by our team that is deficient in the G protein-coupled receptor 43 (GPCR43). Previously, we had published on the role of GPCR43 in whole body metabolism in mice and also in immune response specifically for the neutrophil function, and they were keen to investigate if metabolites produced by gut bacteria act on the immune system via GPCR43.
The intestinal immune system requires gut microbiota for the maintenance of intestinal health, and disruption of homeostasis leads to intestinal inflammation and disease. These bacteria break down indigestible dietary components releasing short-chain fatty acids (SCFAs), which act as signalling molecules in the colonic lumen. Previously it had been proposed that SCFAs limit intestinal inflammation by modulating the development and function of regulating colonic T-cells (cTregs). Pathogen free mice had reduced SCFA levels and reduced cTreg numbers, which may contribute to their immune defects. Supplying SCFAs in the drinking water of these mice increased the number of cTregs, without altering the numbers of other distinct populations of T-cells.
During this new study we revealed two important features of this signalling pathway. Firstly, we showed that SCFAs can influence cTregs directly, in a germ-free animal. Importantly, our GPCR43 deficient mouse line also enabled us to show that this is a receptor-mediated process. GPCR43 is encoded for by the Ffar2 gene and we used our transgenic Ffar2-/- mice to investigate the contribution of GPCR43 to SCFA signalling in cTregs. We determined that SCFAs regulate the size and function of the cTreg pool via GPCR43 signalling.
I am proud of the findings that have come out of this cutting-edge scientific collaboration, and the interest this has generated for additional research. In fact, this has resulted in several potential new research projects for our team. I also believe this is the latest example of the power of scientific collaboration and the innovation-driven results it can deliver. Referring to an article posted by Peter Simpson earlier this year, it all comes back to ‘open innovation’ at work. It endorses our research strategy and shows how working successfully with external researchers is adding to our achievements and new opportunities for early stage pipeline development.
As a result of this project, GPCR43 is now a potential therapeutic target that could have practical implications in pro-inflammatory diseases such as inflammatory bowel disease, asthma and diabetes. I envision that our on-going research into this area will translate into novel therapies that work for patients.