High resolution systems biology to determine the role of gut microbiota on type 2 diabetes

Type 2 diabetes (T2D), also known as non-insulin dependant diabetes, is a major public health concern in the UK, currently affecting nearly 5 % of the British population and predicted to touch 5 millions individuals by 2025. It is therefore crucial to find new strategies to better prevent and manage T2D. This can be achieved by tailoring treatment to individuals, taking into account their genetic background in interaction with their lifestyle and global environment. Over the last 10 years, the gut microbiota has emerged as a mirror of all these interactions. Our body is inhabited by 10 times more bacterial than human cells, which represent a reservoir of over hundreds of thousands of unique extra genes that are potentially metabolically active. This hugely complex ecosystem bears the potential of new personalised medicine and prevention of metabolic disorders that develop as a result of gene-lifestyle-environment interactions.
Although the gut microbiota has been under investigation for more than half a century, it is only now that new molecular tools, such as the development of high throughput DNA sequencing, enable to explore the mechanisms underlying their contribution to the host metabolism. To date, the detailed mechanisms by which the gut microbiota may influence the development of T2D remain poorly understood. Nevertheless, there is growing evidence that they exert multiple impacts on endogenous energy pathways, including production of short chain fatty acids and regulation of bile acid metabolism that both contribute to the balance of lipid metabolism. In addition, it has been demonstrated that the maternal and neonatal gut microbial environment influence the development of metabolic syndrome later in life, which ultimately leads to T2D, suggesting a programming influence of the gut bacteria on energy metabolism.
Hence, this project aims at unraveling the biological mechanisms underlying the role of the microbial component that contributes towards the development of insulin resistance. We will use a well-characterised mouse model of T2D (db/db mice) in order to reveal the molecular processes underpinning the interaction between a genetic mutation causing an overeating behaviour and the microbial environment by isolating the specific metabolic contribution of each component.
For this purpose, we will cross homozygous wild-type and db/db animals twice to generate a range of genotypes that have been raised under two environmental conditions (control or diabetic microbial environments). This will enable to test the influence of maternal and neonatal microbial environments on heterozygous (db/+) animals, which are susceptible to developing T2D. We will also be able to assess the impact of the diabetic neonatal environment on the energy metabolism of control wild-type animals. Measurements of the microbe - energy metabolism interactions will be performed using a systems biology approach combining metabolic profiling, transcriptomics and metagenomics data. Upon completion, this original approach will provide new insights into the role of the maternal and neonatal microbial environment on metabolic programming of energy pathways and the aetiology of T2D. In addition, this project will generate unique animal models that are prone to developing T2D and which have been exposed from conception to birth to a diabetic microbial environment. These will enable to test new diet interventions of high interest for further research leading to the development of new prophylactic or therapeutic treatments to stop the progression of T2D.

Type 2 diabetes (T2D) has been increased in the UK over the last ten years, which can be partly explained by a combination of poor early diagnosis and inappropriate prophylactic strategies as well as low treatment compliance leading to an ineffective management of the disorder. It is known that T2D results from complex interactions between genetic and environmental factors. Thus, having a more individualised prophylactic and therapeutic strategy is the way forward towards efficient control of T2D. To date, an important effort is directed towards a more personalised medical approach by stratifying populations in subgroups that share common disease patterns. One emerging environmental component that contributes to stratify patients is the gut microbiota. Indeed, gut microbiota play an essential role in many functions, including energy metabolism. It has been shown that type 2 diabetic patients displayed a gut dysbiosis accompanied by strong perturbations of the microbial metabolic activity. Besides, it has recently arisen that the maternal microbial environment may have a programming influence on the future child's metabolic health. Hence, this project aims at addressing the complex interactions between genetics, development and microbial environment to improve understanding of the aetiology of T2D. For this purpose, we will dissociate the genetic from the microbial component by crossing diabetic and wild-type animals under controlled microbial conditions to generate discordant genotype/microbiota individuals such as wild-type animals raised in a diabetic microbial environment, in which we will be able to assess the influence of the microbiota on energy metabolism. The biological mechanisms underlying this interaction will be investigated by a high resolution systems biology approach combining metagenomics, metabolomics and transcriptomics analysis. This unique approach will provide new insights into the pathophysiological processes leading to T2D

This project will investigate the fundamental links between T2D and gut microbiota in an animal model, so it is realistic to expect full impact of the project to be reached within a 10 to 15 years timeframe.

Public health
The prevalence of type 2 diabetes (T2D) in the UK has been constantly increasing over the last 10 years and is predicted to affect 5 million individuals by 2025. Therefore, the largest impact of this project will be on public health. This project will pave the way towards the development of new prophylactic and therapeutic strategies. Providing novel mechanistic details of the complex gene-microbe interactions will facilitate the selection of appropriate pre/pro/synbiotics as well as potential new drug targets. The advantage of targeting the gut microbiota over more traditional endogenous targets is that it considerably reduces the risk of side effects and increases the range of patients that can be treated. Compliance to treatment is also usually improved with nutraceuticals compared with tablets or injections.
Potential beneficiaries therefore include a large panel of individuals, from overweight pregnant mothers to patients at risk of developing- or affected by- T2D and their family members who will benefit from a personalised nutrition plan, which may be accompanied by a nutraceutical and/or a new treatment to limit the development of further complications and improve their overall quality of life. Community workers and clinicians will also be able to provide better advice and support to affected patients by proposing a tailored intervention that has been adjusted to patient's gut microbial metabolism.

Pharmaceutical sector
The diabetes drug market has been estimated by Standard & Poor's to approximate $ 35 billion in 2012 and is predicted to be worth $ 58 billion in 2018. There is therefore a large scope for economical growth for pharmaceutical companies that will produce the next generation of anti-diabetic drugs. Indeed, anti-diabetic drugs currently fail to restrain this epidemic and are associated with many side-effects that make them difficult to use in specific cases such as patients with chronic liver disease. Therefore, a new approach to tailor treatment to individuals is needed that takes into account the patient's genetic background in interaction with his metabolism, lifestyle and global environment. The pharmaceutical sector is therefore expected to greatly benefit from the new knowledge generated by the proposed work. The new animal model, that is genetically unaltered but has been grown within a diabetic microbial environment, will enable to further test various interventions to limit or delay the development of T2D in offsprings exposed to a western diet. As detailed in the Pathways to Impact, we intend to develop links with the pharmaceutical sector in order to further develop new therapeutics that target the metabolic pathways involved in the gut microbiota-host interaction designed to prevent the development of T2D and its complications.

NHS and global UK economy
T2D and its associated complications are estimated to cost over £ 23 billion per year to the UK economy. Of this, £ 14 billion is directly spent by the NHS, which represents almost 10 % of its budget. Efficiently preventing and managing T2D would therefore considerably lighten the burden on the UK economy. This is also the conclusion of the the 2012 report of the London School of Economics, which states that policy makers should prioritise diabetes prevention and "invest in early detection or screening initiatives". By exploring the gut microbial metabolism during the development of T2D, this project will enable to identify biomarkers of specific bacterial activity relevant to this metabolic disease and fulfils the above recommendation.