During the past decade it has become evident that we are host to a dynamic ecosystem, the gut microbiota, that interacts with our diet to produce several bioactive metabolites (1, 2), which influence host physiology and metabolism (3, 4). Our ground-breaking studies in germ-free (GF) mice demonstrated that the gut microbiota should be considered an environmental factor that contributes to obesity and insulin resistance (5, 6), and our studies comparing patients and controls have demonstrated that the gut microbiota is associated with development of cardiometabolic diseases (CMD), such as obesity, diabetes and cardiovascular disease (7, 8). However, the current challenge is to move beyond descriptive studies and identify how the gut microbiota contributes to host metabolism and the development of therapies for CMD.
Approximately 40% of the obese population, and 4% in the Swedish general population, suffer from type 2 diabetes (T2D), with increased risk for developing cardiovascular disease. So why are not all obese individuals at risk for developing T2D? This proposal builds on the overarching hypothesis that the gut microbiota determines who will develop insulin resistance and subsequent T2D by loss of disease protecting bacteria and production of disease causing metabolites. To address these essential questions we will capitalize on a recently established prospective cohort that phenotypes 5,200 men and women in respect to prediabetes and T2D. We will combine this prospective population-based study with gnotobiotic mouse studies to delineate mechanisms and develop human intervention studies.
We will test our hypothesis by addressing the following aims:
1) to clarify if the microbiome is altered in prediabetic subjects and thus can contribute to the development of T2D.
2) determine whether an altered microbiota can predict who will develop T2D.
3) test the mechanisms by which altered gut microbiota contributes to prediabetes and T2D.
4) design interventions based on the above findings.