Introduction
Type 2 diabetes (T2D) and pre-diabetes are growing global health concerns. In 2019, an estimated 583 million people had diabetes worldwide (nearly 10% of the world’s adults), with T2D making up around 90%.1 T2D also rose from the 18th leading cause of death worldwide in 1990 to 9th in 2017.2 Pre-diabetes, an asymptomatic precursor to T2D, affects 84.1 million adult Americans (>30%), while another 28 million (>10%) have T2D.3 Pre-diabetes is characterized by insulin resistance, or a decrease in the body’s ability to use insulin signaling to uptake glucose, resulting in more insulin being needed to process the same amount of glucose as a healthy subject. This leads to elevated blood glucose levels.
In T2D, insulin production is no longer sufficient to compensate for insulin resistance and can be measured by a glucose tolerance test (GTT) in which glucose levels spike higher after a glucose challenge and take longer to return to pre-challenge levels than in insulin-sensitive individuals. Insulin resistance is also associated with small blood vessel disease,4 cardiovascular disease,5 non-alcoholic fatty liver disease,6 metabolic syndrome,7 and polycystic ovary syndrome.8 Adding to this health crisis, up to 70% of individuals with pre-diabetes will eventually develop diabetes in their lifetime.9 Alarmingly, efforts to slow or reverse the increasing prevalence of pre-diabetes and T2D have not been successful, with the rate of increase accelerating, especially in developed countries.10 As pre-diabetes and T2D continue to burden global public health systems, novel treatments to control and prevent pre-diabetes and T2D are urgently needed. Investigation of therapeutics with the ability to mitigate abrupt blood glucose spikes and lower elevated glucose levels is an important step to addressing this disease in both humans and animals.
Over the past several years, the gut microbiome has been linked to many human metabolic conditions including T2D.11 Elevated blood glucose has been associated with differences in the microbiome, with differences seen in the order, family, genus, species, and strain level between those in normal versus abnormal ranges. While causal relationships have not yet been established, early evidence shows that altering the microbiota by fecal transplantation can lead to improvements in insulin sensitivity and glucose metabolism.12 Faecalibacterium prausnitzii is a naturally occurring commensal bacterium found in the gastrointestinal tract of birds and mammals.13 14 In humans, F. prausnitzii comprises 3%–5% of the microbiome of a healthy gut and has been shown in numerous microbiome analyses to be lower in abundance in many disease states including irritable bowel disease, Crohn’s disease, asthma, depression, and metabolic disorders.15 16 Reduction of F. prausnitzii in the intestinal microbiota has been correlated with elevated blood glucose and T2D,17–28 and it has been found that different strains of F. prausnitzii may be present in healthy compared with disease states.29 30 From these observations, we hypothesize that administering specific strains of F. prausnitzii could modulate glucose metabolism and improve diabetic biomarkers. The aim of this study was to test whether live bacteria and/or bacterial extracts (postbiotics) from specific strains of F. prausnitzii31 have a positive impact on glucose metabolism in mice with diet-induced pre-diabetes or T2D. Both formulations have their benefits. Live cells have the potential to be incorporated into the microbiome and provide long-term excretion of effector molecules. However, as F. prausnitzii is an obligate anaerobe, the feasibility of its development into a probiotic is challenging, especially considering the costs associated with keeping anaerobes viable during processing and administration. If the molecules from cultures of F. prausnitzii are as effective as live F. prausnitzii, continuous administration of these products could represent a much more practical approach. We selected male C57BL/6J diet-induced obese (DIO) mice as a model system, as these mice have a genetic predisposition to develop elevated blood glucose, pre-diabetes, and ultimately non-insulin-dependent type II diabetes when fed a high-fat diet.32 The primary endpoints of these studies were changes in fasting blood glucose, glucose tolerance (as measured by GTTs), and percent HbA1c for longer term treatment.