Grant: Project Grant

Many Canadians are overweight or obese and have a higher risk of type 2 diabetes and fatty liver disease. Sticking to a diet to prevent or reverse obesity is hard. Bariatric surgery is effective because it stops some of the nutrients from being absorbed through the gut. Surgery is not possible for many overweight people and surgery is not selective for nutrients that are worse for diabetes or fatty liver disease. We found a new way to trap a source of fuel that comes from gut bacteria. There are 2 forms of lactate. L-lactate is made by us. D-lactate is mainly made by bacteria. We discovered that D-lactate fuels the liver to store fat and increases blood glucose. Nearly all metabolism research is on L-lactate. There is more L-lactate in the blood, but D-lactate is a better fuel for the liver to store fat and make glucose. Usually, we think of blood glucose and liver fat coming from nutrients after eating food. However, gut microbes are always producing D-lactate, which may be one reason that is so hard to lower blood glucose and liver fat by dieting. D-lactate from bacteria also promotes liver inflammation. Our "first-generation" D-lactate trap is a long string (or polymer), which keeps D-lactate in the feces and removes it from the body. This prevents D-lactate entering the blood. This trap is safe since it is biodegradable and does not to cross the gut barrier. We already know that our "trap" lowers blood glucose and insulin in obese mice. We will now build a better trap by blocking D-lactate production from all bacteria and by forcing bacteria to eat D-lactate transforming it into beneficial bacterial factors. There are lots of associations between the microbiome, obesity, diabetes or fatty liver disease. This work is new because we have found a bacterial metabolite that fuels higher blood glucose, liver fat and inflammation. Safely trapping D-lactate or stopping its production from bacteria can help lower blood glucose and liver fat without changes in diet.