gut BacteriaS D-Lactate: A New Target for Obesity and Metabolic Disease

McMaster University researchers have uncovered a novel pathway involving gut bacteria that contributes to obesity-related metabolic diseases, offering a promising new therapeutic avenue.

Hamilton, ON – In a notable breakthrough, researchers have identified a previously underappreciated molecule produced by gut bacteria that plays a crucial role in the growth of obesity, type 2 diabetes, and fatty liver disease. By developing a method to trap this molecule in the gut, scientists have demonstrated dramatic improvements in metabolic health in mice, suggesting a potential new strategy for treating these widespread conditions.

A New Branch in the Cori Cycle

The revelation builds upon the foundational work of Carl Ferdinand and Gerty Theresa Cori, who were awarded the Nobel Prize in Physiology or Medicine in 1947 for elucidating the Cori cycle. This classic metabolic pathway describes the exchange of lactate and glucose between muscles and the liver, a vital process for energy regulation.

“This is a new twist on a classic metabolic pathway,” explains Jonathan Schertzer, senior and corresponding author of the study and a professor in the Department of Biochemistry and Biomedical Sciences at mcmaster University. “We’ve known for nearly a century that muscles and the liver exchange lactate and glucose – a process called the Cori cycle. What we’ve discovered is a new branch of that cycle, where gut bacteria are also part of the conversation.”

D-Lactate: The Microbial Culprit

The Canadian team observed that obese mice, and even humans with obesity, exhibit elevated levels of D-lactate in their blood. Unlike the more common L-lactate, which is produced by muscles and plays a role in the Cori cycle, D-lactate is primarily generated by gut microbes.Crucially, the research indicates that D-lactate is a potent driver of increased blood sugar and liver fat accumulation.

The “Gut Substrate Trap” Solution

To counteract the effects of D-lactate, the researchers engineered a “gut substrate trap.” This innovative solution is a safe, biodegradable polymer designed to bind to D-lactate within the gut, preventing its absorption into the bloodstream.

When administered to obese mice, this trap led to remarkable improvements. The mice experienced lower blood glucose levels, reduced insulin resistance, and a significant decrease in liver inflammation and fibrosis. Notably, these positive outcomes were achieved without any changes to their diet or overall body weight.

A Paradigm Shift in Metabolic Disease Treatment

This research represents a significant departure from conventional approaches to treating metabolic diseases. instead of targeting hormones or directly intervening in liver function, the strategy focuses on intercepting a microbial fuel source before it can exert its harmful effects.

“This is a completely new way to think about treating metabolic diseases like type 2 diabetes and fatty liver disease,” states Schertzer. “Instead of targeting hormones or the liver directly, we’re intercepting a microbial fuel source before it can do harm.”

Schertzer, who holds a Canada Research Chair in Metabolic Inflammation and is affiliated with McMaster’s Center for Metabolism, Obesity, and Diabetes Research (MODR) and the Farncombe Family Digestive Health Research Institute, emphasizes the growing importance of the microbiome in chronic disease development.

Future Implications and Funding

the study, funded by the Canadian Institutes of Health Research (CIHR), underscores the critical role the gut microbiome plays in maintaining metabolic health and highlights the potential of microbiome-targeted therapies. This discovery opens exciting avenues for developing novel treatments for millions affected by obesity and related metabolic disorders worldwide.

Source:

Journal reference: Fang,H., et al. (2025). Gut substrate trap of D-lactate from microbiota improves blood glucose and fatty liver disease in obese mice. Cell Metabolism. doi.org/10.1016/j.cmet.2025.07.001