Hidden fuels of gut bacteria may drive diabetes and liver disease

Canadian researchers have discovered a surprising way to increase blood sugar levels and alleviate liver inflammation, by trapping gut bacteria as little-known fuels produced before entering the bloodstream.

The discovery was published on July 29 Cell metabolismelucidates how our microbiome affects metabolic diseases such as type 2 diabetes and fatty liver disease, and opens the door to novel therapies that act completely in the intestinal tract.

From the intestine to the liver: a new player in metabolism

For decades, scientists have learned about the so-called Cori cycle, a feedback loop in which muscles produce lactic acid that the liver uses to make glucose. This classic road won the Nobel Prize for Carl and Gerty Cori in 1947. But now, researchers at McMaster University and partner institutions have discovered a distortion of microorganisms in this cycle: Intestinal bacteria stir up different forms of lactic acid-lactic acid-D-lactic acid-can penetrate the blood and excessive fuel.

“What we found was a new branch of the cycle, and gut bacteria were also part of the conversation,” said Jonathan Schzell, a senior author of the study and a professor in the Department of Biochemistry and Biomedical Sciences of McMaster.

Unlike the more familiar L-lactic acid made by muscle, D-lactic acid is produced primarily by intestinal microorganisms. In obese patients, D-lactic acid levels in the blood are higher, and the team found that it may help explain why the liver ends up producing too much glucose and fat.

How polymer traps change the game

To test their hypothesis, scientists developed a “gut substrate trap”, a biodegradable polymer that binds to the D-type lactic acid in the intestine and prevents it from entering the blood. Obese mice had better blood sugar control over feeding polymers, reduced insulin resistance, and decreased signs of hepatitis and fibrosis, even though their weight and diet remained the same.

“We don’t target hormones or the liver directly, but instead intercept it before it is caused to cause the microbial fuel to cause damage,” Schertzer said.

The main findings of the study include:

• People and mice with obesity have significantly higher blood levels, but l-lactate has significantly higher blood levels
• Single intestinal bacterial strains produce more blood sugars in mice with D-lactic acid elevated
• Dietary polymer made from D-lactic acid captured in the intestine by L-shaped lactic acid, increasing its excretion in feces
• This “D-lactic acid trap” improves insulin sensitivity, reduced liver inflammation and fibrosis in obese mice

Microbial shortcuts for fatty liver?

In mouse models of metabolic dysfunction-associated steatohepatitis (MASH), polymer treatment is also effective, a progressive form of fatty liver disease. Mice receiving D-lactic acid trapping polymers had fewer liver scars, activated immune cells and lower markers of inflammation.

“We found that oral delivery of specific poly-l-lactic acid forces the excretion of intestinal D-lactic acid, thereby reducing blood D-lactic acid and improving liver outcomes,” the authors wrote. It is worth noting that these effects occur without altering overall food intake, weight or composition of gut bacteria.

What makes D-type lactic acid so effective?

Although D lactic acid appears much lower in the body than L lactic acid, it may be more metabolically destructive. The team showed that D-lactic acid promotes liver fat and glucose formation more effectively than well-known twins. It also activates immune cells in the liver that are involved in disease progression.

“D-lactate may be a more effective substrate for liver mitochondrial respiration,” the authors noted. Nevertheless, they stressed the need for more work to accurately understand how D-lactate contributes to human metabolic diseases and how its metabolism differs from L-lactate’s metabolism.

Impact on human health

While most of the data are from mouse models, the researchers found elevated D lactation levels in obese patients, suggesting human relevance. They warn that future research is needed to confirm whether the gut trap strategy plays a role in humans and how it can be integrated with other diabetes or liver disease treatments.

“This adds a microbial layer to the Cori cycle,” Schertzer said. “This suggests that stopping a microbial metabolite in the gut can bring far-reaching benefits to metabolism and liver health.”

As scientists continue to explore how the microbiome shapes chronic diseases, the study provides a powerful example of how targeting bacterial byproducts provides new therapeutic avenues without direct exposure to human cells.

Magazine: Cell metabolism

doi: 10.1016/j.cmet.2025.07.001

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