Gut-liver axis: How a bacterial molecule may worsen diabetes

Scientists have discovered a molecule, D-lactate, produced by gut bacteria, which enters the bloodstream and fuels the liver to make more glucose and fat than necessary. They believe this opens new pathways to improving blood sugar levels and reducing liver damage when treating metabolic diseases like type 2 diabetes and fatty liver disease.

Researchers at McMaster University, Université Laval, and University of Ottawa, in Canada, developed a way to trap this molecule in the gut before it can enter the body through the blood. In doing so, the researchers say they then observed “dramatic improvements” in blood sugar control and fatty liver disease in obese mice.

“This is a completely new way to think about treating metabolic diseases like type 2 diabetes and fatty liver disease. Instead of targeting hormones or the liver directly, we’re intercepting a microbial fuel source before it can do harm,” says Jonathan Schertzer, senior and corresponding author and professor in the Department of Biochemistry and Biomedical Sciences at McMaster University. 

Building on Nobel Prize research

Their research builds on work by Nobel Prize scientists Carl Ferdinand Cori and Gerty Theresa Cori, who first investigated how the human liver and muscles exchange fuel. In 1947, they found muscles in the body generate lactate that fuels the liver to produce blood glucose, which cycles back in the form of lactate (L-lactate) to feed the muscles.

The Canadian team of the paper published in Cell Metabolism found that obese mice and humans have higher levels of a lesser-known molecule called D-lactate in their blood. This specific molecule, compared to the more familiar L-lactate produced by muscles, mainly originates from gut bacteria. 

The study reveals D-lactate produced by gut bacteria increases blood sugar and liver fat more “aggressively.”The study reveals D-lactate increases blood sugar and liver fat more “aggressively.”

“This is a new twist on a classic metabolic pathway,” says Schertzer.

“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.”

Liver and muscles exchange fuel

The scientists created a “gut substrate trap,” using a safe, biodegradable polymer bound to D-lactate in the gut to prevent it from being absorbed. They fed the trap to mice with metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH).

In these mice, the system effectively lowered blood glucose, while lowering their insulin resistance, and reducing liver inflammation and fibrosis, without changing their diet or body weight.

As such, the researchers conclude that microbial-derived D-lactate contributes to host glucose and fat metabolism and can be trapped to “improve metabolic disease during obesity.”

Earlier this week, researchers warned of a global surge in liver cancer cases driven by a long-term liver condition caused by excess fat in the liver, which causes MASH in some patients. They noted that three in five liver cancer cases can be prevented through lifestyle changes that reduce these liver conditions.

Previously, researchers investigating body-gut bacteria relationships also found that certain microbiome dynamics may impact fatty liver disease and high cholesterol. Their study highlights that when gut bacteria produce bile acids, the body counters this by producing a counter-molecule, called bile acid-methylcysteamines, which helps maintain metabolic balance.