4 Minutes
A team of Canadian researchers has identified an unexpected mechanism to improve blood sugar control and reduce liver damage in obesity: intercepting a microbial metabolite produced in the gut before it reaches the bloodstream. Published in Cell Metabolism, the study shows that D‑lactate — a form of lactate largely produced by intestinal bacteria — drives the liver to overproduce glucose and fat. By engineering a biodegradable “substrate trap” that binds D‑lactate in the gut, researchers reversed markers of insulin resistance and fatty liver in obese mice, offering a prototype approach for new metabolic disease therapies.
Microbial D‑lactate and metabolic disruption
The Cori cycle, described by Carl and Gerty Cori in the mid‑20th century, explains how muscle-generated L‑lactate is shuttled to the liver and converted back to glucose to fuel tissues. This new work extends that metabolic conversation to include the gut microbiome. Unlike L‑lactate produced by muscles, D‑lactate mostly originates from gut bacteria. The Canadian team — from McMaster University, Université Laval and the University of Ottawa — measured elevated D‑lactate levels in obese mice and found similar trends in people with obesity.
Experimental data showed that circulating D‑lactate stimulates hepatic pathways that increase glucose production and lipid accumulation. In effect, microbial D‑lactate acts as an alternative fuel signal that pushes the liver toward gluconeogenesis and steatosis (fatty liver). This discovery reframes how researchers view host–microbe metabolic interactions and identifies D‑lactate as a microbial metabolite with systemic metabolic consequences.
Gut substrate trap: design, mechanism and results
To prevent D‑lactate from entering circulation, researchers developed a gut substrate trap: a safe, biodegradable polymer that selectively binds D‑lactate in the intestinal lumen and blocks its absorption. Mice fed the polymer experienced meaningful metabolic improvements without changes in diet or body weight. Key outcomes included lower fasting blood glucose, reduced insulin resistance, and decreased liver inflammation and fibrosis.
How the trap works
The polymer acts locally in the gut, sequestering D‑lactate molecules so they are eliminated with fecal matter rather than transported across the intestinal barrier. Because the intervention targets a microbial fuel source rather than host hormones or liver enzymes, it offers a novel therapeutic angle with potentially fewer off‑target effects.
Implications for type 2 diabetes and fatty liver disease
Intercepting D‑lactate could complement existing treatments for metabolic disease. By lowering a microbial driver of hepatic glucose production and lipid accumulation, substrate trapping may reduce the progression of insulin resistance, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Further work is needed to adapt this approach for human trials, optimize dosing and verify long‑term safety.
Scientific context and next steps
This research integrates microbiome science with classical metabolic physiology. It highlights how microbial metabolites can act as systemic signaling molecules, reshaping host metabolism. Next steps include validating the polymer in larger animal models, investigating effects on the human gut microbiome, and exploring whether dietary or probiotic strategies can similarly modulate D‑lactate production.
Expert Insight
Dr. Elena Morales, a metabolic researcher not involved in the study, commented: “Targeting microbe‑derived metabolites is an elegant strategy. Rather than suppressing host pathways directly, this approach neutralizes a harmful input at its source. If translatable to humans, substrate trapping could become a useful adjunct to lifestyle and pharmacologic therapies for diabetes and fatty liver.”
Conclusion
The discovery that gut‑derived D‑lactate promotes hepatic glucose and fat production reveals a new microbe‑to‑host metabolic axis. A biodegradable gut substrate trap that sequesters D‑lactate improved glucose regulation and liver pathology in obese mice, pointing to a promising new direction for therapies aimed at type 2 diabetes and fatty liver disease. Continued research will determine whether this microbial‑targeted tactic can be adapted safely and effectively for clinical use.
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