Overfeeding in the first weeks of life programmed muscle loss in old mice through the early loss of a single gut bacterium
Overfeeding in the first weeks of life programmed muscle loss in old mice through the early loss of a single gut bacterium
Biologists reduced mouse litter sizes so that each pup received more maternal milk. Mice overfed in infancy lost the gut bacterium Akkermansia muciniphila for life and experienced faster declines in muscle mass and strength in old age. Three independent experiments confirmed that this bacterium plays a causal role in muscle aging. The study was published in Nature Communications on October 7, 2026.
The researchers kept 8–9 pups in some litters and 3–4 in others. With fewer pups sharing the milk, each received more and gained weight rapidly. Developmental researchers use this approach to model overfeeding in infancy while keeping the food itself unchanged.
From the third week of life, Notch signaling, which determines the fate of intestinal stem cells, suppressed the formation of mucus-secreting goblet cells in these mice. The protective mucus layer became thinner. This layer is home to Akkermansia muciniphila, a bacterium that feeds on mucus and colonizes the gut in both mice and humans during infancy. The loss of mucus deprived the bacterium of a place to establish itself, and its abundance remained low for the rest of the animals’ lives.
By advanced old age, at 24–28 months, the effects were apparent in the muscles: mice overfed in infancy had weaker grip strength, tired sooner on a treadmill, and developed thinner muscle fibers surrounded by scar tissue. Median lifespan in males fell by 6,67%, from 30 to 28 months.
The researchers traced the mechanism to a specific molecule. Akkermansia muciniphila produces acetate, a short-chain fatty acid detected in muscle by the receptor GPR43. The related receptor GPR41 responds to other similar acids. Loss of the bacterium reduces acetate availability and weakens GPR43 signaling, which in turn reduces the number and energy output of mitochondria in muscle cells. When the researchers silenced the GPR43 gene in the muscles of old mice, acetate supplementation could no longer restore their mitochondria or muscle strength.
Transplanting gut microbiota from old donors that had been overfed in infancy into healthy mice was sufficient to cause muscle loss and metabolic dysfunction, even on standard feed. In mice with no history of overfeeding, removing Akkermansia muciniphila from a community of six bacterial species was enough to weaken their muscles. Together with the GPR43 gene-silencing experiment, these findings provide three independent lines of evidence that loss of this bacterium alone is sufficient to cause muscle aging. The full pathway from the bacterium to mitochondria was investigated only in males; in females, only muscle loss itself was confirmed. A different way of inducing overfeeding, giving nursing mothers a high-fat diet, reproduced the same early steps in the pathway: loss of the intestinal barrier and the bacterium.
Interventions at either end of this pathway can interrupt it. At the later stage, an eight-week course of the live bacterium restored grip strength, coordination, and endurance in old mice that had been overfed in infancy. Restoring the bacterium is now also being tested in humans: the registered ARMOR trial, which transplants gut microbiota from young athletes into people aged 65–84, includes muscle strength among its outcome measures. At the early stage, supplementing nursing mothers’ diets with alanyl-glutamine restored intestinal mucus layer development in their offspring before the defect appeared.
Akkermansia muciniphila colonizes the human gut during the first year of life. It is present in nine out of ten healthy adults, accounting for up to 3% of their gut microbiota, and its relative abundance naturally declines with age. In 2021, European Union regulators recognized the pasteurized form of the bacterium as a safe novel food for human consumption.
The study traces the origins of age-related muscle weakness back to infancy: for one cause of sarcopenia, the critical window falls within the first few weeks of life, two years before the problem becomes apparent.