Gut bacteria metabolites directly extend the lifespan of host flies

Gut microbiota influences multiple aspects of host physiology, including metabolic and immune functions. Many metabolites produced by gut bacteria can cross the intestinal epithelium (which the bacteria may not be able to cross) and enter host tissues, providing a pathway through which microbial activity can influence host physiology. However, determining the specific contribution of individual gut bacterial metabolites to host lifespan has remained challenging.

To address this gap, a research team led by Associate Professor Shin Kurihara from the Faculty of Biology-Oriented Science and Technology, Kindai University, Japan, and Professor Takayuki Kuraishi of Kanazawa University, Japan, used gnotobiotic flies colonized with genetically engineered Escherichia coli (E. coli). This experimental system enabled the researchers to compare flies carrying bacteria that could produce polyamines with those carrying bacteria genetically modified to lack polyamine production. "Polyamines, including putrescine and spermidine, are known gut microbial metabolites associated with improved biological functions and lifespan extension. We wanted to understand whether polyamines produced specifically by gut bacteria can directly influence the lifespan of a host, independent of polyamines obtained from the diet," says Dr. Kurihara. The study findings were published online in the journal mBio on September 10, 2026.

The researchers first examined the effect of dietary polyamines using germ-free flies maintained on a chemically defined, polyamine-free diet supplemented with either putrescine or spermidine. Both supplemented groups showed significantly longer lifespans than flies maintained on a diet without polyamines. The mean lifespan was 20.8 days for flies receiving putrescine and 21.1 days for those receiving spermidine, compared to just 18.2 days for the polyamine-deficient control group.

The team then investigated whether polyamines produced specifically by gut bacteria could contribute to lifespan extension. The researchers colonized the flies with one of the three genetically distinct E. coli strains: SK929, a wild-type strain capable of producing putrescine; SK930, a mutant strain in which three genes involved in putrescine biosynthesis had been deleted; and SK931, a complemented strain which was capable of producing putrescine. All groups were maintained on a modified polyamine-free diet, allowing the researchers to assess the contribution of bacterial polyamine production.

Putrescine was detected in whole-body homogenates of flies colonized with SK929 and SK931, at approximately 1.2 nmol/mg and 1.3 nmol/mg, respectively. However, it was below the detection limit in flies colonized with SK930. The researchers also detected spermidine in all three groups, consistent with the ability of flies to synthesize polyamines themselves. The higher putrescine levels in flies carrying the polyamine-producing strains suggested the uptake of bacterial-derived putrescine by the host and its conversion to spermidine.

The lifespan results showed sex-dependent differences. In male flies, those colonized with the putrescine-producing SK929 and SK931 strains achieved average lifespans of 13.8 and 12.6 days, respectively, compared with 11.0 days for flies colonized with the polyamine-deficient SK930 strain. Both polyamine-producing groups showed significantly longer lifespans than the SK930 group.

The effect in female flies was less consistent between strains. While females colonized with SK929 had a mean lifespan of 14.9 days, significantly longer than the 11.0 days of the control group carrying the SK930 strain, the complemented SK931 strain yielded an average lifespan of only 10.7 days.

The researchers also investigated the underlying molecular mechanisms that influence the extension of their lifespan. Compared to the polyamine-deficient control cohort, host interaction with polyamine-producing bacteria correlated with a significant downregulation of TotM and Halo expression. Because TotM is associated with the JAK/STAT immune/stress-response pathway, which becomes activated with age, its downregulation may contribute to lifespan extension. However, the precise mechanism remains to be elucidated.

"This experimental approach allows us to examine how individual metabolites produced by gut bacteria influence the lifespan of its host," explained Dr. Kurihara. "Although we focused on polyamines in this study, the same strategy could help us investigate the long-term effects of other bacterial metabolites. Ultimately, this insight could drive the development of functional foods and probiotics that optimize polyamine production, offering novel, diet-based strategies to regulate gut microbial metabolism for health maintenance."

Overall, the study provides a controlled experimental demonstration that gut bacteria-derived polyamines actively modulate host lifespan, while establishing a robust methodological framework to investigate how other microbiota-derived molecules impact long-term host health.