Researchers at Kobe University have discovered that gut microbes that were thought to feed exclusively on dietary fiber also metabolize sugar that the body transfers from the circulation into the intestine, and from which the microorganisms produce short-chain fatty acids (SCFAs) that are crucial to many body functions. The team’s studies in humans and in mice involved using a new imaging technique to show that glucose is excreted into the intestinal lumen, that excretion is amplified by the antidiabetic drug metformin, and that the intestinal glucose is metabolized by gut microbiota into short-chain fatty acids. The team said the discovery of this symbiotic relationship could point the way to developing novel therapeutics.
“The production of short-chain fatty acids from the excreted glucose is a huge discovery,” said Kobe University endocrinologist Wataru Ogawa, MD, PhD. “While these compounds are traditionally thought to be produced through the fermentation of indigestible dietary fibers by gut microbiota, this newly identified mechanism highlights a novel symbiotic relationship between the host and its microbiota.”
Research lead Ogawa and colleagues reported on their findings in Communications Medicine. In their paper, titled “Metformin-regulated glucose flux from the circulation to the intestinal lumen,” the investigators concluded, “A previously unrecognized, substantial flux of glucose from the circulation to the intestinal lumen exists, which likely contributes to the symbiosis between gut microbiota and the host. This flux represents a novel target of metformin’s action in humans.”
Metformin is one of the most widely prescribed antidiabetic drugs worldwide, the authors wrote, but while the antidiabetic action of the drug is believed to occur primarily through the inhibition of hepatic gluconeogenesis, “… its underlying mechanisms remain not fully understood.”
Gut microbes produce many substances that our body needs but cannot produce itself. Among them are short-chain fatty acids that are the primary energy source for the cells lining our guts but that also have other important roles. It’s thought that these SCFAs are produced by bacteria feeding on undigested fiber. However, in previous work using an imaging technique called [18F]FDG PET-MRI, Ogawa’s team found that people who take metformin excrete glucose to the inside of their guts. Ogawa reasoned, “If glucose is indeed excreted into the gut, it is conceivable that this could affect the symbiotic relationship between the gut microbiome and the host.”
Ogawa and colleagues set out to learn more about the details of the glucose excretion and its relationship with the gut microbiota. Ogawa added, “We had to develop unprecedented bioimaging methods and establish novel analytical techniques for the products of the gut microbial metabolism.” The authors further explained, “To provide further insight into the metformin-induced transfer of glucose from the circulation to the intestine, we developed a new bioimaging system based on PET-MRI that allows quantitation of glucose flux to the intestinal lumen … We also analyzed metformin-induced changes in the dynamics of glucose and its derivatives in the intestine with the use of stable isotope (13C)–labeled glucose and mass spectrometry in mice.”
The investigators used the new methods to not only see where and how much glucose enters the intestine, but also, through their mouse experiments, to find out how the sugar is then transformed. They also evaluated how the diabetes drug metformin influences these results both in humans and in mice.
Their results indicated that first, glucose is excreted in the jejunum, a part of the small intestine, from where it is then transported inside the gut to the large intestine and the rectum. “It was surprising to find that even individuals not taking metformin exhibited a certain level of glucose excretion into the intestine,” Ogawa pointed out. The results also showed that in both humans and mice, irrespective of whether they were diabetic or not, metformin increased glucose excretion into the intestine by a factor of almost four. “This finding suggests that intestinal glucose excretion is a universal physiological phenomenon in animals, with metformin acting to enhance this process,” Ogawa noted.
Credit: © MORITA Yasuko, fromCommunications Medicine2025 (DOI: 10.1038/s43856-025-00755-4) (CC BY-NC-ND)
The authors further stated in their paper, “Individuals who do not receive metformin treatment excrete approximately one-fourth of the amount of glucose excreted by those who receive metformin treatment. This finding is also unexpected and it suggests that the glucose flux has physiological significance independent of metformin’s action.”
The findings indicated that during its passage through the intestine, the glucose gets transformed by gut microbiota into short-chain fatty acids. “SCFAs are generated by the gut microbiota as a result of the metabolism of indigestible dietary fiber,” the team noted. “However, our current findings suggest that, even in the absence of such fiber, glucose excreted into the intestine serves as a source for SCFA production.”
Ogawa and his team are now conducting further studies with the aim of understanding how metformin and other diabetes drugs affect glucose excretion, the gut microbiome, and their metabolic products.
Noting limitations of their study, they wrote, “In conclusion, we have here uncovered a previously unrecognized and substantial glucose flux from the circulation to the intestine and have provided evidence that this flux may contribute to the symbiotic relation between the host and gut microbiota in mice and humans … Further studies are warranted to understand the physiological relevance of glucose excretion into the intestine and its contribution to the glucose-lowering effect of metformin.”
NewsDrug regulationFatty acidGastrointestinal microbiomeMetforminMice
