Gut microbes that were thought to feed exclusively on dietary fiber also get fed sugar from our guts, from which they produce short-chain fatty acids that are crucial to many body functions. The Kobe University discovery of this symbiotic relationship also points the way to developing novel therapeutics.
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 have other important roles, too, and that are thought to be produced by bacteria who feed on undigested fiber. However, in a previous study, the Kobe University endocrinologist OGAWA Wataru found that people who take the diabetes drug metformin excrete the sugar glucose to the inside of their guts. He says: "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 his team set out to learn more about the details of the glucose excretion and its relationship with the gut microbiota. "We had to develop unprecedented bioimaging methods and establish novel analytical techniques for the products of the gut microbial metabolism," he says. They used their new methods to not only see where and how much glucose enters the guts, but also used mouse experiments to find out how the sugar is transformed after that. In addition, they also checked how the diabetes drug metformin influences these results both in humans and in mice.
The Kobe University team now published their results in the journal Communications Medicine. They found that, first, glucose is excreted in the "jejunum," a part of the small intestine, and is transported from there 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. This finding suggests that intestinal glucose excretion is a universal physiological phenomenon in animals, with metformin acting to enhance this process," Ogawa explains. In both humans and mice, irrespective of whether they were diabetic or not, metformin increased the excretion by a factor of almost four.
And second, on the way down, the glucose gets transformed into short-chain fatty acids. Ogawa says: "The production of short-chain fatty acids from the excreted glucose is a huge discovery. 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."
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. He says: "Intestinal glucose excretion represents a previously unrecognized physiological phenomenon. Understanding the underlying molecular mechanisms and how drugs interfere with this process could lead to the development of novel therapeutics aimed at the regulation of gut microbiota and their metabolites."
This research was funded by the Japan Society for the Promotion of Science (grants 22K18393, 20K17511 and 21K08578), the Japan Science and Technology Agency (grant JPMJMI20G1), the Japan Diabetes Society, the Manpei Suzuki Diabetes Federation, the Cell Science Research Foundation, the Suzuken Memorial Foundation, the Japan Diabetes Foundation and Nippon Boehringer Ingelheim Co. Ltd. It was conducted in collaboration with researchers from the RIKEN Center for Biosystems Dynamics Research, Kindai University, Kyushu University, the University of Hyogo and the University of Fukui.
Kobe University is a national university with roots dating back to the Kobe Higher Commercial School founded in 1902. It is now one of Japan's leading comprehensive research universities with nearly 16,000 students and nearly 1,700 faculty in 10 faculties and schools and 15 graduate schools. Combining the social and natural sciences to cultivate leaders with an interdisciplinary perspective, Kobe University creates knowledge and fosters innovation to address society's challenges.
