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Substance produced by gut following bariatric surgery regulates metabolic health in mice

New research in mice has identified a key player produced by the gut that links surgical and dietary weight-loss therapies to improvements in metabolic and digestive health. Interventions such as bariatric surgery or a high-fiber diet can protect against the development of metabolic diseases like type 2 diabetes. Some health benefits from bariatric surgery can even occur independently from weight loss, although exactly how this happens is not clear. Further research on mechanisms underlying these effects may one day lead to new ways to treat metabolic diseases.

Reg3g is an antimicrobial peptide (a mini version of a protein) produced in the small intestine to help prevent resident bacteria from invading the intestinal wall. Because previous studies have shown that Reg3g confers health benefits in addition to its antibacterial properties, the researchers sought to examine whether Reg3g can also contribute to the health effects of bariatric surgery or high-fiber diet and offer protection against metabolic diseases like type 2 diabetes. The researchers found that levels of Reg3g ramp up in mice after a type of bariatric surgery called vertical sleeve gastrectomy (VSG). To determine if Reg3g was responsible for the beneficial metabolic effects of VSG, the researchers performed VSG on male mice that were genetically altered to lack Reg3g. When compared to normal mice, the mice lacking Reg3g slowly regained weight and did not show improvements in blood glucose (sugar) levels and insulin production, implicating Reg3g in weight loss maintenance and better metabolic health after bariatric surgery. The researchers also saw improved metabolic health when they administered Reg3g to mice who did not undergo surgery, pointing to a possible role for Reg3g in protection against type 2 diabetes. When the researchers looked at the microbiome (the community of microbes in the gut) following VSG or a high-fiber diet, they found that these interventions changed the composition of the microbiome by boosting levels of certain beneficial bacteria, which in turn stimulated Reg3g production. Furthermore, Reg3g was found to play an important role in improving gut function, such as strengthening the gut barrier and reducing cellular stress in the small intestine.

These results suggest that changes to the microbiome due to bariatric surgery or a high-fiber diet stimulate production of Reg3g, which in turn mediates a variety of health benefits. Interestingly, the researchers also found that Reg3g is elevated following VSG in young people with obesity. If Reg3g causes similar metabolic effects in humans as in mice, it could mean that Reg3g-based treatments might have therapeutic value for people with metabolic diseases like type 2 diabetes.

Shin JH, Bozadjieva-Kramer N, Shao Y,…Seeley RJ. The gut peptide Reg3g links the small intestine microbiome to the regulation of energy balance, glucose levels, and gut function. Cell Metab 34: 1765-1778, 2022.

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