Helicobacter pylori infection impairs glucose homeostasis through gut microbiota dysbiosis

Epidemiological data show that Helicobacter pylori (H. pylori) infection is not only the most important risk factor for gastric cancer, but is also associated with poor glycemic control in patients with diabetes. However, the direct causal and functional relationship between H. pylori infection and dysglycemia is unclear. A retrospective cohort study was conducted to examine the association between H. pylori infection and glycemic levels in individuals with Type 2 diabetes. C57BL/6 diabetic mice were infected with H. pylori, and the resulting changes in colonic inflammation and intestinal Glucagon-like peptide-1 (GLP-1) secretion were thoroughly examined using immunohistochemistry, RNA sequencing, metagenomic sequencing, and targeted metabolomics. The microbial and metabolomics profiles were analyzed and compared in antibiotic-treated mice through fecal transfer experiments. H. pylori infection aggravated insulin resistance in diabetic individuals and mice. We identified a unique H. pylori-induced epithelial inflammation and reduced intestinal GLP-1 secretion in the colon. H. pylori infection also interrupts the normal microbial composition in the colon, leading to a decrease in SCFA-producing bacteria and a reduction in acetic and propionate acids. Similar changes were observed in antibiotic-treated mice after receiving fecal transplants from H. pylori-infected diabetic mice. In vitro studies revealed that the intestinal flora of H. pylori-positive diabetic mice inhibited proglucagon transcription, cAMP levels, and GLP-1 secretion in colonic endocrine cells, with SCFA supplementation reversing this effect on GLP-1 production. These microbial, metabolic, and GLP-1 alterations were also seen in antibiotic-treated mice after receiving fecal transplants from H. pylori-infected diabetic mice. H. pylori eradication with antibiotics improved glucose metabolism and GLP-1 secretion to levels comparable to uninfected controls. Our studies offer evidence that H. pylori infection significantly contributes to the progression of glucose impairment and insulin resistance. Therefore, incorporating H. pylori status into preventive strategies for diabetes should be taken into account. (Chinese Clinical Trial Registry Center, ChiCTR2200063489, Registered 08 September 2022, https://www.chictr.org.cn/showproj.html?proj=178102 ).