High-fat-diet–induced modulations of leptin signaling and gastric microbiota drive precancerous lesions in the stomach

•A high-fat diet (HFD) induces rapid dysbiosis and intestinal metaplasia, which are precancerous lesions of the stomach with increased gastric leptin.•Gastric dysbiosis has limited effect on the onset of intestinal metaplasia.•A HFD does not decrease microbial abundance in db/db mice with mutated leptin receptor.•The loss of leptin receptor in the gastrointestinal tract attenuates the effects of a HFD on dysbiosis and intestinal metaplasia. Obesity is a risk factor for malignancy in various tissues, and has been associated with gut microbiota alterations. However, the link between obesity-associated microbiota and gastric pathogenesis has not been clarified. We demonstrated that high-fat-diet (HFD) feeding causes intestinal metaplasia, which are precancerous lesions of the stomach, with augmented gastric leptin signaling. The aim of this study was to investigate the precise role of leptin signaling in the altered microbiota composition and pathogenesis in the stomach during diet-induced obesity. Male C57 BL/6 J, leptin receptor (Lepr)-mutated db/db, and gastrointestinal epithelium-specific Lepr conditional knockout (T3 b-Lepr cKO) mice were fed a HFD or control diet. Gastrointestinal microbiota was analyzed by 16 S rRNA gene sequences and quantitative polymerase chain reaction. Transplantation of gastric microbiota of HFD-fed mice was performed to evaluate metaplasia onset in recipient mice. One week of HFD caused severe microbial dysbiosis in the stomach. The microbiota changes were accompanied by increased gastric leptin, leading to the consequent development of intestinal metaplasia. Transplantation of gastric microbiota from HFD-fed mice induced intestinal metaplasia in recipient mice; however, only a limited effect on pathogenesis was noted. HFD-fed db/db mice did not show a decrease in microbial abundance. Moreover, T3 b-Lepr cKO mice failed spontaneous obesity, and suppressed decreased abundance of gastric microbiota and occurrence of intestinal metaplasia during HFD feeding similar to db/db mice. Gastric leptin signaling modulates the gastric microbiota community and regulates the pathogenesis in the gastric mucosa.