Potential Benefits of Metformin Via Roseburia Intestinalis in High-fat Diet-fed Mice With Colorectal Adenomas.

Metformin (Met) is a pharmaceutical agent for the treatment of type 2 diabetes mellitus. Intriguingly, it may also play a role in the gastrointestinal tract, the gut microbial communities, and the tissue-resident immune cells. The present study aimed to investigate whether the administration of Met achieved protective effects on high-fat diet (HFD)-fed mice with colorectal adenomas (CRA) and elucidated its mechanism via the gut microbiota. AOM/DSS was administered in an HFD-induced diet to induce CRA in mice. 16 S rRNA sequencing was conducted to analyze the gut microbiota profile of mice. Met reduced the inflammatory response in the intestine and alleviated HFD-induced intestinal flora disturbances, and Roseburia intestinalis (R. intestinalis) colonization enhanced the efficacy of Met. Met suppressed CRA cell proliferation, which was further reduced by R. intestinalis. Met blocked NF-κB signaling by activating GILZ through increased R. intestinalis abundance. GILZ deletion in macrophages weakened the inhibition of CRA growth by Met and R. intestinalis, leading to increased macrophage M1 polarization. Inhibition of the NF-κB signaling reversed the activation of macrophage M1 polarization by knockdown of GILZ and reduced the proliferation of CRA cells. Our results shed light on the impact of Met on gut microbiome alteration in treating CRA.