Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada.
Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.
Mol Metab. 2022 Jul;61:101498. doi: 10.1016/j.molmet.2022.101498. Epub 2022 Apr 20.
BACKGROUND/PURPOSE: Type 2 diabetes and obesity increase the risk of developing colorectal cancer. Metformin may reduce colorectal cancer but the mechanisms mediating this effect remain unclear. In mice and humans, a high-fat diet (HFD), obesity and metformin are known to alter the gut microbiome but whether this is important for influencing tumor growth is not known.
Mice with syngeneic MC38 colon adenocarcinomas were treated with metformin or feces obtained from control or metformin treated mice.
We find that compared to chow-fed controls, tumor growth is increased when mice are fed a HFD and that this acceleration of tumor growth can be partially recapitulated through transfer of the fecal microbiome or in vitro treatment of cells with fecal filtrates from HFD-fed animals. Treatment of HFD-fed mice with orally ingested, but not intraperitoneally injected, metformin suppresses tumor growth and increases the expression of short-chain fatty acid (SCFA)-producing microbes Alistipes, Lachnospiraceae and Ruminococcaceae. The transfer of the gut microbiome from mice treated orally with metformin to drug naïve, conventionalized HFD-fed mice increases circulating propionate and butyrate, reduces tumor proliferation, and suppresses the expression of sterol response element binding protein (SREBP) gene targets in the tumor.
These data indicate that in obese mice fed a HFD, metformin reduces tumor burden through changes in the gut microbiome.
背景/目的：2 型糖尿病和肥胖症会增加结直肠癌的发病风险。二甲双胍可能会降低结直肠癌的风险，但介导这种效果的机制仍不清楚。在小鼠和人类中，已知高脂肪饮食（HFD）、肥胖和二甲双胍会改变肠道微生物组，但这是否对肿瘤生长有影响尚不清楚。
患有同源 MC38 结肠腺癌的小鼠接受二甲双胍或来自对照或二甲双胍治疗小鼠的粪便处理。
我们发现，与喂食标准饮食的对照相比，当小鼠喂食高脂肪饮食时，肿瘤生长会加快，而这种肿瘤生长的加速可以通过转移粪便微生物组或用高脂肪饮食喂养动物的粪便滤液体外处理细胞来部分重现。用口服给予的二甲双胍而非腹腔内注射治疗高脂肪饮食喂养的小鼠可抑制肿瘤生长并增加短链脂肪酸（SCFA）产生菌 Alistipes、Lachnospiraceae 和 Ruminococcaceae 的表达。从接受口服二甲双胍治疗的小鼠转移的肠道微生物组可增加循环中的丙酸和丁酸，减少肿瘤增殖，并抑制肿瘤中固醇反应元件结合蛋白（SREBP）基因靶标的表达。
这些数据表明，在肥胖的高脂肪饮食喂养小鼠中，二甲双胍通过改变肠道微生物组来减轻肿瘤负担。
