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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. [Display omitted] • Oral but not intraperitoneal injection of metformin is associated with changes in the gut microbiome and reductions in MC38 tumor cell growth in mice fed a high-fat diet. • Transferring feces from mice treated with oral metformin into metformin naïve mice inhibits tumor growth independently of changes in body mass, blood glucose or serum insulin. • Metformin fecal transfers to metformin naïve mice leads to increased abundance of short chain fatty acid producing microbes. • Metformin fecal transfers reprogram tumor metabolism reducing the expression of SREBP and cholesterol synthesis genes. [ABSTRACT FROM AUTHOR]

Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia. [Display omitted] • Thermoneutrality, fat, and fructose elicit genomic/histological features of NASH • Inhibiting hepatocyte ACLY reduces lipogenesis, gluconeogenesis, and dyslipidemia • ACLY inhibition in hepatic stellate cells reduces their activation and proliferation • Pharmacological inhibition of ACLY reduces NASH and fibrosis in mice Morrow et al. establish a translational mouse model of NASH and find that inhibition of ATP-citrate lyase (ACLY) in hepatocytes increases fatty acid oxidation and reduces gluconeogenesis as well as serum and liver lipids. Pharmacological inhibition of ACLY reduces liver fibrosis and the activation and proliferation of hepatic stellate cells. [ABSTRACT FROM AUTHOR]