Untargeted metabolomics reveals the inhibition effect of a high-fat diet on colorectal cancer tumorigenesis in obesity-resistant mice via regulating bile acid, glutathione, and glycerophospholipid metabolisms

The interplay between high fat intake and cancer is complex and multifaceted. Contradictory results exist between obesity, high-fat diet (HFD), and colorectal cancer (CRC), necessitating further research. In this study, we investigated the effect of HFD on tumorigenesis in obesity-resistant and obesity-susceptible mouse models. Our results revealed that HFD significantly inhibited CRC HCT116 and HT-29 xenograft tumor growth in obesity-resistant BALB/c nude mice in comparison with a low-fat diet (LFD). HFD feeding did not induce increases in body weight, serum pro-inflammatory cytokines, and lipid accumulation in the liver and white adipose tissue (WAT) in nude mice. However, HFD promoted tumor growth in melanoma B16-F10-bearing C57BL/6J mice, accompanied by obesity and increased pro-inflammatory cytokine levels. Untargeted metabolomics showed that HFD induced significantly changed metabolites in serum, tumor, and liver samples of the HCT116 xenograft model. In all samples, many glycerophospholipids (e.g. LysoPE (0:0/20:1) and LysoPC (16:1)) and bile acids (e.g. glycocholic acid and chenodeoxycholic acid) were significantly reduced by HFD. Enrichment and pathway analyses suggested that bile acid biosynthesis and metabolisms of lipids, amino acids, and organic acids were significantly regulated by HFD. Additionally, the glutathione metabolism was significantly downregulated, while the TCA cycle was upregulated by HFD in tumor samples. Moreover, univariate and multivariate analyses on the differential metabolites in tumors suggested that uracil, chenodeoxycholic acid, glutathione, LysoPE (0:0/20:1), and SM (d18:1/18:0) were the main metabolite biomarkers for discrimination between LFD- and HFD-fed xenograft tumors. These findings suggest that HFD elicits an anti-tumorigenic effect against CRC in obesity-resistant BALB/c nude mice via regulating bile acid, glutathione, and glycerophospholipid metabolisms.