Changes of the fecal metabolome accompany an increase in aberrant crypt foci in the colon of C57BL/6 mice fed a high-fat diet

Authors: Zeng, Huawei; Safratowich, Bryan; CHENG, WEN-HSING - Mississippi State University; Magnuson, Andrew; Picklo, Matthew

Submitted to: Biomedicines
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/6/2022
Publication Date: 11/11/2022
Citation: Zeng, H., Safratowich, B.D., Cheng, W., Magnuson, A.D., Picklo, M.J. 2022. Changes of the fecal metabolome accompany an increase in aberrant crypt foci in the colon of C57BL/6 mice fed a high-fat diet. Biomedicines. 10(11). Article 2891. https://doi.org/10.3390/biomedicines10112891.
DOI: https://doi.org/10.3390/biomedicines10112891

Interpretive Summary: Colon cancer is a major public health issue in the US, with approximately 140,000 new cases and 50,000 deaths per year. Obesity has emerged as one of the leading environmental risk factors for colon cancer development as supported by epidemiological studies as well as controlled experimental animal studies. Our recent studies have shown that accumulation of excess body fat is associated with inflammation and formation of pre-cancer lesions in the colon. However, little is known about the underlying metabolic basis in the colon. In this mouse model study, we demonstrate that there is an accumulation of certain key lipid species, which may affect the overall lipid metabolism during the tumorigenesis in the colon. These data provide novel insights into obesity-related cancer risk and will be useful for scientists who are interested in the prevention of obesity-related colon cancer.

Technical Abstract: High-fat diet (HFD)-induced obesity is a risk factor for colon cancer. Our previous data show that a HFD (45% versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation and microbial dysbiosis in C57BL/6 mice. To explore the underlying metabolic basis, we hypothesize that AOM treatment triggers a different fecal metabolomic profile in C57BL/6 mice fed the HFD or the AIN. We found that 65 of 196 identified metabolites were significantly different among the 4 groups of mice (AIN, AIN+AOM, HFD, HFD+AOM). A sparse partial least-squares discriminant analysis (sPLSDA) showed that concentrations of 9 fecal lipid metabolites were increased in the HFD+AOM compared to the HFD, which played a key role in overall metabolome group separation. These 9 fecal lipid metabolite concentrations were positively associated with the number of colonic ACF and abundance of dysbiotic bacteria. These data suggest that the process of AOM-induced ACF formation may increase selective fecal lipid concentrations in mice fed a HFD but not AIN. Collectively, the accumulation of these critical fecal lipid species alters the overall metabolome during the tumor-igenesis in the colon.