A high-fat diet (HFD) may drive colorectal tumorigenesis by inducing gut microbial dysbiosis, metabolomic dysregulation with elevated oncogenic lysophosphatidic acid, and gut epithelial barrier impairment, according to a study in Gastroenterology.
Investigators examined the role of HFD in driving colorectal cancer (CRC) through modulating gut microbiota and metabolites.
The study authors fed 8-week-old male C57BL/6 mice with HFD or control diet (CD). After 1 week, the mice received 6 doses of weekly intraperitoneal injection of azoxymethane (AOM, 10 mg/kg) to mimic sporadic CRC. Their drinking water was supplemented with an antibiotics cocktail (0.2 g/L ampicillin, neomycin, and metronidazole, and 0.1 g/L vancomycin) for 2 weeks, and every other 2 weeks until the end of the study.
The male germ-free BALB/c mice were divided into 2 groups under a CD (6 mice/group) and gavaged once with fecal samples from HFD-fed or CD-fed mice.
Histologic examination of colon sections confirmed that HFD-fed mice had greater proportions of adenocarcinoma and high-grade and low-grade dysplasia vs CD-fed mice (P <.05). Colon sections in the HFD-fed mice had significantly more Ki-67-positive cells, which indicates increased cell proliferation (P <.01). Gut microbiota depletion by antibiotics dramatically decreased colon tumor number and volume in HFD-fed mice (both P <.01), but not in the CD-fed mice.
The HFD-fed mice had a significant shift in gut microbiota composition, with increased pathogenic bacteria Alistipes sp. Marseille-P5997 and Alistipes sp. 5CPEGH6 and depleted probiotic Parabacteroides distasonis, as well as impaired gut barrier function. The HFD-modulated gut microbiota promoted colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota were essential to HFD-associated colorectal tumorigenesis.
Histologic examination of colon sections also confirmed the decreased proportions of adenocarcinoma, high-grade dysplasia, and low-grade dysplasia in antibiotics-treated HFD-fed mice compared with HFD-fed mice without antibiotics (P <.01), concomitant with significantly reduced Ki-67 positive cells (P <.05).
Though studies in humans are still needed, researchers noted, “HFD-modulated gut microbiota could promote colorectal tumorigenesis through elevating oncogenic genes expression and impairing gut barrier function.” “Modulating gut microbiota and metabolites could be a potential therapeutic strategy in the prevention and treatment of HFD-associated CRC,” they concluded.
Yang J, Wei H, Zhou Y, et al. High-fat diet promotes colorectal tumorigenesis through modulating gut microbiota and metabolites. Gastroenterol. Published online August 27, 2021. doi: 10.1053/j.gastro.2021.08.041