High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites

Area of Science:

• Gastroenterology
• Oncology
• Microbiology

Background:

• Dietary fat intake is a known risk factor for colorectal cancer (CRC).
• The mechanisms by which high-fat diets (HFD) influence CRC development are not fully understood.
• Modulation of gut microbiota and metabolites by HFD may play a crucial role in CRC pathogenesis.

Purpose of the Study:

• To investigate the role of HFD in driving CRC.
• To elucidate the impact of HFD on gut microbiota composition and metabolites.
• To determine the effect of HFD on gut barrier function and its contribution to colorectal tumorigenesis.

Main Methods:

• Mice models of colorectal cancer (AOM and Apcmin/+ models) were fed HFD or control diets.
• Antibiotics were used to deplete gut microbiota, and germ-free mice received fecal microbiota transplants.
• Gut microbiota composition, metabolites, and gut barrier integrity were analyzed using metagenomic sequencing, LC-MS, and other methods.

Main Results:

• HFD significantly promoted colorectal tumorigenesis in both mouse models.
• Antibiotic treatment attenuated tumor formation in HFD-fed mice, indicating the importance of gut microbiota.
• HFD induced gut microbial dysbiosis, impaired gut barrier function, and altered metabolite profiles, including elevated lysophosphatidic acid, which promotes CRC cell proliferation.

Conclusions:

• HFD drives colorectal tumorigenesis by inducing gut microbial dysbiosis, metabolic dysregulation, and gut barrier dysfunction.
• Lysophosphatidic acid elevation and gut barrier impairment are key mechanisms linking HFD to CRC.
• Targeting gut microbiota and metabolites may offer therapeutic strategies for HFD-associated colorectal cancer.