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

Gastroenterology. 2022 Jan;162(1):135-149.e2. doi: 10.1053/j.gastro.2021.08.041. Epub 2021 Aug 27.


Background and aims: Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites.

Methods: HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy.

Results: HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression.

Conclusions: HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.

Keywords: Colon Cancer; Dietary Nutrient; Gut Products; Microbiome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Azoxymethane
  • Bacteria / drug effects
  • Bacteria / metabolism*
  • Bacterial Translocation
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / ultrastructure
  • Colon / metabolism
  • Colon / microbiology*
  • Colon / ultrastructure
  • Colorectal Neoplasms / chemically induced
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / microbiology*
  • Colorectal Neoplasms / ultrastructure
  • Diet, High-Fat*
  • Disease Models, Animal
  • Dysbiosis
  • Fecal Microbiota Transplantation
  • Feces / microbiology
  • Gastrointestinal Microbiome*
  • Genes, APC
  • Germ-Free Life
  • Humans
  • Lysophospholipids / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Permeability
  • Tumor Cells, Cultured


  • Anti-Bacterial Agents
  • Lysophospholipids
  • Azoxymethane
  • lysophosphatidic acid