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

Abstract

See Covering the Cover synopsis on page 2; See editorial on page 38.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 Apc min/þ 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 AOMtreated mice and Apc min/þ 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 Alistipes sp. Marseille-P5997 and Alistipes sp. 5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFDmodulated 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.

Gut Microbiota as Regulators of Th17/Treg Balance in Patients With Myasthenia Gravis

“…Accordingly, regulating the immune imbalance of Thl7/Treg cells and inducing the reconstruction of immune tolerance may become a potential treatment modality for autoimmune diseases, such as MG. Studies have revealed that environmental factors, especially dietary factors, can alter the gut microbiota composition and its metabolic activity , which produce adverse implications for human health ( 31 ). For instance, alterations in the gut microbiota caused by a Western high-fat diet have recently been recognized as a major contributing factor to the colorectal cancer epidemic ( 32 ) . High -sucrose- high - fat dietary patterns were supposed to participate in the asthma pathogenesis through intestinal bacteria ( 33 , 34 ).…”

Gut Microbiota and Dietary Factors as Modulators of the Mucus Layer in Inflammatory Bowel Disease

“…Likewise, as pointed by a recent analysis of the relation between dietary factors and the microbiome of healthy volunteers and IBD patients, processed and animal foods are associated with increased abundances of Firmicutes and Ruminococcus species, but plant foods and fish positively influence SCFA-producing commensals and restrain pathobionts, diet thereby influencing a characteristic microbial environment of intestinal inflammation [114]. Furthermore, high-fat diet also drives colorectal tumorigenesis in mice via intestinal dysbiosis, metabolite dysregulation and gut barrier dysfunction [115].…”

Microbial-Driven Immunological Memory and Its Potential Role in Microbiome Editing for the Prevention of Colorectal Cancer

“…Antigen-specific activation of T and B cells imparts the immunological memory to the existing microbiome. their microbial communities have more disease (Yang et al, 2021). Further, the combined effects of the host response and bacteria on intestinal inflammation and CRC were illustrated in a study showing that inoculation of Rag-2-deficient mice with H. hepaticus induced inflammation and colonic tumors (Erdman and Poutahidis, 2017).…”

“…The gut microbiome evolves and diversifies throughout life depending on the type of birth, diet, lifestyle, geographic factors and medications ( Fiorentini et al., 2020 ; Dixit et al., 2021 ). The impact of diet and the microbiota on CRC is evidenced by data showing that mice fed a high fat diet leading to changes in their microbial communities have more disease ( Yang et al., 2021 ). Further, the combined effects of the host response and bacteria on intestinal inflammation and CRC were illustrated in a study showing that inoculation of Rag-2-deficient mice with H. hepaticus induced inflammation and colonic tumors ( Erdman and Poutahidis, 2017 ).…”