Role of gut microbiome in suppression of cancers

Abstract

The pathogenesis of cancer is closely related to the disruption of homeostasis in the human body. The gut microbiome plays crucial roles in maintaining the homeostasis of its host throughout lifespan. In recent years, a large number of studies have shown that dysbiosis of the gut microbiome is involved in the entire process of cancer initiation, development, and prognosis by influencing the host immune system and metabolism. Some specific intestinal bacteria promote the occurrence and development of cancers under certain conditions. Conversely, some other specific intestinal bacteria suppress the oncogenesis and progression of cancers, including inhibiting the occurrence of cancers, delaying the progression of cancers and boosting the therapeutic effect on cancers. The promoting effects of the gut microbiome on cancers have been comprehensively discussed in the previous review. This article will review the latest advances in the roles and mechanisms of gut microbiome in cancer suppression, providing a new perspective for developing strategies of cancer prevention and treatment.

Keywords: Gut microbiome; cancer; suppression.

Figure 1.

The mechanisms of gut microbiome inhibiting the initiation of cancers. A. Modulation of immune homeostasis: (1) Microbiota-derived cyclic di-AMP activates STING-dependent type I IFN production, leading to activation of innate immunity (including monocytes, NK cells and DCs); (2) Clostridium species modified bile acids to signal liver sinusoidal endothelial cells to produce CXCL16, a chemokine that recruits NKT immune cells to perform antitumor surveillance in the liver. B. Inhibition of cancer related gene expression and oncogenic pathways: (1) Butyrate inhibits HDACs, inducing histone hyperacetylation to activate p21/WAF1 and drive G1 arrest; (2) Butyrate activates WAF1 via Sp1 sites (p53-independently), halting cell cycle and tumor proliferation; (3) SCFAs activate GPCRs, such as FFAR3/2 and GPR109A, in gut/immune cells, leading to beneficial effects on cancer prevention. C. Inflammation reduction: Hypoacylated LPS derived from intestinal Prevotella exhibits weak TLR4 excitability and induces inflammatory tolerance in intestinal epithelial cells, thereby inhibiting the onset of CRC. D. Inhibition of cell proliferation and induction of apoptosis: (1) Clostridiales produced TMAO induced GSDME-mediated pyroptosis in tumor cells by activating the endoplasmic reticulum stress kinase PERK and thus enhanced CD8⁺ T cell-mediated antitumor immunity in TNBC. (2) Butyrate induces apoptosis (Bax and Bcl-2) and activates MAPK signaling to suppress proliferation/migration via endocan regulation, inhibiting cancer progression; (3) Certain SCFAs, such as PUFAs, inhibit hepatocellular carcinoma (HCC) growth by blocking β-catenin and cyclooxygenase-2 (COX-2); (4) SCFAs reduce cell viability and induce apoptosis in HCC cell lines through activation of GSK-3β, leading to β-catenin degradation. (E) Direct anti-tumor effects: (1) Firmicutes convert bile acids to lithocholic acid (LCA), which suppresses gallbladder cancer (GBC) by targeting GLS-glutamine metabolism to trigger ferroptosis; (2) Butyrate (Roseburia intestinalis) binds TLR5 on CD8⁺ T cells, activating NF-κB to boost activity; (3) Lactobacillus plantarum L168 and indole-3-lactic acid enhance IL12a production in dendritic cells via H3K27ac enrichment at IL12a enhancers, priming CD8⁺ T cell immunity to suppress tumor growth. (4) Clostridium butyricum inhibits the Wnt/β-catenin pathway, reshapes gut microbiota, elevates SCFAs, and activates GPR43/109A to suppress colorectal tumorigenesis.

Figure 2.

The mechanisms of gut microbiome delaying cancer progression. Clostridium sporogenes-derived IPA suppresses IL-17A in Th17 cells via mTOR/ribosome pathways, while its BCFAs/SCFAs enhance Treg activity and IL-22 production. L. intestinalis effectively suppressed tumor growth in CRC mice through increasing the infiltration of immune cells in the TME, particularly DCs, through NOD1/NF-κB signaling pathway. Lactococcus lactis GEN3013 boosts cytotoxic immune cells (CD4⁺/CD8⁺ T, NK) in TME; Propionates derived from several gut bacteria activate the AMPK/mTOR pathway through the vitamin D receptor (VDR), inhibit glycolysis in CRC cells. Butyrate exerts its inhibitory effects on tumor growth by enhancing CD8⁺ T cell cytotoxicity through GPR109A/HOPX signaling, inducing lung cancer cell cycle arrest (cell cycle proteins/CD90) and apoptosis, modulating thermal apoptosis/metastasis proteins (CD147/VEGF/MMP-9), and reprogramming cancer metabolism via pyruvate accumulation and glycolysis suppression, Butyrate can also curb the tumor cell invasion/migration by modulating proteolysis via suppressing uPA and enhancing TIMP-1/2 activity. Finally, IP6 from yeast/actinomycetes inhibits the expression of liver metastasis-linked Tnfrsf1b by restoring the abundance of L. helveticus/L. lactis.

Figure 3.

Mechanisms of gut microbiome enhancing effects of cancer therapy. Gut microbiota-driven strategies synergize with cancer therapies by reshaping the TME and augmenting ICB efficacy. Key mechanisms include: (1) Probiotics: Beneficial bacteria (e.g., Akkermansia muciniphila, Bifidobacterium spp., Lactobacillus) enhance dendritic cell (DC) maturation, promote CD8⁺ T-cell infiltration, and boost effector functions via cytokine production (IL-12, IFN-γ). (2) Prebiotics: dietary compounds (e.g., inulin, FOS) increase SCFA production (e.g., butyrate) and inhibit regulatory T cells (Tregs). (3) Anti-cancer metabolites: SCFAs (e.g., butyrate) recruit CCR9⁺CXCR3⁺CD4⁺ T cells and enhance CD8⁺ T-cell stemness. Phenolic acids induce tumor cell apoptosis through mitochondrial dysfunction. (4) FMT and engineered microbes: restores microbial diversity in non-responders, upregulates immunomodulatory metabolites (e.g., punicic acid), and synergizes with ICB (anti-PD-1/CTLA-4) to improve survival. (5) traditional Chinese medicine (TCM): formulations like Wenzi Jiedu recipe remodel gut microbiota, elevate CD8⁺ T-cell proportions, and suppress colorectal cancer (CRC) progression via immune-associated cytokine.