Fusobacterium nucleatum promotes liver metastasis in colorectal cancer by regulating the hepatic immune niche and altering gut microbiota

Abstract

Liver metastasis is the major cause of death in colorectal cancer (CRC) patients. Nevertheless, the underlying mechanisms remain unknown. Gut microbiota intricately affect the initiation and progression of CRC by instigating immune response through the secretion of pro-inflammatory cytokines. In this study, we investigated the contribution of Fusobacterium nucleatum (F.nucleatum) to the microbiota-liver axis of CRC in mice, focusing on the correlation between liver immunity and gut microbiota alterations. When F. nucleatum was orally administered to mice, CRC liver metastasis was evidently exaggerated and accompanied by noticeable deleterious effects on body weight, cecum weight, and overall survival time. Further evaluation of the immune response and cytokine profiles revealed a substantial increase in the levels of pro-inflammatory cytokines such as IL6, IL12, IL9, IL17A, CXCL1, MCP-1, TNF-α, and IFN-γ in the plasma of mice treated with F. nucleatum as compared to that in the untreated control mice. Besides, hepatic immune response was also modulated by recruitment of myeloid-derived suppressor cells, reduction in the infiltration of natural killer (NK) and T helper-17 (Th17) cells, as well as increase in regulatory T cell accumulation in the liver. Additionally, sustained F. nucleatum exposure abridged the murine gut microbiota diversity, inducing an imbalanced and restructured intestinal microflora. In particular, the abundance of CRC-promoting bacteria such as Enterococcus and Escherichia/Shigella was evidently elevated post F. nucleatum treatment. Thus, our findings suggest that F. nucleatum might be an important factor involved in promoting CRC liver metastasis by triggering of liver immunity through the regulation of gut microbiota structure and composition.

The crosstalk between the gut microbiota and tumor immunity: Implications for cancer progression and treatment outcomes

“…Administration of Fusobacterium nucleatum aggravated tumor liver metastasis in CRC mice ( 65 ). The plasma levels of proinflammatory cytokines including CXCL1, Eotaxin, IFN-γ, IL-6, IL-9, IL-12, IL-17A, MCP-1 and TNF-α were increased in F .…”

Gut microbiome in gastrointestinal cancer: a friend or foe?

“…The enrichment of F. nucleatum reduced the diversity of gut microbiota in mice leading to dysbiosis of intestinal microbiota. F. nucleatum significantly increased the serum level of proinflammatory cytokines and reduced the cytotoxicity of immune cells to promote liver metastasis in mice [72]. Current data from preclinical and clinical studies pointing to the targeting gut microbiota and gut-liver axis can be used to monitor and prevent the progression of HCC.…”

Effects of gut microbiota on immune responses and immunotherapy in colorectal cancer

“…Meanwhile, cytokines (IL-10, IL-17) secreted by activated M2 macrophage, in turn, promote CRC cells invasion and metastasis by activating NF-κB pathway ( 79 ). Fusobacterium nucleatum can boost liver metastasis by modulating liver microenvironment featured with accumulation of MDSCs, and reduction of NK and Th17 cells ( 80 , 81 ). Peptostreptococcus anaerobius was also reported to induce chronic inflammation and modulate tumor microenvironment by recruiting MDSCs, TANs and TAMs ( 82 ).…”