Journal
CANCER IMMUNOLOGY RESEARCH
Volume 9, Issue 10, Pages 1111-1124Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-1019
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Funding
- National Natural Science Foundation of China [82072623]
- Natural Science Foundation of Zhejiang [LGD21H160002]
- National Key R&D Program of China [2016YFC1303200]
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The study identified a link between reduced abundance of A. muciniphila and colorectal cancer; supplementation with A. muciniphila suppressed colonic tumorigenesis; A. muciniphila induced M1-like macrophages may serve as a therapeutic target in the colorectal cancer tumor microenvironment.
The interplay between gut microbiota and the host immune system is emerging as a factor in the pathogenesis of colorectal cancer. Here, we set out to identify the effect of Akkermansia muciniphila (A. muciniphila) on colorectal cancer pathogenesis. A. muciniphila abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with A. muciniphila suppressed colonic tumorigenesis in Apc(Min/+) mice and the growth of implanted HCT116 or CT26 tumors in nude mice. Mechanistically, A. muciniphila facilitated enrichment of M1-like macrophages in an NLRP3-dependent manner in vivo and in vitro. As a consequence, NLRP3 deficiency in macrophages attenuated the tumor-suppressive effect of A. muciniphila. In addition, we revealed that TLR2 was essential for the activation of the NF-kappa B/NLRP3 pathway and A. muciniphila induced M1-like macrophage response. We observed positive correlations between M1-like macrophages, NLRP3/TLR2 and A. muciniphila in patients with colorectal cancer, which corroborated these findings. In summary, A. muciniphila induced M1-like macrophages provide a therapeutic target in the colorectal cancer tumor microenvironment.
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