<i>A. Muciniphila</i> Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs

Abstract

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 <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>) on colorectal cancer pathogenesis. <i>A. muciniphila</i> abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with <i>A. muciniphila</i> suppressed colonic tumorigenesis in <i>Apc^Min/+</i> mice and the growth of implanted HCT116 or CT26 tumors in nude mice. Mechanistically, <i>A. muciniphila</i> facilitated enrichment of M1-like macrophages in an NLRP3-dependent manner <i>in vivo</i> and <i>in vitro</i>. As a consequence, NLRP3 deficiency in macrophages attenuated the tumor-suppressive effect of <i>A. muciniphila</i>. In addition, we revealed that TLR2 was essential for the activation of the NF-κB/NLRP3 pathway and <i>A. muciniphila</i> induced M1-like macrophage response. We observed positive correlations between M1-like macrophages, NLRP3/TLR2 and <i>A. muciniphila</i> in patients with colorectal cancer, which corroborated these findings. In summary, <i>A. muciniphila</i>-induced M1-like macrophages provide a therapeutic target in the colorectal cancer tumor microenvironment.