Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance

Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We find that microbial metabolites from healthy mice or humans are growth-repressive, and this response is attenuated in mice and patients with CRC. Microbial profiling reveals that Lactobacillus reuteri and its metabolite, reuterin, are downregulated in mouse and human CRC. Reuterin alters redox balance, and reduces proliferation and survival in colon cancer cells. Reuterin induces selective protein oxidation and inhibits ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricts colon tumor growth, increases tumor reactive oxygen species, and decreases protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange. [Display omitted] •Microbial metabolites from the healthy colon inhibit colon tumorigenesis•Lactobacillus reuteri and reuterin levels are reduced in mouse and human colon cancer•Reuterin induces protein oxidation and inhibits ribosomal biogenesis•L. reuteri and reuterin decrease tumor growth and prolong survival in mice Colon cancer has a significantly altered microbiome that promotes tumor growth. Bell et al. identified a decrease in anti-tumor bacteria Lactobacillus reuteri in colon cancer. L. reuteri inhibits colorectal cancer by inducing oxidative stress and inhibiting protein translation. Recolonization with L. reuteri increases survival in multiple colon tumor models.