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 found that microbial metabolites from healthy mice or humans were growth-repressive, and this response was attenuated in mice and patients with CRC. Microbial profiling revealed that Lactobacillus reuteri and its metabolite, reuterin were downregulated in mouse and human CRC. Reuterin altered redox balance, and reduced survival, and proliferation in colon cancer cells. Reuterin induced selective protein oxidation, and inhibited ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricted mouse colon tumor growth, increased tumor reactive oxygen species, and decreased protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange. Overall design: 16s rRNA-sequencing of FECES from 16 CRE negative (control), 11 APC/p53 KO (Double mutant), and 14 APC/p53 KO + KrasG12D knock-in (Triple mutant). They are futher subdivided into early/late fecal samples (CRE: 8/8, Double: 5/6, Triple: 7/7). 16s rRNA sequencing of COLONIC TISSUE from 8 CRE negative (control), 7 APC/p53 KO (DoubleMut) and 10 APC/p53 KO w/ Kras G12D knock in (Triple mut) where early is pre-tamoxifen injection and late is 10 days following tamoxifen injection. COLONIC TISSUE collected 10 days following tamoxifen injection.