Reuterin Produced by a Healthy Microbiome Inhibits Colon Cancer Growth

The gut microbiome can generate and signal through metabolites, but how this contributes to colon cancer growth remains unclear. Thus, Bell and colleagues investigated fecal metabolites associated with colon tumorigenesis and indicated those obtained from healthy mice reduced growth and colony formation of colon cancer cell lines as well as induced cell death with similar results observed using healthy human fecal metabolites. Metabolomic analysis identified reuterin, which is produced by Lactobacillus reuteri, a natural colonizer of the human gut, as the most inhibitory compound. L reuteri was the only species reduced in both fecal samples from DoubleMut (Apc and Trp53 inactivation) and TripleMut (APC/p53 knockout with a Kras G12D knock-in allele) colon tumorigenesis mouse models as well as the tumor mucosa of TripleMut mice, with the reduction of this bacterial species being regulated by redox balance and homocysteine degradation. A decrease in reuterin was also observed in human and murine colon cancer, and its presence was found to inhibit in vitro cancer cell growth as well as reduce colony formation and induce cell death of colon cancer cell lines. Moreover, this effect was preferential to cancer cells, as normal colon epithelial cells were significantly less sensitive to reuterin's growth inhibitory effects, which occur through induction of oxidative stress and increasing levels of reactive oxygen species (ROS). Furthermore, supplementation with glutathione or the use of sodium sulfide to prevent protein oxidation diminished reuterin's ability to reduce cell growth, with additional analyses revealing reuterin-induced protein oxidation inhibits ribosomal biogenesis and downstream protein translation, ultimately reducing cancer cell growth in in vitro models. In vivo studies using murine models of colon cancer confirmed the reduction in tumor growth when L. reuteri and reuterin are present through an increase in ROS. This study demonstrates how a healthy microbiome can reduce cancer cell growth through production of several metabolites including reuterin and suggests L. reuteri as a potential probiotic treatment for colorectal cancer.

Bell HN, Rebernick RJ, Goyert J, Singhal R, Kuljanin M, Kerk SA, et al. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell 2021 Dec 23 [Epub ahead of print].

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