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

Hannah N Bell; Ryan J Rebernick; Joshua Goyert; Rashi Singhal; Miljan Kuljanin; Samuel A Kerk; Wesley Huang; Nupur K Das; Anthony Andren; Sumeet Solanki; Shannon L Miller; Peter K Todd; Eric R Fearon; Costas A Lyssiotis; Steven P Gygi; Joseph D Mancias; Yatrik M Shah

doi:10.1016/j.ccell.2021.12.001

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

Cancer Cell. 2022 Feb 14;40(2):185-200.e6. doi: 10.1016/j.ccell.2021.12.001. Epub 2021 Dec 23.

Authors

Hannah N Bell¹, Ryan J Rebernick², Joshua Goyert¹, Rashi Singhal¹, Miljan Kuljanin³, Samuel A Kerk¹, Wesley Huang¹, Nupur K Das¹, Anthony Andren¹, Sumeet Solanki¹, Shannon L Miller⁴, Peter K Todd⁵, Eric R Fearon⁶, Costas A Lyssiotis⁷, Steven P Gygi⁸, Joseph D Mancias⁹, Yatrik M Shah¹⁰

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; VA Ann Arbor HealthCare System, Ann Arbor, MI 48109, USA.
⁶ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁹ Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].

Abstract

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.

Keywords: Lactobacillus reuteri; Microbiome; Reuterin; colorectal cancer; metabolites; protein oxidation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers
Cell Line, Tumor
Cell Proliferation / drug effects
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology*
Disease Models, Animal
Energy Metabolism
Gastrointestinal Microbiome*
Glutathione / metabolism
Glyceraldehyde / analogs & derivatives*
Glyceraldehyde / metabolism
Glyceraldehyde / pharmacology
Host Microbial Interactions
Humans
Intestinal Mucosa / metabolism
Intestinal Mucosa / microbiology
Intestinal Mucosa / pathology
Metabolomics / methods
Metagenomics / methods
Mice
Models, Biological
Oxidation-Reduction* / drug effects
Oxidative Stress
Propane / metabolism*
Propane / pharmacology
Signal Transduction
Xenograft Model Antitumor Assays

Substances

Biomarkers
3-hydroxypropionaldehyde
Glyceraldehyde
Glutathione
Propane

Abstract

Publication types

MeSH terms

Substances

Grants and funding