Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers | Genome Medicine | Full Text

Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers | Genome Medicine | Full Text

Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

• Vanessa L. Hale†,
• Patricio Jeraldo†,
• Jun Chen,
• Michael Mundy,
• Janet Yao,
• Sambhawa Priya,
• Gary Keeney,
• Kelly Lyke,
• Jason Ridlon,
• Bryan A. White,
• Amy J. French,
• Stephen N. Thibodeau,
• Christian Diener,
• Osbaldo Resendis-Antonio,
• Jaime Gransee,
• Tumpa Dutta,
• Xuan-Mai Petterson,
• Jaeyun Sung,
• Ran Blekhman,
• Lisa Boardman,
• David Larson,
• Heidi Nelson and
• Nicholas ChiaEmail authorView ORCID ID profile

†Contributed equally

Genome Medicine201810:78

https://doi.org/10.1186/s13073-018-0586-6

©  The Author(s). 2018

• Received: 13 June 2018
• Accepted: 8 October 2018
• Published: 31 October 2018

Abstract

Background

Links between colorectal cancer (CRC) and the gut microbiome have been established, but the specific microbial species and their role in carcinogenesis remain an active area of inquiry. Our understanding would be enhanced by better accounting for tumor subtype, microbial community interactions, metabolism, and ecology.

Methods

We collected paired colon tumor and normal-adjacent tissue and mucosa samples from 83 individuals who underwent partial or total colectomies for CRC. Mismatch repair (MMR) status was determined in each tumor sample and classified as either deficient MMR (dMMR) or proficient MMR (pMMR) tumor subtypes. Samples underwent 16S rRNA gene sequencing and a subset of samples from 50 individuals were submitted for targeted metabolomic analysis to quantify amino acids and short-chain fatty acids. A PERMANOVA was used to identify the biological variables that explained variance within the microbial communities. dMMR and pMMR microbial communities were then analyzed separately using a generalized linear mixed effects model that accounted for MMR status, sample location, intra-subject variability, and read depth. Genome-scale metabolic models were then used to generate microbial interaction networks for dMMR and pMMR microbial communities. We assessed global network properties as well as the metabolic influence of each microbe within the dMMR and pMMR networks.

Results

We demonstrate distinct roles for microbes in dMMR and pMMR CRC. Bacteroides fragilis and sulfidogenic Fusobacterium nucleatum were significantly enriched in dMMR CRC, but not pMMR CRC. These findings were further supported by metabolic modeling and metabolomics indicating suppression of B. fragilis in pMMR CRC and increased production of amino acid proxies for hydrogen sulfide in dMMR CRC.

Conclusions

Integrating tumor biology and microbial ecology highlighted distinct microbial, metabolic, and ecological properties unique to dMMR and pMMR CRC. This approach could critically improve our ability to define, predict, prevent, and treat colorectal cancers.