Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer
AffiliationUniv Arizona, Dept Mol & Cellular Biol
Univ Arizona, Univ Arizona Canc Ctr
Univ Arizona, Univ Anim Care
Univ Arizona, Dept Cellular & Mol Med
Univ Arizona, BIO5 Inst
Univ Arizona, Dept Agr & Biosyst Engn
MetadataShow full item record
PublisherAMER SOC MICROBIOLOGY
CitationFunctional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer 2017, 2 (5):e00065-17 mSystems
RightsCopyright © 2017 Daniel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractColorectal cancer (CRC) is one of the most treatable cancers, with a 5-year survival rate of similar to 64%, yet over 50,000 deaths occur yearly in the United States. In 15% of cases, deficiency in mismatch repair leads to null mutations in transforming growth factor beta (TGF-beta) type II receptor, yet genotype alone is not responsible for tumorigenesis. Previous work in mice shows that disruptions in TGF-beta signaling combined with Helicobacter hepaticus cause tumorigenesis, indicating a synergistic effect between genotype and microbial environment. Here, we examine functional shifts in the gut microbiome in CRC using integrated - omics approaches to untangle the role of host genotype, inflammation, and microbial ecology. We profile the gut microbiome of 40 mice with/without deficiency in TGF-beta signaling from a Smad3 (mothers against decapentaplegic homolog-3) knockout and with/without inoculation with H. hepaticus. Clear functional differences in the microbiome tied to specific bacterial species emerge from four pathways related to human colon cancer: lipopolysaccharide (LPS) production, polyamine synthesis, butyrate metabolism, and oxidative phosphorylation (OXPHOS). Specifically, an increase in Mucispirillum schaedleri drives LPS production, which is associated with an inflammatory response. We observe a commensurate decrease in butyrate production from Lachnospiraceae bacterium A4, which could promote tumor formation. H. hepaticus causes an increase in OXPHOS that may increase DNA-damaging free radicals. Finally, multiple bacterial species increase polyamines that are associated with colon cancer, implicating not just diet but also the microbiome in polyamine levels. These insights into cross talk between the microbiome, host genotype, and inflammation could promote the development of diagnostics and therapies for CRC. IMPORTANCE Most research on the gut microbiome in colon cancer focuses on taxonomic changes at the genus level using 16S rRNA gene sequencing. Here, we develop a new methodology to integrate DNA and RNA data sets to examine functional shifts at the species level that are important to tumor development. We uncover several metabolic pathways in the microbiome that, when perturbed by host genetics and H. hepaticus inoculation, contribute to colon cancer. The work presented here lays a foundation for improved bioinformatics methodologies to closely examine the cross talk between specific organisms and the host, important for the development of diagnostics and pre/probiotic treatment.
NoteOpen Access Journal.
VersionFinal published version
SponsorsGordon and Betty Moore Foundation [GBMF4491]; Cancer Biology training grant [CA09213]; [HD026471]; [AI067903]; [CA084291]