Functional changes in the gut microbiome contribute to transforming growth factor β-deficient colon cancer

Scott G. Daniel, Corbie L. Ball, David G. Besselsen, Thomas C Doetschman, Bonnie L. Hurwitze

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Colorectal cancer (CRC) is one of the most treatable cancers, with a 5-year survival rate of ∼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 β (TGF-β) type II receptor, yet genotype alone is not responsible for tumorigenesis. Previous work in mice shows that disruptions in TGF-β 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-β 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.

Original languageEnglish (US)
Article numbere00065
JournalmSystems
Volume2
Issue number5
DOIs
StatePublished - Sep 1 2017

Fingerprint

Helicobacter hepaticus
functional change
transforming growth factors
Microbiota
Growth Factors
Polyamines
Transforming Growth Factors
colorectal neoplasms
Colonic Neoplasms
cancer
Cancer
Genotype
digestive system
Colorectal Cancer
Butyrates
Colorectal Neoplasms
Lipopolysaccharides
Tumors
Oxidative Phosphorylation
DNA

Keywords

  • Bioinformatics
  • Butyrate
  • Colon cancer
  • Gut inflammation
  • Gut microbiome
  • Helicobacter hepaticus
  • Host-pathogen interactions
  • Metagenomics
  • Metatranscriptomics
  • Polyamines
  • Smad3

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Genetics
  • Biochemistry
  • Modeling and Simulation
  • Computer Science Applications
  • Ecology, Evolution, Behavior and Systematics
  • Microbiology

Cite this

Functional changes in the gut microbiome contribute to transforming growth factor β-deficient colon cancer. / Daniel, Scott G.; Ball, Corbie L.; Besselsen, David G.; Doetschman, Thomas C; Hurwitze, Bonnie L.

In: mSystems, Vol. 2, No. 5, e00065, 01.09.2017.

Research output: Contribution to journalArticle

Daniel, Scott G. ; Ball, Corbie L. ; Besselsen, David G. ; Doetschman, Thomas C ; Hurwitze, Bonnie L. / Functional changes in the gut microbiome contribute to transforming growth factor β-deficient colon cancer. In: mSystems. 2017 ; Vol. 2, No. 5.
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abstract = "Colorectal cancer (CRC) is one of the most treatable cancers, with a 5-year survival rate of ∼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 β (TGF-β) type II receptor, yet genotype alone is not responsible for tumorigenesis. Previous work in mice shows that disruptions in TGF-β 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-β 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.",
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