The proposed project will explore the hypothesis that chronic exposure to microbially-produced DNA damaging toxins such as hydrogen sulfide lead to an increased risk of colorectal cancer. According to this hypothesis, sulfate-reducing bacteria (SRBs) in colon can therefore lead to colon cancer unless their ability to generate hydrogen sulfide is attenuated by a competing metabolism such as methanogenesis. To test this, we will combine metabolic, regulatory, and evolutionary modeling with high throughput genomic technologies to explore the relationship between SRBs, methanogens, and the gastrointestinal microbial community in colorectal cancer and normal colonoscopy patients. We propose to conduct metagenome sequencing and assembly to study the possible interactions between the microbiome and hydrogen sulfide production based on the metabolic and regulatory networks of both microbes and tumors. If successful, we will have generated models that are capable of predicting the levels of various metabolite byproducts including toxic DNA damaging agents that impact the incidence of CRC and quantified the relationship between DNA damage and multiple subtypes of cancer.

Public Health Relevance

Colorectal cancer is common (142,570 new cancers annually) and lethal (51,370 cancer deaths each year), and has plausible connections to several microbial agents. If our hypotheses are proven correct, we can identify microbiomes that cause cancer and find ways to quantify that risk by using a combination of modern computational and sequencing techniques and attenuate that risk my manipulating the gut microbiome using antibiotics, probiotics, or prebiotics. This would radically change the way colon cancer is treated

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA179243-01A1
Application #
8691176
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (56))
Program Officer
Daschner, Phillip J
Project Start
2014-06-05
Project End
2019-05-31
Budget Start
2014-06-05
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$408,459
Indirect Cost
$122,348
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kang, Silvia S; Jeraldo, Patricio R; Kurti, Aishe et al. (2014) Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener 9:36