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Discovering the causes of cancer and the means of prevention

The Human Microbiome and Cancer

Rendering of the microbiome depicts many small microorganisms in the shape of a human form.

The microbiome is comprised of microorganisms that live in and on us and contribute to human health and disease.

Credit: Darryl Leja, NHGRI

The microbiome refers to the collection of all of the gene sequences from a community of microbes in the human body. High-throughput DNA amplification and sequencing technologies to characterize the microbial communities provide data for investigations of microbial associations with human disease. Our goal is to establish cohorts with fecal and oral specimens to prospectively evaluate the association between the human microbiome and cancer risk.

While microbiome research has grown exponentially over the past several years, findings have been difficult to reproduce across studies. The variability induced by sample collection and handling has not been systematically assessed. DCEG investigators are pursuing a multi-pronged approach to address microbiome methodologic issues.

Methods Development

Sample collection: DCEG investigators are evaluating and standardizing fecal and oral sample collection protocols to reliably measure the human microbiome in the context of large-scale population studies. Several issues are being considered, such as, preservation of a microbial signature, stability of samples under field conditions, and preservation of samples to maximize multi ‘omics assays.

Standard reference materials: It is crucial to develop appropriate standard reference materials for quality control of samples in large epidemiologic studies. DCEG investigators have developed two types of standards, chemostat produced in an artificial gut system, also called a “Robogut,” and artificial communities with known bacterial mixtures. Negative controls are equally critical; the need to include them in studies is also being evaluated.

Microbiome Quality Control (MBQC) project: The degree of standardization in microbiome measurement necessary for translation to large-scale studies is early in its development. Sources of variation in microbial profiling must be evaluated and optimized so that independent epidemiologic studies can be pooled. DCEG investigators helped coordinate and conduct the MBQC study, a collaborative effort designed to comprehensively evaluate methods for measuring the human microbiome. The MBQC study evaluated the impact of various DNA extraction, sequencing, and bioinformatics methods for fecal samples.

Feasibility of setting up cohort studies: Large, prospective, population-based cohorts are well suited to address numerous important epidemiologic questions about the pathophysiology of human diseases. Given the growing understanding of the role of human microbiome in diverse health conditions, it is imperative to implement an appropriate sample collection strategy. DCEG investigators are conducting numerous feasibility studies to evaluate whether fecal and oral samples can be collected in existing cohorts, prepaid health plans, or screening populations.

Etiologic Studies

Prospective study of the oral microbiome and cancer: Poor oral health and periodontal pathogens have been associated with a number of cancers, mortality, and other chronic diseases, which suggests a role for the oral microbiome in the development of these conditions. DCEG investigators are assessing the association between the oral microbiome and incident cancers of the bronchus/lung, colorectum, esophagus, head/neck, hepatobiliary tract, pancreas, small intestine and stomach, using a case-cohort design within a number of existing cohorts. This multi-cancer, multi-cohort project will allow us to test several hypotheses simultaneously, provide greater insight into the role of the oral microbiome in cancer at several sites, and allow us to evaluate common mechanisms across cancer sites.

Lower gastrointestinal cancer studies: The association between the human gut microbiome and colorectal cancer (CRC) is an important focus of our research. In a case-control study with data and fecal specimens previously collected in DCEG, we found that CRC cases had reduced fecal microbiome alpha diversity, increased carriage of Fusobacterium and Porphyromonas taxa, and reduced abundance of Clostridia taxa. Metabolomic analysis of the same specimens uncovered 41 small molecules that differed between cases and controls, providing potentially improved diagnostic methods or insights on carcinogenesis. Metagenome analyses of associations with CRC and with fecal metabolites corroborated the 16S analyses.

Upper gastrointestinal cancer studies: Gastric cancer is currently the model of bacterially associated cancer; Helicobacter pylori has been classified as carcinogenetic in humans by the International Agency for Research on Cancer. Research within DCEG has evaluated how risk factors for cancer, such as tobacco, body mass index, and pepsinogen levels, are associated with microbial diversity using samples collected in China. We found that among participants with esophageal squamous dysplasia, participants at greater risk for gastric cancer (low pepsinogen I/II ratio) had lower microbial richness than those at lower risk for gastric cancer. Associations were also detected with smoking history and body mass index in these samples. Ongoing studies are being conducted to further evaluate the impact of the oral microbiome on upper gastrointestinal cancer risk.

For more information, contact Rashmi Sinha.

Metabolic Epidemiology Branch – Research Areas