Digestive Diseases News
Fall 2009

NIH Funds DNA Sequencing Centers and Pilot Projects to Study Influence of Microorganisms on Human Health and Disease
Pilot Projects Will Investigate Relationships to Digestive Diseases

While a great deal is known about disease-causing pathogens, relatively little is known about the seemingly innocuous microorganisms living in and on the human body. Called the microbiome, this microbial community outnumbers the body’s own cells by a factor of 10. Mounting evidence suggests the microbiome plays a bigger role in human health and disease than previously thought.

Human Microbiome Sequencing Centers

In June, the National Institutes of Health (NIH) awarded additional funds to the Human Microbiome Project’s (HMP’s) ambitious 5-year effort to sequence the DNA of about 400 human-associated microorganisms. These microbial “genomes” will be added to the 500 or so that have already been or are in the process of being sequenced.

The net result will be a reference database that researchers can use to study associations between human-associated microorganisms and diseases, including digestive diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and esophageal cancer.

“This effort will accelerate our understanding of how our bodies and microorganisms interact to influence health and disease,” said Raynard S. Kington, M.D., Ph.D., NIH deputy director.

The HMP is sequencing microbial DNA collected from five areas of the body: the digestive tract, the mouth, the skin, the nose, and the vagina. HMP-funded sequencing centers include

• The Human Genome Sequencing Center, Baylor College of Medicine, Houston
• The Washington University Genome Sequencing Center, Washington University School of Medicine, St. Louis
• The J. Craig Venter Institute, Rockville, MD

The Broad Institute of the Massachusetts Institute of Technology and Harvard, which previously participated in the project, is also expected to participate in this phase of the project.

Pilot Projects

The HMP also received funding for several pilot projects to compare the microbiomes of healthy people with those of people with specific diseases affecting the mouth, nose, skin, vagina, male urethra, blood, and digestive tract.

“Examining differences between the microbiomes of healthy people and people suffering from disease promises to change how we diagnose, treat, and ultimately prevent many health conditions,” said Kington.

Each pilot project will be reviewed after 1 year to evaluate its progress and its ability to demonstrate a definable relationship between a body site microbiome and disease.

Phillip I. Tarr, M.D., of the Washington School of Medicine in St. Louis, and colleagues have received HMP funding to examine the connection between the intestinal microbiome and necrotizing enterocolitis (NEC), a potentially lethal intestinal disorder common among premature infants.

What causes NEC is unknown, but some research has shown that giving probiotics— “friendly” bacteria—to at-risk infants reduces the incidence and severity of NEC, suggesting certain microorganisms guard against NEC.

“NEC provides a unique opportunity to explore the role of the human enteric microbiome in a devastating disease,” said Tarr. “It affects a readily identifiable at-risk group and occurs in an organ system that is intimately associated with a microbial population in flux.”

Tarr; Barbara B. Warner, M.D., a neonatologist at Washington University who has studied NEC for many years; and their colleagues will examine and compare the microbial contents of stool samples from premature infants before NEC onset and in unaffected controls. Tarr’s group will use metagenomic and targeted sequencing to characterize the nucleic acids in the euteric biomass in these at-risk children. Tarr’s group will also compare the infants’ DNA, looking for gene variants that suggest predisposition to NEC.

Tarr anticipates the project, titled “The Gut Microbiome in Development, Health, and Disease,” will enable development of a data repository for investigators worldwide to study NEC and catalyze efforts to find better treatments.

Three HMP pilot projects will evaluate the relationship between the microbiome and IBD, which causes chronic, bloody diarrhea and painful sores in the tissues lining the gastrointestinal tract.

Two pilot projects will study people with Crohn’s disease, a type of IBD that can occur at any point along the digestive tract. An additional IBD pilot project will study patients who have undergone surgery for ulcerative colitis, a type of IBD that is limited to the large intestine.

The titles of the HMP-funded IBD pilot projects and the projects’ principal investigators are

• “Diet, Genetic Factors, and the Gut Microbiome in Crohn’s Disease,” Gary D. Wu, M.D., University of Pennsylvania School of Medicine, Philadelphia
• “Effect of Crohn’s Disease Risk Alleles on Enteric Microbiota,” Ellen Li, M.D., Ph.D., Washington University School of Medicine, St. Louis
• “The Role of the Gut Microbiota in Ulcerative Colitis,” Vincent B. Young, M.D., Ph.D., University of Michigan, Ann Arbor

Zhiheng Pei, M.D., Ph.D., of the New York School of Medicine, and colleagues have received HMP funding to study the relationship between the microbiome and the development of esophageal adenocarcinoma, a type of cancer linked to gastroesophageal reflux disease (GERD). Rates of esophageal adenocarcinoma, which can be difficult to detect and treat, have dramatically increased during the past 30 years.

Pei’s preliminary studies of male veterans suggest men harbor one of two distinct types of esophageal microbial populations. Veterans in the study with type II esophageal microbiota were 15 times more likely to have esophagitis and Barrett’s esophagus—precursors to esophageal adenocarcinoma— than those with type I esophageal microbiota.

The pilot project, titled “Foregut Microbiome in Development of Esophageal Adenocarcinoma,” will sample microbial populations of the mouth, esophagus, and stomach and characterize changes that occur with the progression of GERD.

James Versalovic, M.D., Ph.D., of the Baylor College of Medicine in Houston, has received HMP funding for his pilot project, “The Intestinal Microbiome in Pediatric Irritable Bowel Syndrome” to test the hypothesis that children have a core microbiome and that children with IBS carry microbial populations that represent unique disease signatures.

NIH Roadmap

The HMP is part of the NIH Roadmap for Medical Research, which, through a series of initiatives, addresses major opportunities and gaps in biomedical research that no single NIH Institute can tackle alone. The HMP is managed by several Institutes, including the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

For more information about the HMP, visit www.hmpdacc.org and www.nihroadmap.nih.gov/hmp.

The NIDDK has patient information about digestive diseases. Fact sheets and easy-to-read booklets are available at www.digestive.niddk.nih.gov.

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NIH Publication No. 10–4552
October 2009