New Pathogen Discovery in Travelers’ Diarrhea by Metagenomic Sequencing

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Diarrheal disease affects one billion people per year worldwide, yet >80% of these cases are of unknown etiology. Travelers’ diarrhea or TD, affects between 20 to 60% of those who travel from developed to low-income countries and impacts 20-40 million travelers worldwide each year. Bouts of travelers’ diarrhea can predispose to development of post-infectious irritable bowel disease (IBD). The travelers are often immunologically naïve to the pathogens that they encounter in the food and water they consume, and some possess genetic polymorphisms that predispose them to TD. Thus, these travelers are sentinels, or barometers, for the presence of pathogens in their host locale; these same pathogens are causes of local pediatric diarrheas.

“Pathogen negative” TD remains an enigma, although this may not be surprising since only a few percent of the bacteria, in or on the human body, have been cultivated, and many of the organisms within the human gut are obligate anaerobes. With few exceptions, most of the bacterial agents implicated in TD are cultivable facultative anaerobes. The failure to associate a pathogen with cases of TD is also be due to non-specific virulence gene assays that yield false negatives and the result of limited assays directed against known viruses and parasites.

We are leveraging the power of deep metagenomic sequencing of DNAs isolated from “pathogen negative” stool samples from TD subjects to identify pathogens and pathogen signatures that could lead to hypothesis-based microbiological and clinical investigations into the etiological nature of unidentified pathogen travelers’ diarrhea. “Pathogen negative” and control healthy traveler samples are being sequenced on the Illumina HiSeq platform and metagenomic sequences assembled and reads mapped to reference genome sequences and a new database of enteric pathogen signatures. The database contains genes, microbial genomes and other features predicted to be associated with diarrheal agents and will be an ongoing resource for data mining for new diarrheal agents.

Funding for this project was provided through the National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health.