Dynamics of Gut Microbiota-Pathogen Interactions and Acquisition of Antibiotic Resistance During Travel to High Infectious Burden Regions
Abstract
Key Problem: Infectious diarrhea threatens deployed military personnel. Due to the mission-aborting potential of infectious diarrhea, the U.S. military prioritized the development of vaccines against common diarrheal disease-causing microorganisms. A vaccine would be cost-effective and may prevent post-infection health problems such as irritable bowel syndrome. Without such a vaccine, antibiotics remain the current standard-of-care for diarrhea. Rapidly increasing antibiotic resistance in human pathogens is a global public health disaster, especially in areas of high infectious disease burden where many military personnel are deployed. Like pathogens, antibiotic resistance genes are often acquired by travel to countries where such genes are prevalent. Furthermore, antibiotic resistance gene acquisition increases the likelihood that subsequent infections (both during deployment and upon return) are resistant to antibiotic treatments. Unfortunately, our understanding of diarrheal disease development and antibiotic resistance gene acquisition during travel is limited. For example, two people may harbor the same diarrheal pathogen, but one person may develop severe diarrhea while the other remains asymptomatic. There is increasing evidence that natural gut bacterial communities (the gut microbiota), which contain trillions of bacteria, play a protective role against diarrhea-causing pathogens. Unfortunately, most existing studies on diarrhea-causing bacteria only focus on easily culturable bacteria such as E. coli and neglect the members of the gut microbiota that cannot be easily cultured in the lab. These uncultivated bacteria often account for a large fraction of gut bacteria and may play a critical role in host susceptibility or resilience to diarrheal infection, potentially explaining the differences in disease presentation and severity seen in groups harboring the same diarrheal pathogens. Given the burden of diarrhea, the risks posed by antibiotic resistance, and the importance of the gut microbiota in maintaining host health, it is critical to understand how these three phenomena are interrelated and to apply this understanding to prevent the spread of diarrhea and antibiotic resistance in international travelers and military personnel. Approach: To achieve this goal, we have enrolled over 200 international travelers who either developed diarrhea or remained asymptomatic during their time abroad. From both groups, we have collected stool samples of their gut microbiota over time and isolated diarrheal pathogens from these samples. By directly sequencing billions of base pairs of DNA from each stool sample, we can capture all members of the bacterial community in the sample (metagenomes) in addition to genome sequences of diarrheal pathogens. We will also utilize a technology by which genes from metagenomes are captured and tested in high-throughput for their ability to confer antibiotic resistance in a model pathogen. Using this method, we will identify antibiotic resistance genes from travelers’ gut bacterial communities without the need to grow thousands of bacterial species. All the diarrheal pathogen genome data, metagenomes, and antibiotic resistance genes will then be mapped back to each unique patient and correlated with our extensive clinical metadata. Finally, we will perform computational analyses on these genetic and functional data and develop models to identify risk factors for the development of diarrhea and acquisition of antibiotic resistance genes during travel. Impact: The chief deliverable of our proposed work is an increased understanding of factors altering the gut microbiota during travel and how these factors affect travelers’ risk of developing diarrhea. We will first assess how traveling to resource-limited regions, where there is high burden of infectious diarrhea, changes the composition of the intestinal microbial community. We will evaluate these dynamics in patie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810225
Entities
People
- Gautam Dantas
Organizations
- United States Army
- Washington University in St. Louis