UMD, UMB Scientists Find Unexpected Bacterial Links to Diarrhea

In rich countries, it’s largely an unpleasant nuisance: diarrhea. But in low-income countries, the illness kills 760,000 children a year—more than AIDS, malaria and measles combined. In about half of cases, the exact microbe that causes the illness is unknown. But a new study by University of Maryland researchers has identified some unexpected bacterial suspects.

The results, produced through the use of sophisticated genetic sequencing, could open up new strategies for preventing and treating the diarrhea, including some that might be relatively simple to implement. The findings appeared in a paper published last week in the journal Genome Biology.

“We were trying to find new bad guys, and we think we did,” says Mihai Pop, a computer scientist at the University of Maryland Institute for Advanced Computer Studies in College Park, who worked with O. Colin Stine, a geneticist and epidemiologist at the UM School of Medicine in Baltimore.

Funded by a six-year, $10.1 million grant from the Bill & Melinda Gates Foundation, the pair took a new approach to analyzing data about 26,000 different types of bacteria present in fecal samples from 992 children under the age of 5 in Bangladesh, Kenya, Mali and The Gambia. About half of the children had diarrheal disease, and through a complex process of elimination, the scientists zeroed in on the bacteria more abundant in the sick children than in those who didn’t have diarrhea.

Besides identifying the usual culprits, which include such strains as E. coli, Shigella and Campylobacter jejuni, Pop, Stine and their colleagues also found links to several bacteria not previously associated with diarrhea, including Streptococcus pneumoniaeand Granulicatella.

“No one had seen strep associated with diarrhea,” Pop says. “That’s a new thing.”

They also found that children who had large numbers of other bacteria, such as Prevotella and Lactobacillus ruminis, seemed to be resistant to getting diarrhea. Stine says these bacteria may keep illness at bay by crowding out other harmful microbes. Children with large amounts of Prevotella, for instance, had lower levels of Strepand E. coli. “All of these bacteria are competing for space,” says Stine.

For Stine, the most surprising discovery was the profusion of harmful bacteria in the intestinal tracts of children in the developing world. Even those who didn’t have diarrhea had an abundance of pathogens; the difference between those who were sick and those who weren’t was primarily in the quantity of these microbes. By contrast, the presence of even a small number of bad bacteria would sicken a child in a developed country. This suggests that in developing countries, humans have become somewhat acclimated to harmful bacteria, because these microbes are widespread.

The results could lead to changes in the fight against diarrheal disease. For instance, antibiotics typically prescribed now don’t work against strep, but if the study findings hold up, doctors might also prescribe antibiotics that do, Pop says. Researchers could also modify their work on vaccines to prevent diarrheal illnesses in response to the newly discovered diarrheal triggers.

In addition, the researchers discovered hundreds of new kinds of bacteria not listed in current databases—new species. While these microbes did not appear to play a crucial role in these diarrhea cases, they add to the overall understanding of the human gut, Stine says.

In the developing world, diarrhea is caused mostly by contaminated food and water. About 780 million people lack access to clean drinking water, and a staggering 2.5 billion don’t have adequate sanitation, according to the World Health Organization. In low-income countries, the average child under 3 has a case of diarrhea every four months. A child with diarrhea is 8.5 times more likely to die in the next 90 days than a child without diarrhea

Stine’s and Pop’s research is part of the Global Enterics Multicenter Study (GEMS), a $20 million study commissioned by the Gates Foundation in 2006. GEMS, which is led by researchers at the University of Maryland Medical Center, is the most comprehensive study ever of diarrheal disease in the developing world; it aims to produce a thorough understanding of the illness. It includes more than 22,500 young children in seven developing countries in Africa and South Asia.

“Finding unrecognized pathogens is essential,” says Ibrahim Khalil, the program officer in charge of diarrheal disease at the Gates Foundation. “It’s been very challenging to determine which are the most important causes of diarrhea.”

The Maryland researchers, who are also getting support from the MPowering the State initiative between the two University of Maryland campuses, are now focusing on unraveling exactly how various kinds of bacteria cause diarrhea, as well as how the different microbes interact in the gut.

“There’s a huge community of bacteria in us and on us. We need to learn more about them,” says Pop. “It’s a challenge, turning the messiness of nature into clear and comprehensible information.”