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Natural, Engineered Microbes Shown to Control Cholera

Distributing water hygiene kits

Distributing water hygiene kits during a cholera outbreak in Haiti (USAID.gov)

14 June 2018. A combination of natural bacteria found in milk products and a synthetic variation of those microbes are shown in tests with lab mice to detect and prevent cholera infections. A team from the Wyss Institute, a biomedical engineering center at Harvard University, describes its discoveries in yesterday’s issue of the journal Science Translational Medicine.

According to World Health Organization, from 1.3 to 4.0 million cases of cholera occur each year, killing as many as 143,000 people. The disease is caused by Vibrio cholerae bacteria, found in contaminated food and water, particularly in low-resource regions with weak public sanitation facilities, and in humanitarian crisis and conflict areas, where normal water supplies and sanitation systems are disrupted. Cholera is characterized by diarrhea and vomiting, which if severe, can lead to dehydration.

Researchers from the lab of biological engineering professor James Collins, with colleagues from Boston University and the Broad Institute — a medical research center affiliated with MIT and Harvard — are seeking feasible solutions to address cholera outbreaks, such as those now occurring in Yemen. One potential solution is to harness the body’s natural microbial communities in the gut that are emerging as an important pathway for understanding and improving human health.

The team focused on bacteria associated with lactic acid, known as Lactococcus lactis, or L. lactis, found in fermented milk products, such as buttermilk, and consumed safely for decades. The V. cholerae bacteria causing cholera are known to be sensitive to acidic conditions, and both the L. lactis and cholera bacteria reside for a time in the small intestine. The researchers tested the effects of L. lactis on cholera bacteria first in lab cultures and then with infant mice, who are more easily infected with cholera than adult mice.

The results show lactic acid produced by the metabolism of L. lactis limited growth of the cholera bacteria in the lab, and prevented infection of intestinal tissue in mice, when the mice were given L. lactis bacteria as well. Mice given both the L. Lactis and cholera bacteria also survived longer than mice given cholera bacteria alone. In separate tests, L. lactis bacteria modified to stop producing lactic acid when metabolized could not limit cholera bacteria.

The team then devised a technique with L. lactis bacteria to detect cholera infections, an important step for controlling outbreaks. The researchers genetically engineered L. lactis, adding a synthetic gene to sense the presence of the protein known as CAI-1, short for cholera autoinducer-1, secreted by cholera bacteria. When the engineered L. lactis senses signals from CAI-1, the bacteria emit a fluorescent enzyme that can be detected in fecal samples. Infant mice infected with cholera and given the synthetic L. lactis left fecal pellets with the reporter enzyme, allowing for researchers to track cholera activity in the animals.

“Our probiotic strategy presents a conceptually new way to prevent and diagnose cholera infection,” says Collins in a Wyss Institute statement. “Further translated into human conditions of V. cholerae infection, it could offer an inexpensive and extendable point-of-need intervention for managing cholera in populations at risk of outbreaks.” A companion article in Science Translational Medicine, from a team at Harvard University’s School of Public Health, engineered the cholera bacteria to develop an oral vaccine that prevented infections in tests with infant rabbits.

Boston University and MIT filed a patent application on the technology, with Collins and 2 of the co-authors listed as inventors. Collins is also co-founder of the biotechnology company Synlogic, a developer of synthetic probiotics for therapies.

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