Sunday, 16 November 2014

Fighting a pathogen with gut microbes

Clostridium difficile infections can be prevented through the rebalancing of bile acids in the gut by introducing certain commensal microbes, according to a study published in Nature. Eric Pamer of the Memorial Sloan Kettering Cancer Center in New York City and his colleagues have demonstrated the efficacy of this approach in both mice and humans.

While antibiotics work wonders fighting myriad infections, they can also wipe out the large contingent of beneficial bacteria that populate the human gut. Such widespread, indiscriminate destruction paves the way for infectious pathogens, including C. difficile—which can cause extreme diarrhea, abdominal pain, and if left untreated, even death.

The researchers sequenced the gut microbiomes of both mice and humans in search of individual species capable of eradicating infection. They discovered that in antibiotic-treated mice, CDI resistance was strongly correlated with the abundances of C. scindens and, to a lesser extent, 10 other bacterial taxa. A similar exploration of the intestinal microbiota of human patients undergoing a stem-cell transplantation procedure that left them vulnerable to CDI also pointed to C. scindens as the most potent source of infection resistance.

Administering C. scindens to antibiotic-treated mice infected with C. difficile resulted in significantly increased survival rates—80 percent, versus 50 percent for a control substance. A cocktail of C. scindens plus three other C. difficile-inhibiting bacteria was even more effective, resulting in 100 percent survival. In addition, the abundance of both C. scindens and the bacterial cocktail were strongly correlated with resistance.

Next, Pamer’s group investigated the mechanism underlying C. scindens-mediated inhibition of infection, focusing on the ability of the microbe to express the enzyme 7a-hydroxysteroid dehydrogenase. This enzyme, rare among intestinal bacteria, is critical for converting primary bile acids to secondary bile acids in the colon. C. difficile spores interpret the presence of primary bile acids as a signal that they are in the gut and should start germinating. The researchers hypothesized that C. scindens may prevent C. difficile growth by blocking this signal. To confirm this hypothesis, they loaded Petri dishes with the intestinal contents of antibiotic-exposed mice. As expected, C. scindens inhibited C. difficile. But when they added a chemical that binds bile acids, C. difficile flourished, suggesting that C. scindens-mediated inhibition of C. difficile is dependent upon modifying endogenous bile acids.
For further details, see the following paper published in Nature: "Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile."