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Defending the “good” bacteria

Yale Medicine Magazine, 2015 - Spring


When faced with dangerous bacteria like Salmonella, the gut releases inflammatory molecules to destroy the invaders. That immune response is so nonspecific that in theory at least, it should kill indiscriminately. Yet the many healthful and even beneficial bacteria that reside in the gut seem unaffected by the friendly fire. So-called commensal strains persist for years through one inflammatory event after another.

A group of researchers led by Andrew Goodman, Ph.D., assistant professor of microbial pathogenesis and a member of the Microbial Sciences Institute at West Campus, recently figured out why: many of the most prominent and stable commensals wield a protein that fends off the antimicrobial peptides (AMPs) that the host uses to attack the invaders. The team reported in Science in January that the protein LpxF serves a little like an umbrella, allowing bacteria to readily shed AMPs at concentrations thousands of times higher than those that kill pathogens.

The discovery, said Goodman, opens the door for researchers to learn “not only how the host tolerates the microbiome—which is well studied—but how the microbiome tolerates the host.”

LpxF works by removing a negatively charged phosphate group from the bacterial surface. That keeps the positively charged AMPs—the gut’s defenders—from binding to bacteria and destroying them.

The LpxF discovery and its satisfying simplicity may mean that the field—which has focused mostly on describing its species diversity—is now poised to move into an exploration of how the ecosystem functions. Understanding that ecosystem is a sine qua non for pursuing potential therapeutic targets.

Goodman, who is trained in both microbial genetics and ecology, had previously assumed that the host-pathogen commensal relationship would be byzantine and difficult to study. Now he is optimistic.

“It’s a glimmer of hope that it’s not going to be so irreducibly complex that we won’t be able to make any headway,” Goodman said, “[and] that there are dedicated mechanisms that we can identify and potentially target.”

LpxF is likely to be one of many resiliency factors waiting to be discovered in the gut, some of which may point to new drugs. This line of study is especially important because faulty or damaged resiliency systems might explain certain forms of disease. Studies of the gut microbiome have typically focused on the bacterial communities of healthy people. But understanding how these communities behave in sick people is crucially important, too. That’s Goodman’s next goal.