Kari Lounatmaa/Science Source
When people take antibiotics for one infection, another can swoop in to take its place: the bacterium Clostridioides difficile, which causes severe, recurring colon infections that kill nearly 30,000 people annually in the United States, most over the age of 65. Now, researchers have a new idea for battling C. diff: They have modified yeast to produce and deliver antibodies that defang the bacterium’s two toxins and spur recovery in infected mice.
If it works in people, the genetically engineered yeast, derived from a strain used in a popular probiotic, could be taken as a daily pill to ward off or treat C. diff infections. Study leader Hanping Feng, a microbiologist at the University of Maryland School of Dentistry, calls the proposed method “inexpensive, very easy to manufacture, and a convenient route” for delivery. “The real advance is that they have a living delivery system” for the therapeutic antibodies, says physician and microbiologist Vincent Young of the University of Michigan, Ann Arbor.
C. diff infections occur most often in elderly people who receive antibiotics for an unrelated illness. The drugs wipe out much of a person’s protective gut microbiota, which makes them vulnerable to infection from C. diff spores lingering in a nursing home or hospital. Although most people given antibiotics targeting C. diff recover, the bacterium returns in one in six cases. Sometimes it comes back repeatedly, with deadly results.
Recently, fecal transplants from healthy people have been shown to quell stubborn C. diff infections by replacing the missing beneficial gut microbes. But they remain experimental and can be risky. Despite screening, the samples sometimes contain other pathogens; the fecal transplants also can’t be given with antibiotics.
Another potential treatment involves immune proteins called monoclonal antibodies that neutralize C. diff’s two toxins. But they normally must be given as an intravenous injection that moves from the bloodstream into the gut. Feng’s team wanted to get around the high cost of manufacturing such antibodies and deliver them directly to the gut. So his group turned to Saccharomyces boulardii, a type of yeast considered safe by the U.S. Food and Drug Administration (FDA) as a probiotic to improve gut health.
The group first designed its own antibody for C. diff, a potent four-pronged protein with two prongs for each of the bacterium’s two toxins. When the researchers injected this antibody followed by C. diff toxins into the abdomens of mice, all of the mice survived; those that got another antibody treatment or a saline solution died.
To test whether the modified S. boulardii could protect mice from C. diff, Feng and colleagues gave mice antibiotics to disrupt their normal gut microbes, and then infected them with the bacteria’s spores. Mice that had begun to receive a weeklong, daily dose of the antibodymaking S. boulardii starting 3 days before C. diff infection all survived the illness, but 60% of those receiving a control yeast strain or saline died within 4 days, the team reports today in Science Translational Medicine. The colon tissue of yeast-treated mice also had less inflammation and none of the tissue damage from C. diff toxins seen in control mice.
The researchers then tested their daily yeast treatment in mice that already had a C. diff infection, dosing them for 4 days. About 70% survived, whereas two-thirds of those receiving control yeast or saline soon died. The results were similar for mice with recurring C. diff infections. In both experiments, the sick mice receiving the modified S. boulardii also regained lost weight faster and had less diarrhea, Feng’s team reports
“It’s really exciting,” says structural biologist Borden Lacy of Vanderbilt University, who studies C. diff toxins. “A lot of what we need to do is give people a window of time in which they can recover a healthy microbiome before toxins cause a lot of damage. This helps extend that window,” Lacy says.
Feng has started a company to develop the yeast for testing in people. FDA will need to weigh in on the safety of the genetically modified yeast, which would be the first drug of that kind, and his company also needs to raise funding from investors. “Unfortunately, it takes a long time,” Feng says. He hopes a clinical trial will begin within 3 years.
Source: Science Mag