Biomedicine

Genetically Engineered Probiotics

A twist on a traditional therapy shows promise for treating bowel disease.

Public interest in probiotics  is on the upswing, if the glut of advertisements for probiotic yogurts—those with added doses of beneficial bacteria—is any evidence. Scientists are bringing this traditional therapy into the 21st century by genetically engineering the microbes to enhance their effect on the immune system. They hope the new bugs will ultimately help treat inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, as well as other disorders that result from an overactive immune system.

Bacterial benefits: The bottom slide shows reduced inflammation in the colon of a mouse treated with genetically engineered bacteria. The top image shows the colon of an untreated animal, and the middle image shows that of an animal treated with unmodified bacteria.

In research published today in the Proceedings of the National Academy of Sciences, scientists deleted a gene from the bacterium Lactobacillus acidophilus, which is commonly found in yogurt. Mansour Mohamadzadeh, associate professor of medicine at Northwestern University, and collaborators had previously shown that the enzyme this gene manufactures increases inflammation, a defining characteristic of Crohn’s disease and ulcerative colitis. But the unaltered form of the bacterium also triggered production of a beneficial immune molecule, IL-10m, which helps to regulate the immune system. The goal of the engineering the microbes was to deliver the beneficial effects without the harmful ones.

When fed to mice with colitis and inflammation of the colon, the engineered bacteria prevented the weight loss and bloody diarrhea that typically accompanies this condition. In addition, the treated mice had 90 percent less inflammation in their colon tissue than did their untreated counterparts.

While probiotic foods and supplements are a huge industry, it’s unclear whether they actually help treat most gastrointestinal diseases. The research published today is part of a trend in microbiology to explore in rigorous detail the effects of probiotics and the mechanisms that underlie them.

“The concept [of probiotics] is wonderful, but the evidence of their [effectiveness] is fairly limited,” says Balfour Sartor, co-director of the Center for Gastrointestinal Biology and Disease at the University of North Carolina, who was not involved in the new study. Because probiotics are considered a food and not a drug, they are not regulated by the U.S. Food and Drug Administration, and therefore don’t require the large clinical tests that drugs do.

Inflammatory bowel disease is one of the prime areas of interest for probiotic treatment, but “there really has been little direct evidence that probiotics are effective in treatment or prevention of Crohn’s disease,” says Sartor. Some research suggests that two different probiotic formulations can help prevent recurrence of ulcerative colitis, he says. “But that’s just two out of thousands of formulations.”

Scientists still don’t know exactly how probiotic bacteria influence the gastrointestinal system, but previous research suggests several possible mechanisms. Beneficial bacteria might temporarily alter the ratio of good to bad bacteria that inhabit the intestine, or they might specifically block activity of bad bacteria. And probiotics seem to influence the immune system, “stimulating protective immune cells or blocking detrimental activities of immune cells,” says Sartor.

Mohamadzadeh’s team is focused on the activity of immune cells.  Researchers looked in detail at the molecular effects of the engineered bacteria and found that the production of regulatory immune cells, rather than of inflammatory immune cells, was enhanced. “When we treat mice with the new strain, we see more accumulation and generation of cells that produce regulatory proteins, which lure and generate regulatory T cells,” says Mohamadzadeh. The regulatory T cells, a type of immune cell, counteract the effects of harmful immune cells that attack the cells lining the gut, he says.

While the research is promising, Sartor cautions that “it’s a huge leap between animal models and disease.” Probiotic treatments “don’t always have the same effects in humans as they do in animals, and there is a big difference in showing protection in animal models [by treating the animals before symptoms occur] versus treating ongoing human disease.”

Mohamadzadeh says that before beginning clinical tests, he plans to study the roles of more kinds of surface proteins in the engineered bacteria, to determine which are helpful and which are harmful. If scientists can identify the molecules the bacteria make that help regulate the immune system, they may be able to develop drugs that have a similar effect. (It’s easier to modify and give controlled doses of chemical compounds than live bacteria, which can behave unpredictably once ingested.)

Mohamadzadeh’s team is also exploring engineered probiotics as a treatment for colon cancer. In preliminary studies in mice designed to mimic colon cancer, treatment with the modified bacteria reduced the number of polyps the animals developed by 90 percent. “We observed an average of just three small polyps in treated mice, compared to about 35 to 50,” he says.

He adds that the bacteria’s ability to reduce inflammation isn’t limited to the gut; the regulatory cells migrate throughout the body. That means the microbes may also be able to help treat other diseases linked to inflammation, such as rheumatoid arthritis and psoriasis.

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