Friendly gut microbes that have been engineered to make a specific protein can help regulate blood sugar in diabetic mice, according to preliminary research presented last week at the American Chemical Society conference in Washington, D.C. While the research is still in the very early stages, the microbes, which could be grown in yogurt, might one day provide an alternative treatment for people with diabetes.
he research represents a new take on probiotics: age-old supplements composed of nonharmful bacteria, such as those found in yogurt, that are ingested to promote health. Thanks to a growing understanding of these microbes, a handful of scientists are attempting to engineer them to alleviate specific ailments. "The concept of using bacteria to help perform (or fix) human disorders is extremely creative and interesting," wrote Kelvin Lee, a chemical engineer at the University of Delaware, in Maryland, in an e-mail. "Even if it does not directly lead to a solution to the question of diabetes, it opens up new avenues of thought in a more general sense," says Lee, who was not involved in the research.
Engineering edible bacteria: Researchers engineered friendly bacteria (dots in the bottom half of the image) to produce a protein that triggers intestinal epithelial cells (top, highlighted in blue) to produce insulin.
People with type 1 diabetes lack the ability to make insulin, a hormone that triggers muscle and liver cells to take up glucose and store it for energy. John March, a biochemical engineer at Cornell University, in Ithaca, NY, and his collaborators decided to re-create this essential circuit using the existing signaling system between the epithelial cells lining the intestine and the millions of healthy bacteria that normally reside in the gut. These epithelial cells absorb nutrients from food, protect tissue from harmful bacteria, and listen for molecular signals from helpful bacteria. "If they are already signaling to one another, why not signal something we want?" asks March.
The researchers created a strain of nonpathogenic E. coli bacteria that produce a protein called GLP-1. In healthy people, this protein triggers cells in the pancreas to make insulin. Last year, March and his collaborators showed that engineered bacterial cells secreting the protein could trigger human intestinal cells in a dish to produce insulin in response to glucose. (It's not yet clear why the protein has this effect.)
In the new research, researchers fed the bacteria to diabetic mice. "After 80 days, the mice [went] from being diabetic to having normal glucose blood levels," says March. Diabetic mice that were not fed the engineered bacteria still had high blood sugar levels. "The promise, in short, is that a diabetic could eat yogurt or drink a smoothie as glucose-responsive insulin therapy rather than relying on insulin injections," says Kristala Jones Prather, a biochemical engineer at MIT, who was not involved in the research.
Creating bacteria that produce the protein has a number of advantages over using the protein itself as the treatment. "The bacteria can secrete just the right amount of the protein in response to conditions in the host," says March. That could ultimately "minimize the need for self-monitoring and allow the patient's own cells (or the cells of the commensal E. coli) to provide the appropriate amount of insulin when needed," says Cynthia Collins, a bioengineer at Rensselaer Polytechnic Institute, in Troy, NY, who was not involved in the research.
In addition, producing the protein where it's needed overcomes some of the problems with protein-based drugs, which can be expensive to make and often degrade during digestion. "Purifying the protein and then getting past the gut is very expensive," says March. "Probiotics are cheap--less than a dollar per dose." In underprivileged settings, they could be cultured in yogurt and distributed around a village.
The researchers haven't yet studied the animals' guts, so they don't know exactly how or where the diabetic mice are producing insulin. It's also not yet clear if the treatment, which is presumably triggering intestinal cells to produce insulin, has any harmful effects, such as an overproduction of the hormone or perhaps an inhibition of the normal function of the epithelial cells. "The mice seem to have normal blood glucose levels at this point, and their weight is normal," says March. "If they stopped eating, we would be concerned."
March's microbes are one of a number of new strains being developed to treat disease, including bacteria designed to fight cavities, produce vitamins and treat lactose intolerance. March's group is also engineering a strain of E. coli designed to prevent cholera. Cholera prevention "needs to be something cheap and easy and readily passed from village to village, so why not use something that can be mixed in with food and grown for free?" says March.
However, the work is still in its early stages; using living organisms as therapies is likely to present unique challenges. More research is needed to determine how long these bacteria can persist in the gut, as well as whether altering the gut flora has harmful effects, says MIT's Prather.
In addition, recent research shows that different people have different kinds of colonies of gut bacteria, and it's unclear how these variations might affect bacterial treatments. "This may be particularly challenging when it comes to determining the appropriate dose of the therapeutic microbe," says Collins at Rensselaer. "The size of the population of therapeutic bacterial and how long it persists will likely depend on the microbes in an individual's gut."
By Emily Singer