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Mysterious medicine

Yale Medicine Magazine, 2018 - Autumn


Research shows that probiotics can treat some ailments, but has not yet shown why.

Take a look up and down the supermarket aisles: probiotics, loaded with the “good bacteria” once relegated to yogurt and a few other fermented foods such as kimchi and pickles, have escaped the dairy cases. They appear in packaged foods now, with cereals, snacks, and even chocolate infused with these good bugs. Studies of the microbiome have provided an unintended boost to the market for probiotics, shedding light on their power and revealing some potential for therapeutic use beyond an occasional yogurt to boost digestion.

Though probiotics have become a multimillion-dollar cottage industry, much of the science behind them remains murky. “The idea certainly has scientific merit,” says Ruslan Medzhitov, PhD, Sterling Professor of Immunobiology and a Howard Hughes Medical Institute investigator whose lab studies the microbiome’s impact on diet and inflammation. “But the vast majority of claims surrounding probiotics are based on very loose connections and correlations. This is not to say that the idea is wrong, just that we don’t know enough about the biology of commensal bacteria to start using them in this wholesale manner.”

Still, those correlations are strong enough that probiotics are beginning a transition from general food supplements to medically valid treatments for serious diseases. Priti Kumar, PhD, associate professor of infectious diseases, is examining a role for probiotics in HIV treatment. One question that has long frustrated HIV researchers is why HIV patients on a successful regimen of antiretroviral therapy (ART) exhibit signs of early immunosenescence. Evidence, Kumar says, points to a change in the composition of the gut microbiome. Could probiotics be used to halt or reverse the premature aging process? Recent studies have examined introducing the bacterial genus Lactobacillus, which is commonly found in yogurt and other over-the-counter probiotics, into the diet of HIV patients. “Just introducing this single probiotic strain in the diet seems to really make a marked improvement, in bringing the immune system several steps toward normalcy,” Kumar says.

While a potential success, this novel therapy also highlights a limitation of the use of probiotics as therapy. To maintain their healthy status, HIV patients must take ART for the rest of their lives. Probiotics must be used in the same way, because most of these good bugs have not evolved to adhere to the gut, and they end up passing through the body very quickly. This finding poses another interesting question: “If something is good for us, then why didn’t we evolve to hold on to it?” asks Medzhitov. “We are holding on to trillions of bacteria. Why are we not holding on to others that are good for us?”

Evolution may provide the answer. A recent finding revealed that some “bad” bacteria in the gut microbiome can promote obesity, which can lead to such metabolic diseases as type 2 diabetes, while other so-called “good” bacteria are associated with lean individuals.

“One is good and one is bad,” says Medzhitov. “However, what we define as good and bad can be different than what would have been considered good and bad in our evolutionary ancestors.” This observation can explain why so-called “good bacteria” are not stable in the human intestines. “From an evolutionary perspective, there is nothing good about them. They make you lean,” says Medzhitov. “That’s good if you are in Hollywood, but not if you are a caveman that can only eat every three days.” Because human genes have not had the time to adjust to the drastic changes in modern life that have occurred only in the last few hundred years, including modern medicine, hygiene, and obesity-causing food abundance, they still operate under the assumption that what are now considered bad bacteria are actually good, and vice versa.

Medzhitov predicts that in the next 10 to 15 years, probiotics will make the leap to synthetic biology, which would incorporate engineering and gene modification in their design. “Once we know enough about how bacteria in the gut adapt to their environment, understanding what makes them stable or unstable in the host, or what makes them good or bad, and apply the tools of synthetic biology, which are increasingly sophisticated, one could theoretically create ‘designer probiotics,’ where we could introduce genes that encode specific proteins that would metabolize certain toxins, for example,” he says.

This novel approach to probiotics would still have to pass muster with public opinion. Just as there is strong support for natural commercially available probiotics at the moment, there is powerful opposition to genetically modified organisms (GMOs) in food. Yet many of these next-generation probiotics by definition must be genetically modified. Jason Crawford, PhD, the Maxine F. Singer ’57 PhD Associate Professor of Chemistry and associate professor of microbial pathogenesis, cites an example of a probiotic he is working on that has the potential to prevent colorectal cancer. “The challenges for this example are in the regulatory landscape, not the science,” he says. “A neutralizing enzyme that we discovered protects humans from a particular toxin, but it needs to be secreted outside the cell as opposed to inside the cell. We need to change that single gene to have a secretion signal. But we can’t easily do that with the current regulatory landscape. As soon as we modify that organism, then it’s a GMO. That is a huge current barrier between research science and market potential.”

Over-the-counter probiotics are not regulated by the Food and Drug Administration. Because other next-generation probiotics will be labeled as GMOs, “it’s a different story,” says Medzhitov. “There is an assumption that if they are genetically modified, there is something unnatural about them, as if all of evolution is not about genetic modification. Bugs exchange genes all the time, they are always being genetically modified. There is nothing unnatural about it.”

As with all other discoveries, these probiotics of the future “would suffer from a certain amount of suspicion,” says Medzhitov. “But over time, science will win.”

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