Day: August 31, 2018

Bacteria used to have an almost unanimously negative connotation. For good reason: The microscopic beings caused infections that made us ill and often killed us. It wasn’t until recently that scientists realized far more bacteria help keep us healthy than make us sick.

We soon learned that our bodies are an entire ecosystem teeming with bacteria, the majority of which reside on our skin and inside our guts. They help digest our food, keep our bowels moving, and when they can, prevent those disease-causing bacteria from making themselves at home.

We also found that some microbes are even more influential than others. Bacteria like lactobacillus and bifidobacteria, which are the organisms found in fermented foods like yogurt and kimchi, are thought to make our guts healthier. This is where the whole idea of probiotics comes from. Store shelves are now filled with probiotic supplements with various claims about our health. But, as we’ve reported before, the pills you buy in the store are mostly unregulated, meaning that, like homeopathic supplements, they don’t need to go through that painstaking FDA drug approval process that forces companies to prove that their product actually is what it says it is and effectively treats the conditions it claims to treat. In fact, there are only a few probiotic supplements out on the market today—Align and Culturelle, among a few others—that have gone through clinical trials to prove they work.

It’s easy to assume that the rest are benign at worst. They’re just bacteria, after all. Unfortunately, that’s not the way our microbiomes work. For the same reason that harmful bacteria can easily take over our guts, supposedly healthy ones can, too. In a study out today in the journal Applied and Environmental Microbiology, researchers report that a probiotic intended to treat a parasitic infection in mice actually made the infection worse.

The researchers were attempting to find new methods to treat Cryptosporidiosis, a major cause of infant diarrhea, especially in the developing world, that’s brought on by a parasite called Cryptosporidium parvum. They gave the mice Lactobacillus reuteri, a commercially available probiotic supplement, to see if the probiotics were able to shift the bacterial ecosystem back to its more normal, healthy state. A properly functioning microbiome should be able to kill off the invader, since it deprives the parasite of a niche in which to live. Without a spot to take hold in, it eventually dies off. But instead, the parasite actually gained momentum. By the end of the study the researchers found more parasites in the mice that received the probiotic than in those that didn’t.

Though the study was technically a failure, as far as the intended goal is concerned, the result is actually quite important. As the researchers note in an accompanying release, the results show that beneficial bugs can affect a parasite’s growth—it just wasn’t in the hoped-for direction. “We didn’t know if cryptosporidium growth in the gut could be affected by diet,” said Giovanni Widmer, the study’s author and molecular biologist at Tufts University’s school of veterinary science, in the statement. Now, Widmer and his team plan to find the mechanism through which this works, and attempt to find a bacterial strain that will inhibit growth, rather than promote it.

It also highlights why it’s important to rigorously test probiotics before they hit the market.

Unlike drugs, bacteria are tricky. While there are a few main bacterial strains that are common in many people, the majority of a person’s gut flora are the result of their diet and environment, and even other habits like exercise. The way probiotics will affect a gut depends on which bacteria are already there, making it difficult to predict how any one probiotic strain will affect a person.

If enough testing and trials are done, researchers can have a clearer picture and be better able to predict what’s going to happen. But we’re not quite there yet.

In the meantime, it’s important to rigorously test probiotics long before they reach store shelves or prescription bottles. A lack of regulation doesn’t necessarily spell disaster, though. Take one of probiotics’ biggest successes to date, the fecal transplant. Researchers have found that for cases of severe infection with the bacteria Clostridium difficile, an introduction of donated healthy stool (dried up and in a pill) can often cure the infection. The treatment has seen great success, and many clinical trials are in the works or completed, but these treatments are still unregulated. We don’t know what we don’t know about them, and there are still many opportunities for transplanted bacteria, whether in a probiotic or in a fecal transplant, to negatively affect the gut.

For now, the one thing we do know is that you can still keep your microbiome healthy by eating a healthy diet full of fiber—bacteria’s favorite treat. No probiotic pills needed.

The United States is currently grappling with a crisis in opioid addiction. The federal government estimates that 2.1 million people had an opioid use disorder in 2016, spurring the Department of Health and Human Services to declare the problem a public health emergency late last year. Roughly 91 people die every day from overdosing on painkillers.

One possible intervention is to strip strip painkiller drugs of their addictive compounds. That brings us to AT-121, a new opioid compound that, according to results from a primate study published in Science Translational Medicine on Wednesday, delivers better pain relief than even morphine—without the sort of euphoric effects that foster drug addiction and dependency issues.

Opioids are more effective at relieving discomfort than other types of drugs, especially for people who experience chronic pain of some kind. They work by binding to receptors in the brain that modulate pain. At the same time, this activity triggers powerful feelings of pleasure, which the user can become used to and develop cravings for with prolonged exposure.

The slide from using painkillers as intended to full-blown addiction can be extraordinarily rapid, exacerbated by the fact that it’s hard to accurately prescribe just the right amount to avoid creating dependency.

Many researchers think a powerful solution is to create a pain reliever that simultaneously will not trigger activity in the pleasure centers of the brain. That’s easier said than done, of course, but there have been some successes in a few prototype compounds, and AT-121 is the latest drug that may prove to be a breakthrough.

AT-121 basically targets the same pain receptors—the mu-opioid receptors—as conventional pain killers, but also goes a step further and binds to a second set of receptors, called the nociceptin opioid receptors, which mediate behaviors governed by emotions and instincts. The combined block of these receptors seems to both block the pleasure-triggering action of painkillers, as well as providing pain relief at much more effective rates.

The team at the helm of these latest findings, led by researchers from the Wake Forest School of Medicine and Mountain View-based Astrea Therapeutics, tested AT-121 in 15 rhesus monkeys. They found that AT-121 could deliver a similar degree of pain relief at a dose 100 times smaller than morphine. Moreover, the monkeys were allowed to self-administer the drug through the push of a button, but would refrain from doing so repeatedly and unnecessarily. The monkeys also lacked other negative side effects common in patients who take morphine, like itching and respiratory problems.

By comparison, when exposed to oxycodone, the animals became hooked, and would continue to administer the drug until they hit a cutoff limit imposed to prevent overdosing. Those same animals experienced sharp drops in drug-seeking behavior when they were subsequently turned on to AT-121.

“The overall results are quite exciting,” says Bryan Roth, a pharmacologist at the University of North Carolina School of Medicine who was not involved with the study. “This is certainly a very promising approach.”

At first glance, the fact that the study focused on monkeys would seem to be a factor against AT-121’s favor. This is definitely true in the sense that humans could react quite differently to the compound and its effects, and it should not be assumed AT-121 is anywhere near ready for people. But Roth emphasizes that since the two species share quite a bit of the same physiology, “the potential translation to humans has a greater potential for success.”

In fact, Roth thinks the main thing the new findings lack is an understanding of whether the drug might inadvertently affect other receptor targets or areas that are outside the brain, and what effects these activities might have. “We would really want to know if it has activity at other receptors and so on that could be important for producing side-effects,” he says.

The rhesus monkey trial was also a fairly short experiment, and there will need to be more extensive trials on primates that account for long-term observations before the drug is considered safe for human testing.

Even if AT-121 flames out during further work, it is far from the only alternative painkiller scientists are testing and tweaking. Roth himself is working on identifying other brain receptors that can interact with opioids in an effort to help design non-addictive drugs. NKTR-181 is another compound that has shown some promise in early testing on animals, by creating a much slower release of the neurotransmitters that encourage addiction. Another compound has been shown in rats to selectively target receptors around inflamed tissue instead of the brain.

Still, these are just baby steps, and it would be seriously irresponsible to pin our hopes of solving the opioid crisis on a single addiction-free drug. It will be several years—possibly more than a decade—before AT-121 or any other alternative opioid earns regulatory approval. In the meantime, people around the country are already addicted and dying. Solving the opioid epidemic requires more than just new drug trials.