Mindy D. had suffered from constipation for years when her gastroenterologist advised her, at 38, to take a popular over-the-counter probiotic. Over the next two years, she experimented with different dosages, sometimes taking it three times a day. But she kept getting sicker—sometimes so ill she couldn't work.
"We shouldn't just presume probiotics are safe."
Her symptoms improved only after she traveled from Long Island to Georgia to see Satish S. C. Rao, a gastroenterologist at Augusta University. "The key thing was taking her off probiotics and treating her with antibiotics," he says.
That solution sounds bizarre, if, like many, you believe that antibiotics are bad and probiotics good. Millions of Americans take probiotics—live bacteria deemed useful—assuming there can be only positive effects. The truth is that you really don't know how any probiotic will affect you. To quote the American Gastroenterological Association Center for Gut Microbiome Research and Education, "It remains unclear what strains of bacteria at what dose by what route of administration are safe and effective for which patients."
"We shouldn't just presume probiotics are safe," says Purna Kashyap, a gastroenterologist from the Mayo Clinic, in Rochester, Minnesota, and a member of the Center's scientific advisory board. Neither the U.S. Food and Drug Administration or the European Food Safety Authority have approved probiotics as a medical treatment. Things can go very wrong in the ill: Among patients with severe acute pancreatitis, one study found that a dose of probiotics increased the chance of death. Even randomized controlled trials of probiotics rarely report harms adequately and the effect over the long-term has not been studied.
Many people pick up a product at a drug store or health store without ever telling a doctor. Doctors are fans, too: in a 2017 survey of healthcare providers at Stanford, more than 60 percent of the respondents said they prescribed probiotics. Many did so inconsistently, leaving the choice of which probiotic up to the patient. Healthy people take them for a range of unproven benefits, including protection from infections or heart disease or to sharpen their brains.
It's fine—unless it isn't. "Probiotics are capable of altering the microbiome in unpredictable ways," explains Leo Galland, an internist in New York who specializes in difficult digestions. "I've had patients who got gas and bloating, constipation or diarrhea from probiotics."
Your Microbiome Is Unique
The booming probiotic market has fed on excitement about the new science of the microbiome, the genetic material of all the microbes that live in our bodies and on our skin. Microbes make up 1 to 3 percent of every human being's body mass—you carry trillions of them, including more than a hundred species and thousands of strains. To identify a microbe, you need to know the genus, species and strain. For example, in Lactobacillus rhamnosus GG, the ingredient in the OTC probiotic Culturelle, Lactobacillus is the genus, rhamnosus is the species and GG is the strain designation.
Variations in your microbiome could help explain why you put on weight or suffer from Crohn's or depression. Each of us has our own unique mix.
A decade ago, the U.S. National Institute of Health (NIH) launched the Microbiome Project to establish a baseline description of health. Scientists sequenced the DNA in more than 2,200 strains, still a small fraction of the whole.
Within a couple of years, we had evidence that our microbiomes are distinctive. Another team used the NIH data set to look into the idea of microbial "fingerprints." A classic computer science algorithm allowed it to assign individuals "codes" defined by DNA sequences of their microbes—no human DNA required. Using information solely from the guts, "Eighty percent of individuals could still be uniquely identified up to a year later," they wrote.
That distinctiveness makes a difference when we try to change our mix by swallowing bacteria considered "pro." Even in healthy people, the reactions to probiotics vary widely, according to a study in Cell in September. The team examined the intestines of healthy volunteers who had taken a cocktail of eleven strains of probiotics for the experiment. Which took up residence in the intestinal lining? The answer depended on the person. Led by Eran Segal and colleagues at the Weizmann Institute of Science, in Rehovot, Israel, the authors concluded that effective supplements would have to be personalized.
Patients with "brain fog" improved dramatically when they were taken off their probiotics and given antibiotics as well.
To truly customize a probiotic, however, we'd have to know the state of an individual's gut microbiome, identify danger signs and link them to symptoms, isolate relevant strains of probiotics that might be needed, and get them into the gut lining effectively. Commercial tests are still at step one. Several companies claim to assess your microbiome based on a stool sample—but the Weizmann team has also shown that the differences between our gut linings aren't apparent from our stool. Galland has explored testing his patients looking for ways to help. "I've concluded that uBiome, American Gut Project, and others don't yield useful information," he observes.
Can A Probiotic Make Your Brain Foggy?
Besides taking her probiotic, Mindy D. had cut out gluten and upped her vegetables and fruits. But soon after she ate her seemingly healthy meals, she would begin to feel dizzy and sometimes even slurred her words, as if she were drunk. "It was such an intense feeling," she said.
A slender 5 ft. 2 inches, she dropped 20 pounds, becoming unhealthily thin. She traveled to see specialists in Minnesota and Connecticut and took two month-long medical leaves before she found Rao in Georgia.
In June, Rao created a stir when he and his coauthors reported that a cluster of his patients with "brain fog"—the "intense feeling" Mindy D. described—improved dramatically when they were taken off their probiotics and given antibiotics as well.
His idea was that lactobacilli and other bacteria colonized their small intestines, rather than making it to the colon as intended—a condition known as "small intestinal bacteria overgrowth" (SIB0) that some gastroenterologists treat with antibiotics. In this group, he argues, the small intestine produced the brain fog symptoms as a consequence of D-lactic acidosis, a phenomenon usually associated with damaged intestines. "If you have brain fogginess along with gas and bloating, please don't take probiotics," Rao says.
The paper prompted a rebuttal at the end of September from Eamonn Quigley, a gastroenterologist at Houston Methodist, who criticized the methodology in detail. Kashyap, of the Mayo Clinic, is skeptical as well. "People were picked for their brain fogginess and they were taking probiotics. Probiotics could be an innocent bystander," he says.
"It's hard for me to imagine the mechanism of say, Culturelle, causing SIB0," says Shira Doron, a specialist in infectious diseases and associate professor at Tufts University School of Medicine who studies probiotics. "The vast majority of people will never suffer a side effect from a probiotic. But probiotics are a live organism so they have a unique set of potential risks that other supplements don't have. They can give you a severe infection in very rare circumstances."
The larger point is that probiotics should be used under a doctor's care. In April, a panel of 14 experts on behalf of the European Society for Primary Care Gastroenterology concluded that "specific probiotics are beneficial in certain lower GI problems." That does not mean any over-the-counter probiotic is likely to help you because it helped your cousin.
"Even your doctor may be going by anecdotal experience, rather than hard science."
Both Galland and Rao use probiotics in their practice, but carefully. "We advise caution against excessive and indiscriminate use of probiotics especially without a well-defined medical indication, and particularly in patients with gastrointestinal dysmotility," when the muscles of the digestive system don't work normally, Rao's team wrote.
"Because there are so many studies out there that are poorly done, that aren't looking at side effects, the science is murky. Even your doctor may be going by anecdotal experience, rather than hard science," Doron adds. Your doctor may tell you that many of his patients report a great experience with probiotics. As Doron points out, however, with disorders like irritable bowel syndrome, the most common gastrointestinal diagnosis, the placebo effect is very strong. Many patients could "respond to anything if they believe it works," she says.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- Research on a "smart" bandage for wounds
- A breakthrough in fighting inflammation
- The pros and cons of a new drug for Alzheimer's
- Benefits of the Mediterranean diet - with a twist
- How to recycle a plastic that was un-recyclable
Sexually transmitted infections (STIs) are surging across the U.S. to 2.5 million cases in 2021 according to preliminary data from the CDC. A new prevention and treatment strategy now in clinical trials may provide a way to get a handle on them.
It's easy to overlook the soaring rates of gonorrhea, chlamydia, and syphilis because most of those infections have few or no symptoms and can be identified only through testing. But left untreated, they can lead to serious damage to nerves and tissue, resulting in infertility, blindness, and dementia. Infants developing in utero are particularly vulnerable.
Covid-19 played havoc with regular medical treatment and preventive care for many health problems, including STIs. After formal lockdowns ended, many people gradually became more socially engaged, with increases in sexual activity, and may have prioritized these activities over getting back in touch with their doctors.
A second blow to controlling STIs is that family planning clinics are closing left and right because of the Dobbs decision and legislation in many states that curtailed access to an abortion. Discussion has focused on abortion, but those same clinics also play a vital role in the diagnosis and treatment of STIs.
Routine public health is the neglected stepchild of medicine. It is called upon in times of crisis but as that crisis resolves, funding dries up. Labs have atrophied and personnel have been redirected to Covid, “so access to routine screening for STIs has been decimated,” says Jennifer Mahn, director of sexual and clinical health with the National Coalition of STD Directors.
A preview of what we likely are facing comes from Iowa. In 2017, the state legislature restricted funding to family health clinics in four counties, which closed their doors. A year later the statewide rate of gonorrhea skyrocketed from 83 to 153.7 cases per 100,000 people. “Iowa counties with clinic closures had a significantly larger increase,” according to a study published in JAMA. That scenario likely is playing out in countless other regions where access to sexual health care is shrinking; it will be many months before we have the data to know for sure.
A decades-old antibiotic finds a new purpose
Using drugs to protect against HIV, either as post exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP), has proven to be quite successful. Researchers wondered if the same approach might be applied to other STIs. They focused on doxycycline, or doxy for short. One of the most commonly prescribed antibiotics in the U.S., it’s a member of the tetracycline family that has been on the market since 1967. It is so safe that it’s used to treat acne.
Two small studies using doxy suggested that it could work to prevent STIs. A handful of clinical trials by different researchers and funding sources set out to generate the additional evidence needed to prove their hypothesis and change the standard of care.
Senior researcher Victor Omollo, with the Kenya Medical Research Institute, noted, “These are prevention interventions that women can control on their own without having to seek or get consent from another person,” as is the case with condom use.
The first with results is the DoxyPEP study, conducted at two sexual health clinics in San Francisco and Seattle. It drew from a mix of transgender women and men who have sex with men, who had at least one diagnosed STI over the last year. The researchers divided the participants into two groups: one with people who were already HIV-positive and engaged in care, while the other group consisted of people who were on PrEP to prevent infection with HIV. For the active part of the study, a subset of the participants received doxy, and the rest of the participants did not.
The researchers intentionally chose to do the study in a population at the highest risk of having STIs, who were very health oriented, and “who were getting screened every three months or so as part of their PrEP program or their HIV care program,” says Connie Celum, a senior researcher at the University of Washington on the study.
Each member of the active group was given a supply of doxy and asked to take two pills within 72 hours of having sex where a condom was not used. The study was supposed to run for two years but, in May, it stopped halfway through, when a safety monitoring board looked at the data and recommended that it would be unethical to continue depriving the control group of the drug’s benefits.
Celum presented these preliminary results from the DoxyPEP study in July at the International AIDS Conference in Montreal. “We saw about a 56 percent reduction in gonorrhea, about 80 percent reduction in chlamydia and syphilis, so very significant reductions, and this is on a per quarter basis,” she told a later webinar.
In Kenya, another study is following a group of cisgender women who are taking the same two-pill regimen to prevent HIV, and the data from this research should become available in 2023. Senior researcher Victor Omollo, with the Kenya Medical Research Institute, noted that “these are prevention interventions that women can control on their own without having to seek or get consent from another person,” as is the case with condom use, another effective prevention tool.
Antibiotic resistance is a potentially big concern. About 25 percent of gonorrhea strains circulating in the U.S. are resistant to the tetracycline class of drugs, including doxy; rates are higher elsewhere. But resistance often is a matter of degree and can be overcome with a larger or longer dose of the drug, or perhaps with a switch to another drug or a two-drug combination.
Research has shown that an established bacterial infection is more difficult to treat because it is part of a biofilm, which can leave only a small portion or perhaps none of the cell surface exposed to a drug. But a new infection, even one where the bacteria is resistant to a drug, might still be vulnerable to that drug if it's used before the bacterial biofilm can be established. Preliminary data suggests that may be the case with doxyPEP and drug resistant gonorrhea; some but not all new drug resistant infections might be thwarted if they’re treated early enough.
“There are some tradeoffs” to these interventions, Celum says, and people may disagree on the cost of increased resistance balanced against the benefits of treating the STIs and reducing their spread within the community.
Resistance does not seem to be an issue yet for chlamydia and syphilis even though doxy has been a recommended treatment for decades, but a remaining question is whether broader use of doxy will directly worsen antibiotic resistance in gonorrhea, or promote it in other STIs. And how will it affect the gut microbiome?
In addition, Celum notes that we need to understand whether doxy will generate mutations in other bacteria that might contribute to drug resistance for gonorrhea, chlamydia or syphilis. The studies underway aim to provide data to answer these questions.
“There are some tradeoffs” to these interventions, Celum says, and people may disagree on the cost of increased resistance balanced against the benefits of treating the STIs and reducing their spread within the community. That might affect doctors' willingness to prescribe the drug.
Turning research into action
The CDC makes policy recommendations for prevention services such as taking doxy, requiring some and leaving others optional. Celum says the CDC will be reviewing information from her trial at a meeting in December, but probably will wait until that study is published before making recommendations, likely in 2023. The San Francisco Department of Public Health issued its own guidance on October 20th and anecdotally, some doctors around the country are beginning to issue prescriptions for doxy to select patients.
About half of new STIs occur in young people ages 15 to 24, a group that is least likely to regularly see a doctor. And sexual health remains a great taboo for many people who don't want such information on their health record for prying parents, employers or neighbors to find out.
“People will go out of their way and travel extensive distances just to avoid that,” says Mahn, the National Coalition director. “People identify locations where they feel safe, where they feel welcome, where they don't feel judged,” Mahn explains, such as community and family planning clinics. They understand those issues and have fees that vary depending on a person’s ability to pay.
Given that these clinics already are understaffed and underfunded, they will be hard pressed to expand services covering the labor intensive testing and monitoring of a doxyPEP regimen. Sexual health clinics don't even have a separate line item in the federal budget for health. That is something the National Association of STI Directors is pushing for in D.C.
DoxyPEP isn't a panacea, and it isn't for everyone. “We really want to try to reach that population who is most likely going to have an STI in the next year,” says Celum, “Because that's where you are going to have the biggest impact.”