Gut Reactions

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By Mary Carpenter

DIFFERENCES in individuals’ microbiomes can alter, sometimes dangerously, the effects of prescription drugs—from antibiotics and antipsychotics to the diabetes drug metformin and the statin rosuvastatin. Of 1,000 drugs screened in a 2018 study, nearly one-quarter had antibiotic effects, though none were being sold as antibiotics. (The microbiome refers to bacteria populating an individual’s gut—which antibiotics can alter, sometimes dramatically.)

“It was possible to essentially transplant a mood disorder into rats,” Nature writer Neil Savage reports on studies at APC Microbiome Ireland. Led by psychiatrist Ted Dinan, the researchers first wiped out rats’ native microbes using antibiotics and then gave them a “dose of gut bacteria” from people being treated for depression—with the result that their behavior was “significantly altered.”

Pharmaceuticals and bacteria have an undeniable effect on each other,” writes Savage. Dinan deems the gut microbiome a “virtual organ in its own right,” and predicts that “in a few years [the US Food and Drug Administration will not] license any drug unless its impact on that virtual organ has been studied.”

More than 200 drugs, prescribed to more than one-third of U.S. adults, have depression or suicide listed as potential side effects on accompanying labels—but in fine print and often unread according to 2018 data from the multi-year NHANES (National Health and Nutrition Examination Survey) study with more than 25,000 participants. About 5% of people taking drugs on the list —including heart and blood pressure medicine and antacids—experienced depression; and of those taking two of the drugs at the same time, 9% became depressed.

“No one knows exactly why certain drugs have this effect,” according to the Health.com report on the NHANES study.University of Miami Clinical Psychiatry Professor Edmi Cortes Torres suggested that “the medications may interfere with neurotransmitters…like dopamine and serotonin.”

The ability of certain “good” bacteria to synthesize neurotransmitters, as well as those chemicals the body uses to produce mood-regulators such as serotonin, may explain the link between low diversity of gut microbes and mental health conditions such as schizophrenia. In addition, with psychotropic drugs, such as those used in treating Parkinson’s disease, gut molecules that break down the drug can significantly decrease the amount that reaches the brain.

Notable for its varying effect on different individuals, the drug rosuvastatin in a 2016 study produced a 50% drop in LDL cholesterol in 46% of patients, but 11% of participants had no reduction or even had an increase in LDL.  Psychopharmacogeneticist Sony Tuteja at the University of Pennsylvania suggests that the drug might throw microbes in the intestinal tract out of balance in a way that either alters cholesterol metabolism or that renders the statins less effective.

“It could be bidirectional,” says Tuteja. “The microbiome is affecting the drug and the drug is affecting the microbiome.” Savage explains the possibility that using statins to lower LDL levels can make the gut “more congenial for some bacteria and less so for others.”

The antibiotics Cipro and Levaquin, in the drug class fluoroquinolones, have since 2018 carried the FDA’s strongest “black box” warning. The warning associates these drugs with “disabling and potentially permanent” side effects on the central nervous system, nerves, muscles and joints—which include causing Achilles tendon tears. According to the FDA, the benefit of taking these drugs may not be worth the risk.

The CDC has denied a petition from South Carolina oncologist and public safety expert Charles Bennett asking that suicide be added to the black box warning on fluoroquinolones, but it may accede to Bennett’s request that “long-term toxicity” caused by the drugs be recognized as a condition covered by insurance.

The penicillin-based antibiotic Amoxicillin carries warnings for sedation, anxiety and hallucinations, and has been linked to three reported cases of psychosis. And doxycycline, along with other tetracycline antibiotics, risks causing sexual dysfunction—indicating the possibility that it inhibits serotonin reuptake, which could explain its risk for suicide.

Besides implications for drug treatment, microbiome differences can affect the success of fecal transplantation, a medical approach to persistent infection with the bacterium C.diff., which can be severe and even fatal. Because previous antibiotic treatment of C.diff. may have altered the balance of healthy bacteria in the gut, fecal transplants administered via colonoscopy or using upper endoscopy can restore a healthy balance.

Fecal transplants may also help with symptoms of Irritable Bowel Syndrome (IBS), a condition with no clear cause but linked to unhealthy microbiota. In a 2018 Norwegian study of 164 IBS patients, depending on the dose, 75% and 89% of those receiving fecal transplantation showed improvement that was sustained for at least a year—although 23.6% in the placebo group also reported improved symptoms. According to NBC, the study used transplant samples from a so-called “super donor [who had been] breast fed, consumed a nutritious diet, took no regular medications, was a nonsmoker and had taken antibiotics only a few times.”

Among seven large studies using fecal transplantation for IBS symptoms included in a 2021 survey, however, positive effects occurred in only four—with no effect in the other three studies. But the survey also revealed “marked differences” among the studies on a number of variables, including selection processes for the donors and patients, transplant dose and route of administration.

The constantly changing makeup of an individual’s microbiome may pose difficulties in treatment approaches. Developers working on algorithms for microbiome-based diet apps, for example—which recommend food choices based on an individual’s microbiome—rely on genetic profile and family history but must also respond to fluctuating factors such as physical activity, sleep, stress and medications.

Three of my close family members, unrelated to each other, suffered torn Achilles tendons while taking Cipro. And while for the past six months I expected rosuvastatin was making it okay to consume cholesterol with abandon, I now know the drug could be having no effect or even increasing my LDL levels. I also just learned that eating foods high in fat or cholesterol can reduce its effectiveness.  

—Mary Carpenter regularly reports on need-to-know topics in health and medicine.