The Effects of Non-Antibiotic Drugs on the Microbiome

The trillions of microbes in our gut play incredibly important and complex roles in our health. I’ve written several articles on the gut microbiome and its connections to:

• skin health 
• allergies
• food cravings
• bone health
• ocular health
• the thyroid
• autoimmune disease
• brain health
• heart health

Because the health of our gut microbiome is so important, I’ve also extensively discussed why we should think twice about taking antibiotics. Thanks to more widespread appreciation of the gut microbiome, more and more patients and doctors understand the potential negative impacts of antibiotics on normal healthy bacteria. But a study published in March of this year suggests that many non-antibiotic drugs can also affect the microbiome. In this article, I’ll break down the findings of this study and discuss whether this is truly cause for concern.

Drug–microbe interactions

The interaction of drugs and the microbiome is not a new concept. It’s been known for quite some time that microbes influence the efficacy and toxicity of drugs, and several studies had previously found that metformin (1), PPIs (2), NSAIDs (3), and atypical antipsychotics (4) can all alter the composition of the microbiota.

Antibiotics can have adverse effects on the gut microbiome, but did you know that nearly a quarter of non-antibiotic drugs can as well? Learn which of your prescriptions might be influencing your gut microbiome – for better or for worse 

However, the effects of many other non-antibiotic drugs on the microbiome had never been assessed, even though many have known gastrointestinal side effects. The goal of this study, therefore, was to systematically profile interactions between drugs and individual gut microbes. It was titled “Extensive impact of non-antibiotic drugs on human gut bacteria” and published in the journal Nature.

For the study, the authors monitored the growth of 40 human gut isolates comprising 38 different bacterial species, which were grown in an anaerobic medium that largely “recapitulates the species relative abundance in human gut microbiomes.” The species were chosen based on their prevalence and abundance in the healthy human gut microbiota and their phylogenetic diversity. Most strains were commensal, or normal, gut flora, but the set also included four potential pathogens, including Clostridium difficile and the probiotic strain Lactobacillus paracasei.

They tested 1,079 pharmaceuticals that are commonly administered to humans, including:

• 835 with targets in human cells
• 156 with antibacterial activity (144 antibiotics and 12 antiseptics)
• 88 with antifungal, antiviral, or antiparasitic activity

Drugs have widespread activity against beneficial microbes

Unsurprisingly, many of the antibacterials tested had broad-spectrum activity, meaning that they inhibited pathogenic bacteria but also inhibited normal commensal bacteria. Of the 156 antibacterials tested, 78 percent were active against at least one commensal species, and most had activity against many potentially beneficial microbes. Additionally, 47 of the 88 antifungals, antivirals, and antiparasitics had anti-commensal activity.

The most novel finding, though, was that 203 out of the 835 human-targeted non-antibiotic drugs showed activity against normal gut microbes. That’s almost a quarter (24 percent) of non-antibiotic drugs having a significant effect on the gut microbiome. Most of these drugs only inhibited the growth of a few strains, but 40 drugs affected at least 10 strains!

The effects weren’t limited by drug class, either. Almost every type of drug tested showed some activity against normal gut flora. I’ve listed the categories below, along with the specific names of drugs that affected more than 10 microbial strains:

• Cancer therapies: 8-azaguanine, 5-fluorouracil, floxuridine, tamoxifen citrate, amethopterin, etoposide, doxorubicin hydrochloride, streptozotocin, aprepitant
• Anti-inflammatories: diacerein, anthralin, auranofin, methotrexate, zafirlukast
• Antihistamines: loratadine (Claritin), terfenadine, clemizole, astemizole
• Antidiabetic drugs: troglitazone
• GI disorder drugs: pinaverium bromide, oxethazaine
• NSAIDs: tolfenamic acid
• Antipsychotics: methiothepin maleate, thioridazine hydrochloride
• Antihypertensives: felodipine
• Antiarrhythmics: amiodarone hydrochloride
• Anticoagulants: dicumarol
• Hormones or hormone modulators: estradiol valerate, diethylstilbestrol, diestrol, tiratricol (thyroid hormone analogue), clomiphene citrate

The microbes affected

Microbial responses varied by drug, but the abundance of key commensals Roseburia intestinalis, Eubacterium rectale, and Bacteroides vulgatus were among the most sensitive. R. intestinalis and E. rectale are known producers of the beneficial microbial metabolite butyrate, a key promoter of gut barrier integrity, while B. vulgatus is an important producer of the metabolite propionate, which stimulates the release of gut satiety peptides and has been shown to help prevent weight gain (5). The authors write:

Overall, species with higher relative abundance across healthy individuals were significantly more susceptible to human-targeted drugs. This suggests that human-targeted drugs have an even larger impact on the gut microbiome, with key species related to healthy status […] being relatively more affected. (6) 

They also stressed that the doses used in the study to probe drug–microbe interactions were well within physiologically relevant concentrations and that their data are likely to underestimate the impact of human-targeted drugs on gut bacteria.

Lastly, there was a strong overlap between resistance against antibiotics and resistant against non-antibiotic drugs, suggesting that consuming non-antibiotic drugs could potentially increase the risk of acquiring antibiotic resistance.

On-target or off-target effects?

I want to stress that there is still much we don’t understand here. For instance, is an altered gut microbiome an on-target or off-target effect of the drug? As the lead author on the study, Dr. Peer Bork, pointed out in a press release, “This shift in the composition of our gut bacteria contributes to drug side-effects, but might also be part of the drugs’ beneficial action” (7).

In other words, your prescription might only be working because it is changing your gut microbiome. For example, metformin, a drug commonly used to treat diabetes, has been shown to alter the gut microbiome, increasing abundance of the beneficial microbes Akkermansia muciniphila, Butyrivibrio, and Bifidobacterium bifidum (8). Transplanting fecal material from humans receiving metformin into germ-free mice has been shown to improve glucose intolerance, suggesting that the microbiome is responsible for the therapeutic effects (9).

All that being said, metformin seems to be the exception, not the rule—it’s clear that many of these drugs are negatively impacting microbial composition. These off-target effects on the microbiome suggest that treating one disease with a pill could potentially be causing another disease down the road. In other words, taking a proton pump inhibitor might help control your acid reflux in the short term, but it will also cause a shift in your gut microbiome that predisposes you to irritable bowel syndrome (10), gut infections (11), liver disease (12), and other conditions.

While pharmaceuticals can be a valuable tool in the management of disease, this study further supports the notion that if we can address the root cause of disease and support a healthy gut microbiome, we’re much more likely to achieve lasting, long-term health.

Now I’d like to hear from you. Did you know about the effects of non-antibiotic drugs on the gut microbiome? Start the discussion in the comments below!

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