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Almost of half of 41 common drug classes were associated with alterations of the microbiota of the human gut, Dutch researchers reported.

Extensive changes in taxonomic structure, metabolic activity, and resistome (antibiotic-resistant genes) were seen in human fecal samples following use of 18 of 41 common drug categories, with the four most frequent culprits being proton pump inhibitors (PPIs), metformin, antibiotics, and laxatives, reported Arnau Vich Vila, MSc, of the University Medical Center Groningen at in Barcelona.

Vich Vila and colleagues performed metagenomics sequencing on 1,883 fresh frozen fecal samples from three independent cohorts: a population-based group, patients with inflammatory bowel disease, and patients with irritable bowel syndrome, intermixed with healthy controls.

Differences between drug users and non-users were assessed by looking at the effect of single medication use and also factoring in the use of multiple drugs by each participant. Cohort-specific results were combined in a meta-analysis using inverse variance.

"Our work highlights the importance of considering the role of the gut microbiota when designing treatments and also points to new hypotheses that could explain certain side-effects associated with medication use," Vich Vila said. These associations need to be functionally investigated in light of the importance of the gut microbiota in health and the widespread use of many drugs.

Drug-induced changes to the gut microbiota can increase the risk of enteric infections and obesity, Vich Vila noted.

After correcting for polypharmacy, seven drug categories remained significantly associated with changes in 46 intestinal taxa and pathways.

The gut microbiota of PPI users, for example, showed a greater abundance of upper GI tract streptococcal bacteria and increased fatty acid biosynthesis, while metformin users had higher levels of potentially infective Escherichia coli.

In other associations:

• An increase in antibiotic resistance mechanisms was associated with eight different medication categories: anti-androgen oral contraceptives, beta-sympathomimetic inhalers, laxatives, metformin, other oral antidiabetics, PPIs, nonsteroidal anti-inflammatory drugs, and triptans
• Selective serotonin reuptake inhibitor depressants were linked to an abundance of Eubacterium ramulus, generally considered a beneficial degrader of dietary flavonoids
• Oral steroids were associated with an enrichment of methanogenic bacteria, which have been linked to elevated body mass index

"We already know that the efficiency and the toxicity of certain drugs are influenced by the bacterial composition of the gastrointestinal tract and that the gut microbiota has been related to multiple health conditions," Vich Vila said in a UEGW press release. "Therefore, it is crucial to understand which are the consequences of medication use in the gut microbiome."

The investigators pointed to of changes in the gut microbiota associated with obesity, diabetes, liver and neurodegenerative diseases, and cancer.

Gail Cresci, PhD, RD, of the Cleveland Clinic in Ohio, who was not involved in the study, commented that it's well known that medications can alter the composition and diversity of gut microbes, in particular those that alter gastric pH (such as PPIs), destroy bacteria (antibiotics), or alter motility (laxatives).

"Metagenomics sequencing is now moving the field forward regarding gut microbiome function and medical therapies," she told 麻豆传媒. "This has been seen with immunotherapeutic agents using the microbiome composition and function as a means to gauge cancer immune therapy response, and toxicity, and using prebiotics, probiotics, postbiotics, and fecal microbiota transplant to modulate immune therapy," said Cresci, who was not involved in the Dutch research.

Similarly, David T. Rubin, MD, of the University of Chicago, said the study contributes to the evolving understanding of just how variable the gut microbiota can be. "It is certainly appreciated that diet and inflammation affect the composition of the gut microbiota, but assessment of the impact of many medical therapies had not been previously described," he told 麻豆传媒.

"The finding that most of these treatments indeed affect the composition of the gut microbiota in direct or indirect ways has implications for how these medications may be impacting other biological functions, including metabolism," said Rubin, who was not involved with the research. "It will be of interest to further understand longitudinal changes over time, and whether the microbiome reverts to its baseline or compensates in other ways."

Characterizing the study as associative, Jack Gilbert, PhD, of the University of California San Diego, said it nevertheless identified potentially important drug-related changes. "This is preliminary, but provides some testable hypotheses for future work," he told 麻豆传媒.

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