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Compared with people who have not received antibiotics, those treated with certain drugs show differences in their gut microbiome up to 8 years later, with the strongest differences associated with prior treatment with clindamycin, fluoroquinolones, and flucloxacillin, new research showed.

“We can see that antibiotic use as far back as 4-8 years ago is linked to the composition of a person’s gut microbiome today,” said first author Gabriel Baldanzi, of the Department of Medical Sciences, Uppsala University, Uppsala, Sweden, in a press statement for the study, published in Nature Medicine.

“Even a single course of treatment with certain types of antibiotics leaves traces,” he said.

Antibiotics, though sometimes critical in the treatment of infections, have well known effects on the gut microbiome, as the drugs can fail to distinguish between the bad and beneficial bacteria that is important for optimal functioning gut health.

Clindamycin and fluoroquinolones, in particular, can cause gastrointestinal (GI) symptoms such as nausea, diarrhea, and vomiting, and those drugs are linked to an increased risk for Clostridioides difficile infection, Baldanzi told Medscape Medical News.

“However, these conditions typically occur during or shortly after the course of treatment,” he said.

Previous research has meanwhile shown that the reductions in gut flora diversity can be longer lasting, and, with high antibiotic use linked to an increased risk for health effects including GI infections and type 2 diabetes, there is further interest in the nature and longevity of the effects.

To investigate, Baldanzi and colleagues evaluated data from the Swedish Prescribed Drug Register, along with data from Swedish biobanks on fecal metagenomes of 14,979 adults.

The study excluded those receiving antibiotic prescriptions within 30 days of the study, as well as individuals with inflammatory bowel disease (IBD) and chronic pulmonary disease.

Overall, the most prescribed antibiotics to the study population were penicillin V, extended-spectrum penicillins, and tetracyclines.

The results showed that, after a multivariate adjustment, antibiotic use for less than 1 year prior to fecal sampling was associated with the greatest reduction species diversity. Specifically, clindamycin, fluoroquinolones, and flucloxacillin had the strongest associations with changes in the abundance of individual species.

In measures of species richness, each course of clindamycin less than 1 year before fecal sampling was associated with an average of 47 fewer species that were detected, while each course of fluoroquinolones or flucloxacillin was associated with an average of 20 and 21 fewer species detected.

Furthermore, the use of the antibiotics 4-8 years prior to sampling was linked to altered abundance of 10%-15% of the species studied.

“Some antibiotics, such as clindamycin and fluoroquinolones, are known to produce profound changes in the gut microbiome, so it was expected that some of these changes might remain for at least 4-8 years, possibly longer,” Baldanzi said.

“However, it was surprising to see that something as simple as species richness — that is, the number of different microbial species in the gut microbiome — did not recover.”

“This indicates that some bacterial species may be lost from the gut after treatment with certain antibiotics,” he added.

Conversely, no associations with were detected for extended-spectrum penicillins, specifically pivmecillinam and sulfamethoxazole-trimethoprim or amoxicillin, amoxicillin-clavulanic acid.

Long-Term Changes Even After One Course

Evidence of changes in the gut years later was observed even after just one course for some drugs, according to an evaluation of 7664 participants, comparing 3356 who had one course and 4308 with no antibiotic courses in the 8 years before fecal sampling.

Those results showed a single course of tetracyclines, flucloxacillin, fluoroquinolones, clindamycin, sulfamethoxazole-trimethoprim, cephalosporins, or macrolides less than 4 years or 4-8 years before sampling was associated with lower microbiome species diversity.

Overall, the results were consistent across the populations based on age and sex.

Baldanzi noted that it was further unexpected to see flucloxacillin associated with a loss of diversity.

“Flucloxacillin is considered a narrow-spectrum antibiotic with activity against a group of bacteria called Gram-positive bacteria,” he said. “We need further studies to better understand the mechanisms behind this finding.”

An evaluation of gut microbiome recovery further showed the most rapid recovery occurring within the first 2 years following antibiotic exposure, with a markedly slower recovery observed in later years.

Of note, the recovery rate following antibiotic use was found to be proportional to the magnitude of the initial reduction in diversity, the authors noted.

Clinical Effects?

In terms of clinical implications of the changes in gut diversity, previous research has further linked the use of clindamycin, fluoroquinolones, and flucloxacillin with greater abundances of species that are specifically associated with higher BMI, serum triglycerides, and the risk for type 2 diabetes.

However, evidence of causality is lacking, and more research is needed to better understand the precise implications, Baldanzi said.

“We know that the composition of the gut microbiome often reflects a person’s cardiometabolic health — cholesterol levels, glucose levels, and body fat,” he explained. “Changes in the gut microbiome have also been described in gut conditions such as constipation and inflammatory bowel disease.”

“However, whether changes in the gut microbiome produced by antibiotics can contribute to the development of these conditions years later has yet to be determined,” Baldanzi added.

Key questions in looking ahead include the possibility of genetic or other factors that may predispose certain individuals to the effects. “This was not something we examined in our study, [but] it is definitely an area that warrants further investigation,” Baldanzi said.

Meanwhile, simply turning to other antibiotics to avoid gut effects can be complicated by an array of factors, he noted.

These include “the type and severity of the infection, the antimicrobial resistance profile of the bacteria causing the infection, prior antibiotic use, and whether the patient has any allergies.”

Of note, since the study was conducted in Sweden, various antibiotics more commonly used in other countries, which may have similar effects, were not evaluated.

Another Argument for Antibiotic Hesitation

The findings nevertheless add to the considerations in existing efforts to reign in antibiotic use.

“The primary reason for a restrictive use of antibiotics is the risk of resistance development,” Baldanzi said. “Still, our study adds another argument for reducing antibiotic use: Namely, gut microbiome alterations that may persist for many years.”

“As the microbiome field advances, our understanding of the long-term impact of antibiotic treatment beyond infections and resistance may reveal additional health implications.”

Better Understanding of Long-Term Effects Will Be ‘Critical’

Commenting on the study, Adam Faye, MD, an associate professor of medicine and population health and director of clinical research at the IBD Center at NYU Langone Health in New York City, noted that “I think while we have suspected based on prior data that antibiotics can influence the gut microbiome for longer periods of time than initially thought, this gives additional credence/data to support this.”

“Understanding not just the duration of impact but also the changes that can occur based on differing antibiotic courses is quite impactful to help guide future research in this space,” he added.

In previous research, Faye and colleagues showed an increased risk for IBD even 5 years after an antibiotic course, therefore “an 8-year effect isn’t entirely surprising,” he noted.

“That said, the notion that a single antibiotic course can influence microbiome composition for years to come is still remarkable,” he noted.

“The impact does diminish the further out you get from the exposure, so understanding its long-term effects, not just on the microbiome, but on clinical outcomes, will be critical for putting this finding in proper context.”

Faye agreed that, ultimately, the broader implications are that “antibiotics have revolutionized medicine and are genuinely lifesaving, but in cases where a viral infection is suspected, or where clinical data support a watchful waiting approach, avoiding antibiotics when they aren’t clearly indicated may help reduce the long-term risks associated with microbiome disruption.”

Baldanzi and Faye had no disclosures to report. The other authors’ disclosures are detailed in the published study.