Jhe development of antibiotics was a breakthrough in medicine. But if they can save lives, they have a dark side. Drug-resistant microbes were responsible for more than a million deaths in 2019, according to a study published earlier this year in The Lancet.
Additionally, a growing number of studies are finding that even a short course of antibiotics can alter the composition of bacterial species in the gut. These community changes can be profound, with some people’s microbiomes taxonomically resembling those of critically ill critical care patients after taking the drugs. And microbes that survive treatment tend to carry resistance genes, potentially allowing pathogens to acquire the means to evade our best pharmacological weapons.
Overall, pathologist and microbiologist Gautam Dantas of Washington University School of Medicine in St. Louis says the results are a warning that “taking antimicrobials is a gamble every time you do it, even if it is fully justified”.
Probing healthy microbiomes
One of the tricky things about studying the effects of antibiotics is that the gut microbiomes of patients they’ve been prescribed are “already messy for other reasons,” Dantas says, especially in hospitalized people. In such cases, it can be difficult to separate the effects of the antibiotic on the microbiome from disease-related alterations. The researchers, including Dantas and his colleague, infectious disease specialist Jennie Kwon, therefore turned to healthy volunteers.
“Many people prescribe [antibiotics] thinking there’s very little harm, especially if it’s just an oral pill for a few days,” says Kwon. “Our question was, is it true? When you give a healthy person a short course of antibiotics, does it disrupt the gut microbiome? »
The team recruited 20 healthy volunteers and divided them into four groups, each given a different antibiotic or a combination of antibiotics for five days. The chosen drugs – levofloxacin, azithromycin, cefpodoxime and a combination of azithromycin and cefpodoxime – are often given to patients with community-acquired pneumonia, although the disease is sometimes viral. Fecal samples were taken and analyzed before, during and after the course of antibiotics, with the last sample taken six months after treatment. From these samples, the researchers mapped how the taxonomic diversity of bacteria in the gut changed and any fluctuations in the copy number of resistance genes.
Antibiotic disruption of gut microbiomes in healthy volunteers
After taking antibiotics, the diversity of microbes in the intestines of healthy volunteers decreases sharply.
ADAPTED FROM FIGURE 1C BY ANTHONY ET AL. CELL REP39:110649, 2022
Immediately after taking antibiotics, total and culturable species richness decreased, the team found. For most volunteers, these measurements returned to baseline values after two months, but the species present remained altered, notes Winston Anthony, a doctoral candidate at Washington University School of Medicine in St. Louis who co-authored the Cell reports article published by the team last month announcing the results. This means that antibiotics “fundamentally restructure the microbiome,” he says.
In three of the healthy volunteers, who were assigned to different treatment groups, the gut microbiome was particularly disrupted. They continued to have reduced microbiome diversity even at the end of the six months. “Their gut microbiota became more similar to that of an intensive care patient than to that of a healthy individual,” Kwon says. Still, she noted that they and the other participants felt good.
W. Joost Wiersinga, an infectious disease specialist at the University of Amsterdam who has separately studied the effects of antibiotics in healthy people, says The scientist the new work “adds to the evidence that antibiotics can have major adverse effects on the gut microbiome in healthy adults.”
Indeed, in the 2018 study by Wiersinga and colleagues, healthy volunteers who took a week-long course of broad-spectrum antibiotics experienced a decline in gut microbiome diversity and an overgrowth of Streptococcus and Lactobacillus genres. Although these bacteria became less abundant over time, the composition of the participants’ microbiome remained different from its initial state throughout the duration of the study, which was up to 31 months after taking antibiotics.
‘Antibiotic wound healing’ may have lasting impact on resistance
In addition to inducing changes in microbiome composition, antibiotics appear to increase the prevalence of resistance genes. In the study by Anthony et al., for three of the four antibiotics (all except levofloxacin), there was a higher relative number of antibiotic resistance genes in samples taken six months after treatment – a change than the authors call it “antibiotic wound healing”.
This long-term increase in resistance genes is a notable insight for Francisco Guarner, a digestive system researcher at Vall d’Hebron University Hospital in Barcelona who was not involved in the study. He describes the gut microbiome as an ecosystem disrupted by antibiotics. “When you take antibiotics, certain network bacteria disappear [and] the others invade, so the balance is different. In this new balance, what you gain are bacteria that are more resistant to antibiotics.
Gut bacteria that harbor antibiotic resistance genes can pose several threats. When gut bacteria and pathogens mix, the resistance genes can be transferred, allowing pathogens to acquire resistance. A recently published study observed that resistant intestinal commensals can even degrade antibiotics in the gut, thereby protecting pathogens from drug effects.
See “How the microbiome influences drug action”
In other research, Kwon is investigating whether certain healthy people in the community can serve as reservoirs for resistance genes, which could potentially be passed on to others.
Why do some people’s microbiomes react differently to antibiotics?
It’s not yet clear why some people’s gut microbes seem to be particularly disrupted by antibiotics. “There’s a lot of variation between individuals,” Wiersinga notes, about whether people’s microbiomes return to their original state, and if so, how long it takes.
Absence of recovery of the intestinal microbiome after taking antibiotics in some healthy volunteers
For some presumed healthy volunteers, the diversity of gut microbes recovers much more slowly, if at all.
ADAPTED FROM FIGURE 5B BY ANTHONY ET AL. CELL REP39:110649, 2022
The state of the microbiome before treatment may play a role in this, Anthony notes. In his study with Dantas and Kwon, the three volunteers whose gut microbiomes came to resemble those of intensive care patients started out with slightly lower species diversity. Anthony offers several hypotheses to explain this initial difference, including that they may have had rounds of antibiotics before the study. Discerning the cause of differential responses to antibiotics could help refine their use, Kwon says, although future studies will need to uncover the microbial and metabolomic factors involved and determine whether they have predictive clinical value.
Ultimately, Wiersinga sees the accumulated findings as a reminder for doctors to “think twice when we prescribe antibiotics: does my patient really need them?”
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