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Sequencing Reveals Changes in Gut Microbiome from PPI Treatment, Supports Link to C. Diff Infection

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NEW YORK (GenomeWeb) — A study using sequencing to measure changes in the gut microbiome of healthy subjects treated with proton pump inhibitors has found that the medication appears to reduce the diversity of gut bacteria in a way that could potentially predispose patients to Clostridium difficile infection.

The study, by a team from the Mayo clinic, appeared last week in the journal Microbiome. Senior author John DiBaise told GenomeWeb that prior observational studies had identified a strong enough link between PPI use and the incidence of C. difficile infection that the US Food and Drug Administration requires that the package inserts for such drugs contain a warning about this risk. However, the mechanism of the link between PPIs and C. diff infection remained unclear.

"No studies had really evaluated what happens in people when they take PPIs in terms of the gut micriobiome," DiBaise said. "But it was an interesting question for us because this has been a long-observed risk, and also because of the work going on at Mayo around fecal transplants."

In their initial effort, the team set out to examine how treatment with PPIs affected the makeup of healthy individuals' gut microbiomes and to compare the gut microbial landscape of those subjects to patients suffering from C. diff infection.

The researchers enrolled nine healthy subjects who were divided into either a low-dose or a high-dose PPI group. They then performed high-throughput 16S hypervariable tag sequencing on stool samples from these volunteers at baseline, and then at time points both during and after one month of PPI treatment, and one month after cessation of PPI use. They also sequenced stool samples from five patients with treatment-naïve C. diff infection to compare to the PPI-treated subjects.

According to the authors, PPI usage at both low and high dosages resulted in a decrease in the microbial diversity of stool samples after both one week and one month of treatment, based on a measure of diversity called an observed operational taxonomic unity, or OTU.

Importantly, the OTU levels seen in the volunteers post-PPI treatment were significantly lower than those pre-treatment, and looked very similar to the OTU counts for the five patients with untreated C. diff infection.

"The diversity [in the PPI-treated subjects] didn't decrease necessarily to the same extent as in those with active C. diff infection," DiBaise said. "But it did decrease significantly to an extent approaching that level.

"What this suggested to us is that the lower diversity doesn't mean that these people are definitely going to develop C. diff, but it may make them more susceptible, for example, if some other hit comes along, whether that's an antibiotic or something else," he added.

Also interestingly, the group found that after one month of recovery from PPI treatment, the OTU counts for some, but not all, of the volunteers returned nearly to that of their baseline sequencing results.

Based on the sequencing results and analysis for OTU, the group did not find a significant difference between the effect of low PPI dose and high PPI dose.

Taken together, the authors wrote, the results provide preliminary evidence that PPIs disrupt the healthy human gut microbiome and that this disruption could explain the observed association between prolonged PPI use and the incidence of C. diff infection.

One area the group hoped to also be able to measure changes in gut microbes due to PPI treatment was in specific microbe species or communities, rather than overall diversity. But DiBaise said that the small size of the study didn't allow them to achieve this.

Getting a closer look at the effect of PPI use on specific bacteria is of great interest because of the potential implications for more personalized and safe PPI treatment, he said.

The hope is that doctors could potentially supplement PPI patients with a specific probiotic to counteract the effect of the drugs on specific populations of microbes.

To answer this question, DiBaise said that it would be necessary to conduct larger studies looking not only at healthy volunteers, but also at patients who are actually prescribed PPIs for a medical reason as well as additional C. diff patients at different stages of initial or recurrent infection. The Mayo team is interested in pursuing such larger studies if it can secure funding, he added.

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