Drugs designed for humans can unintentionally affect gut microbes, altering their composition and activity. Drugs that reach the gut, such as entacapone (for Parkinson’s) and loxapine (for schizophrenia), can disrupt microbial communities through mechanisms such as iron depletion, favoring resistant bacteria. These effects can influence drug efficacy, and side effects, and even contribute to health problems.
When drugs are designed to target specific functions in human cells, they often have unintended interactions with the trillions of microbes that live in our gut.
These microbes, which collectively make up the gut microbiome, play crucial roles in digestion, immunity, and even brain function. However, drugs, especially those that are not fully absorbed in the stomach or are excreted into the intestines via bile, can target the gut microbiome and interact with it in complex ways.
Research shows that drugs can significantly alter the balance and behavior of gut microbes. For example, some studies have found that drugs that were not initially intended to kill bacteria can still inhibit the growth of certain gut bacteria.
In one large study, scientists tested 835 drugs intended for humans against a panel of 40 strains of gut bacteria under laboratory conditions. Remarkably, 24 percent of these drugs were able to stop the growth of at least one type of bacteria.
Another study used advanced techniques to analyze the effects of drugs on bacterial communities in human fecal samples. This revealed that many drugs, even if they didn’t kill bacteria outright, could alter the function of the microbiome in unexpected ways.
Interestingly, the changes weren’t always related to the number of microbes present. Instead, some drugs altered the behavior of bacteria without significantly changing the size of the population. This finding emphasizes the importance of looking beyond the “quantity” of bacteria to understand how drugs affect their “quality,” or functionality.
The relationship between drugs and the microbiome is not one-way. While drugs influence gut microbes, microbes also affect how drugs work. Microbes can metabolize drugs, altering their effects in the body, or even accumulate drugs in their cells, potentially modifying the drugs’ activity. For example, gut bacteria can break down a drug into an active or inactive form, influencing its therapeutic outcome or side effects.
A notable example involves proton pump inhibitors (PPIs), medications commonly used to reduce stomach acid. These medications have been shown to disrupt the gut microbiome, increasing vulnerability to harmful infections such as food poisoning.
Similarly, medications that target the brain, such as antipsychotics and antidepressants, often have a more potent effect on gut bacteria compared to other types of medications. This is concerning because the gut microbiome is increasingly recognized for its role in mental health and neurological diseases.
To explore these interactions further, researchers at the University of Southampton conducted an in-depth study of two commonly prescribed medications: entacapone (used for Parkinson’s disease) and loxapine (an antipsychotic used for schizophrenia).
Using stool samples from nine healthy adults, the scientists tested how these drugs affected the entire microbiome, simulating real-life conditions within the gut. The results were published in the journal Nature Microbiology.
They found that both drugs significantly altered microbial activity, with entacapone particularly affecting iron-dependent bacteria. The drug’s ability to bind to and reduce available iron in the gut disrupted microbial communities, favoring bacteria better adapted to low iron levels.
This iron depletion also encouraged the emergence of microbes with antibiotic resistance and virulence genes, raising potential concerns for gut health. Importantly, the study revealed that these changes can be reversed.
By replenishing iron levels, the researchers were able to restore microbial balance. This discovery highlights how certain drug-induced microbiome disruptions can be mitigated or managed through targeted interventions.
These findings are crucial because they reveal previously overlooked effects of medications on gut health. The study also identified iron binding, or “metal sequestration,” as a key mechanism through which drugs like entacapone disrupt microbial ecosystems.
This deeper understanding could lead to innovative strategies to improve drug safety, reduce side effects, and increase the efficacy of treatments for a variety of conditions.
By unraveling these interactions, scientists hope to not only optimize current drug use but also design future drugs that are both effective and microbiome-friendly.
READ MORE:
The Parkinson’s disease drug entacapone disrupts gut microbiome homeostasis via iron sequestration.
Pereira FC, Ge X, Kristensen JM. et al.
Nat Microbiol (2024).
Abstract:
Many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, the mechanisms underlying these effects are not well known. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing, and single-cell chemical imaging to investigate the impact of two widely prescribed drugs on the gut microbiome. Physiologically relevant concentrations of entacapone, a treatment for Parkinson’s disease, or loxapine succinate, used to treat schizophrenia, were incubated ex vivo with human fecal samples. Both drugs significantly impact microbial activity, more so than microbial abundance. Mechanistically, entacapone can complex and deplete available iron resulting in gut microbiome composition and function changes. Microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Further, entacapone-induced iron starvation was selected for iron-scavenging gut microbiome members encoding antimicrobial resistance and virulence genes. These findings reveal the impact of two under-investigated drugs on whole microbiomes and identify metal sequestration as a mechanism of drug-induced microbiome disturbance.
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