In a pioneering new investigation, scientists have discovered that the widely used drug for Parkinson’s disease, entacapone, significantly disrupts the human gut microbiome by causing iron deficiency. This study sheds light on the often-ignored effects of drugs directed at humans on the microbial communities essential for our well-being.
In a pioneering new investigation, under the auspices of the FWF-funded Cluster of Excellence “Microbiomes drive Planetary Health,” researchers from the University of Vienna partnered with the University of Southampton, Aalborg University, and Boston University. They found that the commonly prescribed Parkinson’s medication entacapone markedly disrupts the human gut microbiome through the induction of iron deficiency. This study, featured in Nature Microbiology, reveals new perspectives on the frequently neglected impacts of human-focused drugs on microbial communities that are vital for human health.
While it is well-known that antibiotics can significantly disturb the human gut microbiome, recent research indicates that a variety of human-directed medications—especially those for neurological disorders—can dramatically alter the microbial communities present in our bodies. Although these drugs are designed to positively impact various organs, they can unintentionally disturb the delicate balance of gut bacteria, leading to possible health issues. Up until now, most investigations of these interactions have either depended on patient cohort data influenced by numerous external factors or on studies utilizing isolated gut bacteria, which do not adequately represent the complexity of the human microbiome.
A New Approach to Examine Drug-Microbe Interactions
Employing an innovative experimental method, the international team examined the influence of two drugs—entacapone and loxapine, a treatment for schizophrenia—on fecal samples from healthy human donors. They incubated these samples with therapeutic doses of the medications and then assessed how the drug impacted the microbial communities using advanced molecular and imaging techniques, including heavy water labeling combined with Stimulated Raman Spectroscopy (SRS). The team found that loxapine, and particularly entacapone, severely inhibited numerous members of the microbiome, while E. coli significantly proliferated in the presence of entacapone.
“The findings were particularly striking when we investigated microbial activity, rather than just counting them,” said Fatima Pereira, the study’s lead author and former Postdoctoral researcher at the University of Vienna. “The heavy water-SRS method let us detect subtle yet significant changes within the gut microbiome that are frequently overlooked in traditional abundance assessments.”
Entacapone Causes Iron Shortage, Promotes Harmful Microbes
The researchers theorized that entacapone might interfere with iron accessibility in the gut, which is vital for many microbes. Their experiments confirmed that supplying iron to fecal samples with entacapone negated the drug’s microbiome-changing impacts. Further studies showed that E. coli, which thrived in these conditions, possessed a highly effective iron-uptake mechanism (enterobactin siderophore), enabling the bacteria to flourish even when iron was scarce because of the drug.
“Our research shows that entacapone triggers iron deficiency, revealing a new pathway for drug-induced gut dysbiosis, in which the drug favors E. coli and other potentially harmful microbes that are well-suited to conditions with limited iron,” explained Michael Wagner, scientific director of the Excellence Cluster and vice-head of the Centre for Microbiology and Environmental Systems Science (CeMESS) at the University of Vienna.
Broader Consequences for Drug-Microbiome Dynamics
This finding has wider implications for understanding how other human-targeted medications may impact the gut microbiome. Several drugs, including entacapone, contain metal-binding catechol groups, suggesting that this iron deficiency mechanism could be a common way that drugs alter the microbiome.
Moreover, the results offer a possible path to reduce the side effects associated with drugs like entacapone. By ensuring adequate iron levels in the large intestine, it might be feasible to alleviate dysbiosis and gastrointestinal problems that frequently arise with Parkinson’s disease treatment.
“The next objective is to investigate how we can alter drug regimens to better support the gut microbiome,” stated Wagner. “We are contemplating methods to selectively deliver iron to the large intestine, where it could aid the microbiome without affecting drug absorption in the small intestine.”
The study was part of the FWF-funded Cluster of Excellence “Microbiomes drive Planetary Health,” a collaborative endeavor involving eight leading research institutions in Austria.
