How Common Meds Secretly Wreck Your Patients' Microbiome?

Medscape

3 days ago

Effective ways to combat harmful viruses, bacteria, fungi, and parasitic worms have driven major advances in medicine and contributed to a significant increase in human life expectancy over the past century. However, as knowledge about the role of these microorganisms in promoting and maintaining health deepens, there is a need for a new look at the impact of these treatments.
The list of drugs that can directly alter the gut microbiota is long. In addition to antibiotics, antivirals, antifungals, anthelmintics, proton pump inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), laxatives, oral antidiabetics, antidepressants, antipsychotics, statins, chemotherapeutics, and immunosuppressants can trigger dysbiosis.
A 2020 study published in Nature Communications , which analyzed the impact of common medications on the composition and metabolic function of the gut bacteria, showed that of the 41 classes of medications. Researchers found that 19 were associated with changes in the microbiome, most notably antibiotics, proton pump inhibitors, laxatives, and metformin.
'There are still no protocols aimed at preserving the microbiota during pharmacological treatment. Future research should identify biomarkers of drug-induced dysbiosis and potentially adapt live biotherapeutics to counteract it,' said Maria Júlia Segantini, MD, a certified coloproctologist and member of the Brazilian Society of Coloproctology, from the University of São Paulo.
Known Facts
Antibiotics, antivirals, antifungals, and anthelmintics eliminate pathogens but can also disrupt the microbiota across the gut, skin, mouth, lungs, and genitourinary tract.
'This ecosystem is part of the innate immune system and helps to balance inflammation and homeostasis. Loss of microbial diversity alters interspecies interactions and changes nutrient availability, which can undermine the ability to fend off pathogens,' said Segantini, noting the role of microbiota in vitamin K and B-complex production.
'The microbiome may lose its ability to prevent pathogens from taking hold. This is due to the loss of microbial diversity, changes in interactions between species, and the availability of nutrients,' she added.
Antibiotics, as is well known, eliminate bacterial species indiscriminately, reduce the presence of beneficial bacteria in the gut, and, therefore, favor the growth of opportunistic pathogenic microorganisms. However, in addition to their direct effects on microorganisms, different medications can alter the intestinal microbiota through various mechanisms linked to their specific actions. Here are some examples:
Proton pump inhibitors: These can facilitate the translocation of bacteria from the mouth to the intestine and affect the metabolic functions of the intestinal microbiota. 'In users of these medications, there may be an enrichment of pathways related to carbohydrate metabolism, such as glycolysis and pyruvate metabolism, indicating possible changes in intestinal metabolism,' Segantini explained.
NSAIDs: NSAIDs can modify the function and composition of the intestinal microbiota, favor the growth of pathogenic species, and reduce the diversity of preexisting bacteria by reducing the presence of beneficial commensal bacteria, such as Lactobacillus and Bifidobacterium . 'This is due to changes in the permeability of the intestinal wall, due to the inhibition of prostaglandins that help maintain the integrity of the intestinal barrier, enteropathy induced by NSAIDs, and drug interactions,' said Segantini.
Laxatives: Accelerated intestinal transit using laxatives impairs the quality of the microbiota and alters bile acid. Osmotic agents, such as lactulose and polyethylene glycol, may decrease resistance to infection.
'Studies in animal models indicate that polyethylene glycol can increase the proportion of Bacteroides and reduce the abundance of Bacteroidales bacteria, with lasting repercussions on the intestinal microbiota. Stimulant laxatives, in addition to causing an acceleration of the evacuation flow, can lead to a decrease in the production of short-chain fatty acids, which are important for intestinal health,' Segantini explained.
Chemotherapeutics: Chemotherapeutic agents can significantly influence the intestinal microbiota and affect its composition, diversity, and functionality, which in turn can affect the efficacy of treatment and the occurrence of adverse effects. '5-fluorouracil led to a decrease in the abundance of beneficial anaerobic genera, such as Blautia , and an increase in opportunistic pathogens, such as Staphylococcus and Escherichia coli , during chemotherapy. In addition, it can lead to an increase in the abundance of Bacteroidetes and Proteobacteria while reducing Firmicutes and Actinobacteria . These changes can affect the function of the intestinal barrier and the immune response. Other problems related to chemotherapy-induced dysbiosis are the adverse effects themselves, such as diarrhea and mucositis,' said Segantini.
Statins: Animal studies suggest that treatment with statins, including atorvastatin, may alter the composition of the gut microbiota. 'These changes include the reduction of beneficial bacteria, such as Akkermansia muciniphila , and the increase in intestinal pathogens, resulting in intestinal dysbiosis. The use of statins can affect the diversity of the intestinal microbiota, although the results vary according to the type of statin and the clinical context.'
'Statins can activate intestinal nuclear receptors, such as pregnane X receptors, which modulate the expression of genes involved in bile metabolism and the inflammatory response. This activation can contribute to changes in the intestinal microbiota and associated metabolic processes. Although statins play a fundamental role in reducing cardiovascular risk, their interactions with the intestinal microbiota can influence the efficacy of treatment and the profile of adverse effects,' said Segantini.
Immunosuppressants: The use of immunosuppressants, such as corticosteroids, tacrolimus, and mycophenolate, has been associated with changes in the composition of the intestinal microbiota. 'Immunosuppressant-induced dysbiosis can compromise the intestinal barrier, increase permeability, and facilitate bacterial translocation. This can result in opportunistic infections by pathogens and post-transplant complications, such as graft rejection and post-transplant diabetes,' Segantini stated.
'Alteration of the gut microbiota by immunosuppressants may influence the host's immune response. For example, tacrolimus has been associated with an increase in the abundance of Allobaculum , Bacteroides , and Lactobacillus , in addition to elevated levels of regulatory T cells in the colonic mucosa and circulation, suggesting a role in modulating gut immunity,' she said.
Antipsychotics: Antipsychotics can affect gut microbiota in several ways, influencing bacterial composition and diversity, which may contribute to adverse metabolic and gastrointestinal effects.
'Olanzapine, for example, has been shown in rodent studies to increase the abundance of Firmicutes and reduce that of Bacteroidetes , resulting in a higher Firmicutes / Bacteroidetes ratio, which is associated with weight gain and dyslipidemia,' said Segantini.
She stated that risperidone increased the abundance of Firmicutes and decreased that of Bacteroidetes in animal models, correlating with weight gain and reduced basal metabolic rate. 'Fecal transfer from risperidone-treated mice to naive mice resulted in decreased metabolic rate, suggesting that the gut microbiota would mediate these effects.'
Treatment with aripiprazole increased microbial diversity and the abundance of Clostridium , Peptoclostridium , Intestinibacter , and Christensenellaceae , in addition to promoting increased intestinal permeability in animal models.
'Therefore, the use of these medications can lead to metabolic changes, such as weight gain, hyperglycemia, dyslipidemia, and hypertension. This is due to a decrease in the production of short-chain fatty acids, which are important for maintaining the integrity of the intestinal barrier. Another change frequently observed in clinical practice is constipation induced by these medications. This functional change can also generate changes in the intestinal microbiota,' she said.
Oral antidiabetic agents: Oral antidiabetic agents influence the intestinal microbiota in different ways, depending on the therapeutic class. However, not all drug interactions in the microbiome are harmful. Liraglutide, a GLP-1 receptor agonist, promotes the growth of beneficial bacteria associated with metabolism.
'Exenatide, another GLP-1 agonist, has varied effects and can increase both beneficial and inflammatory bacteria,' explained Álvaro Delgado, MD, a gastroenterology specialist at Hospital Alemão Oswaldo Cruz in São Paulo.
'In humans, an increase in bacteria such as Faecalibacterium prausnitzii has been observed, with positive effects. However, more studies are needed to evaluate the clinical impacts,' he said, and that, in animal models, these changes caused by GLP-1 agonists are linked to metabolic changes, such as greater glucose tolerance.
Metformin has been linked to increased abundance of A muciniphila , a beneficial bacterium that degrades mucin and produces short-chain fatty acids. 'These bacteria are associated with improved insulin sensitivity and reduced inflammation,' he said.
Segantini stated that studies in mice have shown that vildagliptin also plays a positive role in altering the composition of the intestinal microbiota, increasing the abundance of Lactobacillus and Roseburia , and reducing Oscillibacter . 'This same beneficial effect is seen with the use of sitagliptin,' she said.
Studies in animal models have also indicated that empagliflozin and dapagliflozin increase the populations of short-chain fatty acid-producing bacteria, such as Bacteroides and Odoribacter , and reduce the populations of lipopolysaccharide-producing bacteria, such as Oscillibacter .
'There are still not many studies regarding the use of sulfonylureas on the intestinal microbiota, so their action on the microbiota is still controversial,' said Segantini.
Antivirals: Antiviral treatment can influence gut microbiota in complex ways, depending on the type of infection and medication used.
'Although many studies focus on the effects of viral infection on the microbiota, there is evidence that antiviral treatment can also restore the healthy composition of the microbiota, promoting additional benefits to gut and immune health,' said Segantini.
In mice with chronic hepatitis B, entecavir restored the alpha diversity of the gut microbiota, which was reduced due to infection. In addition, the recovery of beneficial bacteria, such as Akkermansia and Blautia , was observed, which was associated with the protection of the intestinal barrier and reduction of hepatic inflammation.
Studies have indicated that tenofovir may aid in the recovery of intestinal dysbiosis induced by chronic hepatitis B virus infection and promote the restoration of a healthy microbial composition.
'Specifically, an increase in Collinsella and Bifidobacterium , bacteria associated with the production of short-chain fatty acids and modulation of the immune response, was observed,' said Segantini.
The use of antiretrovirals, such as lopinavir and ritonavir, has been associated with changes in the composition of the intestinal microbiota in patients living with HIV.
'A decrease in Lachnospira , Butyricicoccus , Oscillospira , and Prevotella , bacteria that produce short-chain fatty acids that are important in intestinal health and in modulating the immune response, was observed.'
Antifungals: As a side effect, antifungals also eliminate commensal fungi, which 'share intestinal niches with microbiota bacteria, balancing their immunological functions. When modified, they culminate in dysbiosis, worsening of inflammatory pathologies — such as colitis and allergic diseases — and can increase bacterial translocation,' said Segantini.
For example, fluconazole reduces the abundance of Candida spp . while promoting the growth of fungi such as Aspergillus , Wallemia , and Epicoccum .
'A relative increase in Firmicutes and Proteobacteria and a decrease in Bacteroidetes , Deferribacteres , Patescibacteria , and Tenericutes were also observed,' she explained.
Anthelmintics: These also affect the intestinal bacterial and fungal microbiota and alter the modulation of the immune response, in addition to having specific effects depending on the type of drug used.
Clinical Advice
Symptoms of dysbiosis include abdominal distension, flatulence, constipation or diarrhea, pain, fatigue, and mood swings. 'The diagnosis is made based on the clinical picture, since tests such as small intestinal bacterial overgrowth, which indicate metabolites of bacteria associated with dysbiosis, specific stool tests, and microbiota mapping with GI-MAP [Gastrointestinal Microbial Assay Plus], for example, are expensive, difficult to access, and often inconclusive for diagnosis and for assessing the cause of the microbiota alteration,' explained Fernando Seefelder Flaquer, MD, a general practitioner and gastroenterologist at Albert Einstein Israelite Hospital in São Paulo.
When caused by medication, dysbiosis tends to be reversed naturally after discontinuation of the drug. 'However, in medications with a high chance of altering the microbiota, probiotics can be used as prevention,' said Flaquer.
'To avoid problems, it is important to use antibiotics with caution and prefer, when possible, those with a reduced spectrum,' advised Delgado.
'Supplementation with probiotics and prebiotics can help maintain the balance of the microbiota, but it should be evaluated on a case-by-case basis, as its indications are still restricted at present.'
Currently, dysbiosis management relies on nutritional support and lifestyle modifications. 'Physical exercise, management of psychological changes, and use of probiotics and prebiotics. In specific cases, individualized treatment may even require the administration of some types of antibiotics,' explained Segantini.
Although fecal microbiota transplantation (FMT) has been widely discussed and increasingly studied, it should still be approached with caution. While promising, FMT remains experimental for most conditions, and its use outside research settings should be carefully considered, particularly in patients who are immunocompromised or have compromised intestinal barriers.
'Currently, the treatment has stood out as promising for cases of recurrent Clostridioides difficile infection , being the only consolidated clinical indication,' said Segantini.
Science Hype
The interest in gut microbiome research has undoubtedly driven important scientific advances, but it also risks exaggeration. While the field holds enormous promise, much of the research remains in its early stages.
'The indiscriminate use of probiotics and reliance on microbiota analysis tests for personalized probiotic prescriptions are growing concerns,' Delgado warned. 'We need to bridge the gap between basic science and clinical application. When that translation happens, it could revolutionize care for many diseases.'
Flaquer emphasized a broader issue: 'There has been an overvaluation of dysbiosis and microbiota-focused treatments as cure-alls for a wide range of conditions — often subjective or lacking solid scientific correlation — such as depression, anxiety, fatigue, cancer, and even autism.'
With ongoing advances in microbiome research, understanding the impact of this complex ecosystem on human health has become essential across all medical specialties. In pediatrics, for instance, microbiota plays a critical role in immune and metabolic development, particularly in preventing conditions such as allergies and obesity.
In digestive surgery, preoperative use of probiotics has been shown to reduce complications and enhance postoperative recovery. Neurological research has highlighted the gut-brain axis as a potential factor in the development of neurodegenerative diseases. In gynecology, regulating the vaginal microbiota is key to preventing infections and complications during pregnancy.
'Given the connections between the microbiota and both intestinal and systemic diseases, every medical specialist should understand how it relates to the conditions they treat daily,' concluded Flaquer.