How the gut microbiome interacts with your prescription drugs

The science community is slowly considering that gut bacteria influence the availability and efficacy of therapeutic medications. Even oncologists are beginning to add the gut microbiome as a factor in treatment plans, as it can indirectly impact an individual's response to chemo/immunotherapy in cancer treatments.

According to Nassos Typas [1], Group Leader and Senior Scientist at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, "Only now are people recognising that drugs and our microbiome impact each other..." Typas said that these interactions might have critical consequences for our health.

Peer Bork, Director of Scientific Activities at EMBL, added, "This calls for us to start managing the microbiome as one of our organs."

But acknowledging this fact is just the first step toward predicting individual health outcomes when administering a drug to a patient based on the host's microbiome.

The final goal would be to predict an individual's response to various commonly used pharmaceuticals based on their microbiome in order to maximise the chances of achieving the desired positive health outcome.

Researchers realise that the varying individual reactions to medications seen in clinical practice may well be modulated by an individual's gut bacteria. Medical professionals must consider whether the patient's expected therapeutic response and side effects might be influenced by their microbiota. They also need to consider how prolonged treatments might drive strain-specific microbiota changes that, in turn, reduce the drug's effectiveness or alter the required dosage.

The optimal goal would be to predict patient responses depending on microbiome composition, allowing healthcare providers to individualise drug treatments and modulate them over time as treatment progresses. Navigating this intricate and complex issue may seem daunting to both health professionals and patients, as a complete understanding of microbiome-to-drug interactions still eludes us.

Several research groups are systematically trying to map drug and bacteria interactions, describe how microbes transform them and, eventually, predict the effect this biotransformation might entail. A newly published study in Nature revealed 70 bacteria-drug interactions [2] after investigating the depletion of 15 structurally diverse medications by 25 representative gut bacterial strains. Nearly half of these bacteria-drug interactions were previously unknown and had never been reported before this study.

There is still a great deal that we do not understand about the microbiome. Further research is necessary to clarify the mechanisms governing these processes.

The final goal would be to predict an individual's response to various commonly used pharmaceuticals based on their microbiome in order to maximise the chances of achieving the desired positive health outcome. Here is what we have learned so far:

The Microbiome Biotransforms Most Drugs

The microbiota processes oral drugs as just another chemical and often transforms them in the gut. This adds a new layer of complexity to a drug's pharmacokinetics, the process by which a drug is absorbed, distributed, metabolised and eliminated by the body. This microbiota-mediated chemical transformation of drugs into secondary metabolites can alter the therapeutic response in patients.

More often than expected, researchers realised that the microbiome can act on a drug like a bomb diffuser: it can reduce the potency or concentration of a drug and render it partially ineffective. In some cases, researchers have reported this unwanted effect, as well as instances of drugs becoming toxic after microbiota alterations. This biotransformation [3] could partially explain the wide range of reported side effects described for many drugs on the market. This fact is strain-dependent: distinct bacterial species within the microbiome transform certain medications while others do not.

Medications affected by this phenomenon range from OTC products to life-saving drugs, including antivirals and chemotherapeutic agents. Scientists primarily employ microbiome-depleted or germ-free animal models to identify these microbiota-drug interactions. To test for bacterial specificity, they painstakingly administer specific bacterial isolates to germ-free animals along with the drug being studied and record the observable interactions.

Although this one-by-one approach is perfectly valid, it does not allow easy generalisation to humans, who host a complete microbiome. The complex strain-to-strain interactions with a drug may result in outcomes different from those reported in individual models.

Bacteria Bioaccumulate Drugs

Besides biotransformation, it is now known that common pharmaceutical drugs can accumulate in the microbiome, altering bacterial function, which in turn may change how the drug is transformed in the first place.

Drug bioaccumulation not only transforms bacterial metabolism but also acts as a drug reservoir, which may lead to toxicity concerns. Researchers continue to discover which medications bind to metabolic enzymes in gut bacteria, altering the form and function of those same bacteria.

Original studies have focused primarily on the pharmacokinetic effects of life-saving therapeutics, including:

Immunotherapies
Specific chemotherapeutic agents
Antimicrobial drugs
Anti-inflammatories

Shaping the Microbiome Composition to the Patient's Advantage

Accepting that the patient's microbiome is an obligatory gatekeeper to any given drug treatment may help us formulate new ways to use this fact to our advantage. If our microbiome represents a critical modifier of health and disease, modulating it before drug treatment to align with the treatment's purpose might increase its beneficial effects on the underlying condition.

Thus, the microbiome becomes a clinically significant pharmaceutical target [4] in itself. In long-term drug treatments for chronic illness, the individualised approach could look something like this:

Identify a chronic disease and propose an appropriate drug treatment.
Profile the patient's microbiome. Shape the microbiome as needed through bacterial therapeutics: diet, drugs or supplements (prebiotics, probiotics, postbiotics) to align drug-microbiome interactions.
Start drug treatment and periodically monitor microbiome changes.
Realign possible negative microbiome deviations.

This new approach might suit long-term treatments, such as those used in psychiatric disorders. In these cases, powerful medications are taken chronically, often with variable and declining results, as treatment sometimes spans an entire lifetime [5].

Studied Drug-Microbe Associations

A recent 2020 Gut publication assessed drug-microbe associations [6] for specific drugs. This was the case for the following list of drugs:

Alpha and beta-blockers
Angiotensin-II-receptor antagonists
Angiotensin-converting enzyme inhibitors
Antihistamines
Calcium
Laxatives
Metformin
Opiates
Oral contraceptives
Paracetamol
Platelet aggregation inhibitors
Proton-pump inhibitors
Selective serotonin reuptake inhibitors (SSRIs)
Statins
Tricyclic antidepressants
Vitamin D3 [7]

Several studies point out how SCFAs produced by specific microbiota may contribute to metformin's therapeutic effect on glucose homeostasis, improving the body's ability to control insulin resistance.

However, scientists feel the need to explore the effect of polypharmacy, the use of five or more medications by an individual on a daily basis. Since nearly one-fourth (24%) of patients in England take three or more prescription drugs, and half of those patients take five or more [8], scientists felt it was necessary to examine polypharmacy's impact on the gut microbiota. This combined effect generates even greater layers of complexity in microbiota-drug interactions.

Postbiotics: Beyond Microbiome-to-Drug Interactions?

As research groups focus on microbiome-to-drug interactions, one must also consider the possible roles that gut-derived metabolites produced by the same bacteria may have on these drugs. These effects may range from chemical reactions and drug binding to deactivation or activation, or possible alterations in active transport of the drug through the mucosa. Bacterially derived metabolites might act as agonists or antagonists to the drug within specific cell receptors, enhancing or reducing the drug's effect within target cells.

One such described case may be metformin [9], a blood glucose-lowering oral drug with intriguing emerging applications in ageing [10], gut homeostasis [11] and even as a chemotherapy adjuvant [12].

Favourable, functional gut microbiota is usually linked to short-chain fatty acid (SCFA) producing bacteria [13]. SCFAs include acetate (C2), propionate (C3) and butyrate (C4). These SCFAs are involved in many normal gut functions, including nutrient digestion, absorption and bowel movements. In addition to all the processes in which they participate, they may also play further roles in the metabolism and effect of certain drugs.

For example, several studies point out how SCFAs produced by specific microbiota may contribute to metformin's therapeutic effect on glucose homeostasis [14], improving the body's ability to control insulin resistance [15]. Furthermore, compared with others, some patients' gut microbiome SCFA-producing profile appeared to offer relief from the adverse gastrointestinal effects of metformin.

The Future of Gut Health and Drug Efficacy

The gut microbiome in humans is an intricate ecosystem. The exchange between commonly used non-antibiotic drugs and gut microbes is equally complex and bidirectional.

Drugs can influence microbiome composition and vice versa. The gut microbiome can also affect a person's response to a medication. It does this by enzymatically changing the drug's structure and modifying its bioactivity, bioavailability or toxicity.

Gut microbiota also indirectly impacts a person's reaction to other non-pharmaceutical treatments, like supplements and dietary wellness products. However, further studies are needed to determine how these treatments affect gut health.

In the study conducted by EMBL and funded by the European Commission Horizon 2020 [16], researchers caution that the study's findings apply only to bacteria grown in the lab. More research is required to understand how gut bacteria medication bioaccumulation manifests inside the human body.