Gut Microbiome alters 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 people are recognising that drugs and our microbiome impact each other..." Typas said that these interactions might have a critical consequence on our health.
Peer Bork, Director of Scientific Activities at EMBL, added, “This calls for us to start treating 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 to maximise the chances of experiencing the desired positive health outcome aimed in the first place.
Researchers realise that varying individual reactions to medications seen in their clinical practice may well be modulated and tied to an individual’s gut bacteria. Medical health professionals must consider whether the patient’s expected therapeutical response and side effects might be influenced by their microbiota. Health professionals also need to consider how prolonged treatments might entice strain-specific microbiota changes that would, in turn, reduce the drug's effectiveness or its dosage.
The optimal goal would be to predict patient responses depending on their microbiome composition, allowing health care providers to individualise drug treatments and modulate them in time as the treatment progresses. Navigating this intricate and complex issue may seem daunting to health professionals and patients, as the complete knowledge of microbiome-to-drug interactions still eludes us due to its mounting complexity.
Several research groups are systematically trying to map drug and bacteria interactions, describe how microbes transform them and, eventually, try to predict the effect this biotransformation might entice. A newly published study by Nature revealed 70 bacteria-drug interactions [2] after investigating the depletion of 15 structurally diverse medications by 25 representative gut bacteria strains. Nearly half of these bacteria-drug interactions were previously unknown and never reported before this study.
There is still a lot that we do not understand about the microbiome. Further research is necessary to realise the mechanism governing these processes.
The final goal would be to predict an individual’s response to various commonly used pharmaceuticals based on their microbiome to maximise the chances of experiencing the desired positive health outcome aimed in the first place. Here is what we have learned so far:
The Microbiome Bio Transforms Most Drugs
Microbiota treats oral drugs as just another chemical and transforms them in the gut most often than not. 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 to secondary metabolites can alter the therapeutic response in patients.
More often than expected, researchers realised that the microbiome acted on the drug like a bomb diffuser: the microbiome can reduce the potency or concentration of a drug to render it partially ineffective. In some cases, researchers reported this unwanted effect and instances of drugs becoming toxic after microbiota alterations. This biotransformation [3] could partially explain the ample range of reported side effects described for any given drug on the market. This fact is strain-dependent: distinct bacterial species within the microbiome transform certain medications while others do not.
Medications affected by the phenomena range from OTC medications to life-saving drugs, including antivirals and chemotherapeutic agents. Scientists primarily employ microbiome-depleted or germ-free animal models to identify these microbiotas-drug interactions. To test for bacterial specificity, they pain-snakingly administer specific bacterial isolates to germ-free animals along the drug to be tested and record the observable interactions.
Although this one-by-one approach is perfectly valid, it does not allow for the generalisation of humans that host a complete microbiome. The complex strain-to-strain interactions with a drug may result in outcomes different from those reported in the individual models.
Bacteria Bioaccumulate Drugs
Besides biotransformation, it is now known that common pharmaceutical drugs eventually accumulate in the microbiome, altering their bacterial function, which, in turn, may change how the drug is transformed in the first place.
Drug bioaccumulation not only transforms the metabolism of the bacteria but also acts as a drug reservoir, which may lead to toxicity concerns. Researchers continue to discover what medications bond to metabolic enzymes in the gut bacteria, altering the from that very same bacterium.
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 health and disease modifier, modulating it before any drug treatment to align with its purpose might positively increase its positive 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 would be somewhat like this:
- Diagnose a chronic disease and propose an adequate drug treatment.
- Profile the patient’s microbiome. Shape the microbiome as needed through bacterial therapeutics: diet, drugs or supplements (prebiotics, probiotics, postbiotics) to align with the microbiome to drug-microbiome interactions.
- Start drug treatment and periodically control for microbiome changes.
- Realign possible negative microbiome deviations.
This new approach might suit long-term treatments, such as psychiatric disorders. In these cases, powerful medications are taken chronically, with often variable and declining results, as the treatment sometimes spans an entire life span [5].
Studied Drug-Microbe Associations
A recent 2020 GUT publication assessed drug-microbe associations [6] for specific drugs. That 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 taken daily. Since nearly one-fourth (24%) of patients [8] in England take three or more prescription drugs (and half of those patients take five or more), scientists felt it was necessary to examine polypharmacy's impact on gut microbiota. This compound effect generates more outstanding orders of complexity in the microbiota-drug interactions.
Postbiotics: Beyond the Microbiome to Drug Interactions?
As research groups focus on the microbiome-to-drug interactions, one must consider the possible roles the gut-derived metabolites produced by the same bacteria under study may have on these drugs. These effects may range from chemical to drug reactions and bindings, resulting in deactivation or activation to possible alterations of 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 the target cells.
One such described case may be metformin [9], a blood glucose-lowering oral drug with intriguing new 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) [13] producing bacteria. SCFAs include acetate (C2), propionate (C3) and butyrate (C4). These SCFAs accumulate many science-described roles in gut normal functions, including nutrient digestion, absorption and bowel movements. On top of all the processes in which they are involved, they also seem to play further roles in the metabolisation 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 to others, some patients' gut microbiome SCFA-producing profile offered 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 impact only the bacteria grown in the lab. More research is required to comprehend how gut bacteria medication bioaccumulation manifests inside the human body.
