We have learned that the environment can overcome genetics in shaping the human gut microbiome. Diet and drugs in particular are major drivers of the gut microbiome’s composition and functional diversity, and scientists are interested in better understanding not only how drugs impact the gut microbiome, but also how gut microbes shape the efficacy and safety of drugs.
A recent narrative review in Gut sheds some light on the clinical impact of interactions between drugs and the gut microbiome.
Although antibiotics are already known to affect gut microbiome diversity, in recent years several human cohort studies have reported that a number of drugs designed to act on human cells also appear to interfere with them. In the beginning, drug-microbe associations were mostly assessed for individual drugs. That is the case of proton pump inhibitors, metformin, angiotensin-converting enzyme inhibitors, alpha and beta blockers, angiotensin-II-receptor antagonists, antihistamines, laxatives, opiates, oral contraceptives, paracetamol, platelet aggregation inhibitors (e.g., aspirin), selective serotonin reuptake inhibitors, tricyclic antidepressants, statins, calcium and vitamin D.
Later, scientists became interested in exploring the impact of polypharmacy on the gut ecosystem as this is a more likely scenario in the clinical setting. In that regard, an in vitro study showed that of a sample of 835 drugs designed to interact with human cells, almost a quarter can hinder the growth of at least one bacterial species. But what are the clinical consequences of reaction types catalyzed by the gut microbiota?
The gut microbiota is like a microbial pharmacist within us, either increasing drugs’ bioavailability (e.g., sulfasalazine, prontosil), decreasing their bioavailability (e.g., digoxin, methotrexate) or increasing their toxicity (e.g., non-steroidal anti-inflammatory drugs).
The direct influence of gut microbes on how we respond to a specific drug by enzymatically transforming drug structure and altering bioavailability, activity or toxicity can affect health outcomes. The drug subject to the most study in this regard is metformin and it is now clear that short-chain fatty acid producers in the gut can contribute to the therapeutic effect of metformin in improving insulin resistance and glucose homeostasis. Likewise, the gut microbiome might mediate the adverse gastrointestinal effects driven by metformin in some patients.
Another example is how the long-term use of proton pump inhibitors leads to a reduction in stomach acidity, which alters gut microbiome composition and reduces colonization resistance to enteric infections. In other cases, the bidirectional interaction between drug and gut commensals is more apparent. That is the case with levodopa, which is converted to dopamine in the gut, leading to decreased drug availability and increased hypertensive crisis through the conversion of bacterial-derived dopamine to m-tyramine.
The gut microbiome can also indirectly impact a patient’s response to immunotherapy in cancer treatment, especially immune checkpoint inhibitors involving blockade of programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) and the cytotoxic T-lymphocyte antigen-4 (CTLA-4). Although the intriguing possibility that targeting the gut microbiome might offer a way of improving response to immunotherapy, challenges remain. Those challenges include the existence of unfavorable bacteria in the gut that can negatively affect the efficacy of immunotherapy, the selection of an optimal fecal microbiota transplant donor when treating refractory Clostridioides difficile diarrhea in the clinical setting, and clarifying the impact of treatments on intestinal microbial composition.
Other factors, including diet, lifestyle, sleep cycles, stress, exercise and disease, can regulate gut microbial composition. As a result, it may be worth considering those parameters in studies exploring the efficacy of drugs mediated by the gut microbiome.
On the whole, greater clarity about the impact of drugs on the gut microbiome and how the microbiome itself metabolizes drugs and affects their efficacy and safety profile will help with finding potential avenues for modulating the gut microbiome to improve current treatments. The complexity of the gut microbiome may also hide additional pathways of drug-microbiome interactions. It would also be important to investigate the role of fungi and viruses that can impact immune response and therefore shape therapeutic response to drugs.
Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut. 2020; 69(8):1510-1519. doi: 10.1136/gutjnl-2019-320204.
Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016; 14(5):273-287. doi: 10.1038/nrmicro.2016.17.
Gopalakrishnan V, Helmink BA, Spencer CN, et al. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018; 33(4):570-580. doi: 10.1016/j.ccell.2018.03.015.