Posted on 16 April 2020
The side-effects of many drugs can be exacerbated by microbes in the gut, as their enzymes can chemically modify drug compounds in a number of ways that render them more harmful.
A Nature study looked at 271 orally administered drugs and 76 human gut bacteria. They found that for at least two thirds of the drugs, there was at least one bacteria that made enzymes allowing it to metabolise that drug compound.
These microbiome-encoded enzymes can directly and substantially affect intestinal and systemic drug metabolism in mice, and can explain the drug-metabolizing activities of human gut bacteria and communities on the basis of their genomic contents.Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R., & Goodman, A. (2019). Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature, 570(7762), 462-467. doi: 10.1038/s41586-019-1291-3
We have known for a long time that the gut microbiota can affect drug activity, but only recently have researchers begun to systematically dissect these interactions. Understanding how different gut microbes alter drug activity may help explain why different people can experience a different severity of side effects from the same drug.
A recent example of this phenomenon concerns the Parkinson’s disease drug Levodopa (L-DOPA). Human decarboxylase enzyme converts Levodopa into dopamine, a neurotransmitter that is deficient in the brains of Parkinson’s disease sufferers. However, if Levodopa is converted to dopamine before it can enter the brain, this can cause serious side effects like cardiac arrhythmia. To prevent premature activation, the decarboxylase inhibitor carbidopa is used alongside Levodopa, yet patients still experience widely varying side effects. A study published last year found that while carbidopa works on human decarboxylase, it does not inhibit the baceterial version of the enzyme, meaning that Levodopa can be converted to dopamine in the gut, before it can reach the brain.
Gut bacteria can also cause toxic effects by reactivating drugs that have been tagged for disposal by the liver. This was found to be the case with the anti-cancer drug irinotican, but researchers were able to target the bacterial enzyme responsible, thus alleviating the drug’s side effects.
Several teams are currently working on ways to inhibit bacterial enzymes in order to reduce drug side-effects. This could allow for the resurrection of drugs that might have failed clinical trials due to bacterial interactions. In cases where a bacterial enzyme cannot be targeted, it may also be possible to alter a patient’s microbiota to a composition that is more favourable for a given drug.
Mapping human microbiome drug metabolism by gut bacteria and their genes: https://doi.org/10.6084/m9.figshare.8119058
Inner Workings: Microbiota munch on medications, causing big effects on drug activity: https://doi.org/10.1073/pnas.2003785117
Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme: DOI: 10.1126/science.1191175
Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism: DOI: 10.1126/science.aau6323