# Intro

New research in the journal Nature has demonstrated that many of the drugs we take every day may have hitherto unknown microbiome effects. Using high-throughput techniques, researchers measured the growth rate of 38 species of common gut bacteria after exposure to over 1,000 drugs at low concentrations. These drugs included many common antipsychotics and even OTC medications like aspirin. They found that almost a quarter of the compounds surveyed inhibited at least one species of bacteria and noted that this is probably an underestimate of their effects.

I must stress that this data is preliminary, in-vitro, and has possible conflicts of interest. So don’t freak out and stop taking your prescription medications because of one study with relatively small effect sizes. Consult your doctor before you do anything with these data!

# The Study

Researchers simulated the effect of small concentrations of common drugs on gut bacteria by measuring their growth rate in-vitro. Thirty-eight species of bacteria were chosen to represent the diversity of the human microbiome and the constraints of high-throughput testing.

All 38 species are found in the gut of healthy individuals and are part of a larger strain resource panel for the healthy human gut microbiome. 1

The species chosen included some disease causing species such as Clostridia difficile and Fusobacterium nucleatum, which cause “C. diff” infections and contribute to peridontal disease, respectively. A common probiotic, Lactobacillus paracasei, was also tested.

Similarly, the compounds were chosen to represent a broad array of drug classes (anti-diabetics, antipsychotics, NSAIDS, etc.).

Most compounds are administered to humans (1,079), and they cover all main therapeutic classes (Supplementary Table 1).1

Unfortunately, only off-patent drugs were screened here, which limits direct comparison of these results to some of the most commonly prescribed drugs today. Furthermore, some of the drugs were tested at lower concentrations than a typical dose would produce due to technique constraints.

In summary, we probed human-targeted drugs largely within physiologically relevant concentrations and our data are likely to under-report the impact of human-targeted drugs on gut bacteria.1

For instance, researchers estimated the the compound Fluvastatin (cholesterol lowering statin; trade name Lescol) reaches approximately 30uM concentration in the human gut while they were only able to test it at 20uM.

Researchers measured the change in growth rate of typical human gut bacteria upon exposure to over 1,000 common drugs –everything from acetaminophen to Zuclopenthixol.

# Results

A most shocking statistic is the sheer number of drugs that could inhibit the growth of gut bacteria despite being classified as non-antibiotic.

Notably, 27% of the non-antibiotic drugs were also active in our screen.1

Somewhat expectedly, compounds that are used to treat viruses, parasites, and similar are more likely to be antibiotic.

More than half of the anti-infectives against viruses or eukaryotes exhibited anticommensal activity (47 drugs; Fig. 1a, b).1

Even though many common drugs weren’t tested due to patent laws, we can draw some conclusions about the possibility of microbiome interactions from chemical similarity:

Drugs from all major ATC indication areas exhibited anticommensal activity, with antineoplastics, hormones and compounds that target the nervous system inhibiting gut bacteria more than other medications (Extended Data Figs 9a, 10).1

All these data point to some fairly alarming consequences, so the researchers attempted to match their in-vitro data with the small amount of in-vivo data in the literature.

Nonetheless, we find high concordance between the effects of drugs in vitro and in humans, confirming clinical relevance and direct anticommensal activity for the aforementioned cases.1

Two notable drugs that correlate well with the in-vivo data are metformin (for type-II diabetes) and omeprazole (for heartburn).

Twenty-seven per cent of the tested drugs slowed the growth of at least one species, and all classes of drugs showed at least some activity.

# Discussion

While the results are notable in and of themselves, the widespread implications are even more so. The researchers comment on the pharmaceutical industry as a whole:

Moreover, one could speculate that pharmaceuticals, used regularly in our times, may be contributing to a decrease in microbiome diversity in modern Western societies.1

And to the possibility that bacterial inhibition from antipsychotics may not be a bug, but a feature:

This raises the possibility that direct bacterial inhibition may not only manifest as side effect of antipsychotics, but also be part of their mechanism of action.1

Even more alarming is the implication that the development of antibiotic resistant superbugs may not be entirely due to antibiotics themselves.

All of these results point to an overlap between resistance mechanisms against antibiotics and against human-targeted drugs, implying a hitherto unnoticed risk of acquiring antibiotic resistance by consuming non-antibiotic drugs.1

It’s not all bad, however. C. diff is a common hospital acquired infection and it notoriously difficult to get rid of. Perhaps this research might open up new ways to combat some antibiotic resistant infections by combining the typical antibiotic course with one of the promising, non-antibiotic drugs found in this study.

These previously unknown drug interactions with the microbiome might be positively contributing to some medications’ therapeutic benefits. On the other hand, they might also be adding to the decline of Western microbiome diversity, and even increasing antibiotic resistance.

# Some Caveats

As I said in the intro, don’t go running off to dump all your drugs down the toilet. First of all, that’s a poor way to dispose of your pharmaceuticals. Secondly:

However, before any translational application can be pursued, our in vitro findings need to be tested rigorously in vivo (in animal models, pharmacokinetic studies and clinical trials) and understood better mechanistically.1

One note on the potential conflicts of interest: the lab where the research was conducted has filed for patents directly profiting from the results of this study. While this is not uncommon (many professors and researchers sign agreements with their employers giving away intellectual property rights), it is worth noting.

[European Molecular Biology Laboratory] has filed two patent applications on repurposing compounds identified in this study for the treatment of infections and for modulating the composition of the gut microbiome, and on the use of the in vitro model of the human gut microbiome to study the impact of xenobiotics…1

A lot of research is still needed to determine the real impact of these drugs on your microbiome.

# My Conclusions

This is quite exciting research. It could explain some of the common side effects in clinical trials with unknown pathophysiology. This data may give us some much needed insight on the variability of drug reactions and new avenues of research to pursue in the future.

As for me, I’ve been considering eating more resistant starch2 lately and this research just convinced me.

We really have a lot to learn about the bacterial friends we carry with us our whole lives.

So what do you think about all this? Ready to throw away your drugs? Is this a whole lot of nonsense? Let me know your thoughts in the comments!

# Bibliography

1 Maier, Lisa, Mihaela Pruteanu, Michael Kuhn, Georg Zeller, Anja Telzerow, Exene Erin Anderson, Ana Rita Brochado, et al. “Extensive Impact of Non-Antibiotic Drugs on Human Gut Bacteria.” Nature, March 19, 2018. https://doi.org/10.1038/nature25979. $$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$$$\uparrow$$

2 Yang, Xiaoping, Kwame Oteng Darko, Yanjun Huang, Caimei He, Huansheng Yang, Shanping He, Jianzhong Li, Jian Li, Berthold Hocher, and Yulong Yin. “Resistant Starch Regulates Gut Microbiota: Structure, Biochemistry and Cell Signalling.” Cellular Physiology and Biochemistry 42, no. 1 (2017): 306–18. https://doi.org/10.1159/000477386. $$\uparrow$$