The overlooked side effect of many drugs
Many FDA approved drugs have an effect on the growth of bacteria commonly found in the gut.
A new study in Nature tested a commercially available drug library of 835 compounds against 38 representative organisms of the human gut microbial community. Not a single antibiotic was tested and yet a quarter of the drugs had antibiotic-like activity when screened against at least one of the bacteria.
The meltdown in the press could not have been more predictable as The Telegraph proclaimed:
Strange wording, considering that if they wanted to be hyperbolic and click-friendly they could have also put "cancer" in the headline as chemotherapy drugs were present in the library. Oh, well, there's always next time. The Guardian where more measured in their coverage.
If we can look past the hyperbole, the research is very interesting and is actually two papers if we consider the companion in Nature Microbiology.
In the Nature Micro paper, the authors lay the groundwork by screening gut bacteria across a range of different defined media. This enabled the team to uncover metabolic idiosyncrasies and nutrient preferences in each of the strains. They also remark that the fact that many of the strains grow in at least one of the relatively simple defined media shows that gut bacteria seem not to have complex metabolic requirements. Importantly for their drug study, they find a growth medium in which the bacterial abundance comes close to that seen in the healthy human gut.
They then took this medium and carried out the drug screen in 96-well plates which was the focus of the second paper. They methodically screened the growth of the bacteria while exposed to a standard concentration of the drugs, which was the same concentration used in high-throughput drug screening. As previously mentioned, they found that 25% of the drugs tested had an effect on the growth on at least one of the bacteria. In some cases, the researchers were able to match this with clinical cohort data which was a nice validation of the screen.
I know people are going to complain that 38 strains aren't enough and that however good the growth medium was, it can't come close to approximating the human gut. This is fair, but I think the benefits of being able to grow the bacteria and watch how they interact with different drugs is worth the sacrifice. Growth media are an important part of microbiology and any way of making them more closely represent and more importantly, accurately predict disease outcomes is valuable. This study will surely inform clinical studies in the future and highlights the need to think about the gut microbiota when treating a patient for almost any disease.
A few commonly used non-antibiotic drugs have recently been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Here, we screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro. Particular classes, such as the chemically diverse antipsychotics, were overrepresented in this group. The effects of human-targeted drugs on gut bacteria are reflected on their antibiotic-like side effects in humans and are concordant with existing human cohort studies. Susceptibility to antibiotics and human-targeted drugs correlates across bacterial species, suggesting common resistance mechanisms, which we verified for some drugs. The potential risk of non-antibiotics promoting antibiotic resistance warrants further exploration. Our results provide a resource for future research on drug–microbiome interactions, opening new paths for side effect control and drug repurposing, and broadening our view of antibiotic resistance.
Extensive impact of non-antibiotic drugs on human gut bacteria
Nature, March 2018 10.1038/nature25979
Lisa Maier, Mihaela Pruteanu, Michael Kuhn, Georg Zeller, Anja Telzerow, Exene Erin Anderson, Ana Rita Brochado, Keith Conrad Fernandez, Hitomi Dose, Hirotada Mori, Kiran Raosaheb Patil, Peer Bork, Athanasios Typas