Although intake of certain non-antibiotic drugs -antidiabetics such as metformin and acarbose, proton pump inhibitors, non-steroidal anti-inflammatory drugs, and second-generation antipsychotics, opioids and statins– that target human cells have been related to changes in the gut microbiome composition, little is known regarding the extent to which this happens for a broader range of drugs.

A recent study, led by Dr. Nassos Typas from the European Molecular Biology Laboratory in Heidelberg (Germany), has found that many non-antibiotic human-targeted drugs may have a direct effect on the gut microbiome that potentially contribute to both their gastrointestinal side effects and therapeutic actions.

The researchers mapped interactions between drugs and human gut bacteria through monitoring the growth of 38 selected bacterial species -including commensals, pathobionts and a probiotic (Lactobacillus paracasei)- found in the gut microbiomes of healthy individuals, upon treatment with each of 1,079 drugs in anaerobic medium broth at 37 ºC. Assessed drugs included human-targeted drugs (835) and anti-infectives (156 with antibacterial activity -antibiotics and antiseptics- and 88 effective against fungi, viruses or parasites). All drugs were tested in concentrations within ranges of what is estimated to be found in the human gut.

78% of the antibacterials inhibited the growth of at least one bacterial species, and several were active against multiple species. Besides this, 24% of drugs that have molecular targets in human cells –including proton-pump inhibitors, antipsychotics, and metformin– inhibited the growth of at least one strain in vitro. The authors said this could be an underestimate of how drugs affect the gut microbiota due to the limited selection of bacterial strains screened. For some of these drugs, the researchers hypothesized that antimicrobial effects could be directly associated to their mechanism of action and thus contribute to therapeutic effects.

Antineoplastics, calcium-channel blockers and antipsychotics were medications with the most inhibitory effect on the gut microbiota.

While most of the human-targeted drugs affected only a few strains, 40 affected at least 10 strains. Major butyrate producers (Eubacterium rectale, Roseburia intestinalis, Coprococcus comes) and propionate producers (Bacteroides vulgatus, Prevotella copri, Blautia obeum) were the most sensitive, whereas gamma-proteobacteria representatives were the most resistant.

The researchers also found a strong correlation between resistance to antibacterials and resistance to human-targeted drugs. It was shown that Escherichia coli that overexpressed the antibiotic-resistance gene tolC -a well-known general resistance mechanism against antibiotics that acts by pushing out several antibiotics in E. coli and other bacteria- was resistant both to antibiotics and 6 of 7 non-antibiotic drugs, whereas E. coli lacking this gene was most sensitive to both. This effect was also seen in a B. uniformis strain. However, for Clostridium difficile, P. distansonis and Bacteroides fragilis, antibiotic resistance was higher than resistance to human-targeted drugs.

These data show that antibiotic resistance mechanisms might also protect bacteria against human-targeted drugs but mechanisms that confer resistance to each drug group may differ. According to the authors, further research is needed in this area in order to explore the role of non-antibiotic drugs in promoting antibiotic resistance. According to the authors: “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”.

To sum up, this is the first study to systematically characterize the impact of non-antibiotic drugs on a gut microbiome-like environment and to show that human-targeted drugs may boost antibiotic resistance. Further research in animal models and further clinical trials will depict a clear picture of mechanisms by which non-antibiotic drugs affect the gut microbiome and whether microbes could be targeted in order to reduce side effects and improve efficacy.

Learn more about the science behind this study in this video from the European Molecular Biology Laboratory:

Reference:

Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018. doi: 10.1038/nature25979.