Systematic identification of microbial effects on the host’s drug response in humans or mammalian model systems is challenging because of their complex diet and microbiota, as well as relatively low scalability. All these processes can change drug action and it is therefore important to systematically identify which bacteria modulate the efficacies of which drugs, and to dissect the mechanisms involved. Third, the metabolic crosstalk between the microbiota and its host can modify host physiology, and consequently drug efficacy 7.
Second, bacteria can alter host drug availability, for instance, by drug sequestration or modification 1, 6. Known as dysbiosis, such altered composition can affect the host’s response to therapeutic drugs 3, 4, 5. First, the microbial composition can change in response to drugs. Several mechanisms have been identified by which microbes influence the host’s drug response. Therefore, it is perhaps not surprising that the microbiota can also impact our response to medications 1. The gut microbiota are among the first cells to encounter orally ingested nutrients and xenobiotics. The bacteria that inhabit our body, known as our microbiota, influence many biological processes in both health and disease and greatly contribute to our metabolic capacity 1, 2. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.
Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. We find that different bacteria dramatically modulate tamoxifen toxicity in C. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells.
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