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Yet, our knowledge of the extent of damage, the antibiotic activity spectra, and the resistance mechanisms of gut microbes is sparse. This limits our ability to mitigate microbiome\u2010facilitated spread of antibiotic resistance. In addition to antibiotics, non\u2010antibiotic drugs affect the human microbiome, as shown by metagenomics as well as\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies. Microbiome\u2013drug interactions are bidirectional, as microbes can also modulate drugs. Chemical modifications of antibiotics mostly function as antimicrobial resistance mechanisms, while metabolism of non\u2010antibiotics can also change the drugs\u2019 pharmacodynamic, pharmacokinetic, and toxic properties. Recent studies have started to unravel the extensive capacity of gut microbes to metabolize drugs, the mechanisms, and the relevance of such events for drug treatment. These findings raise the question whether and to which degree these reciprocal drug\u2013microbiome interactions will differ across individuals, and how to take them into account in drug discovery and precision medicine. This review describes recent developments in the field and discusses future study areas that will benefit from systems biology approaches to better understand the mechanistic role of the human gut microbiota in drug actions.\n                  <\/jats:p>","DOI":"10.15252\/msb.202010116","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T05:11:25Z","timestamp":1616044285000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":128,"title":["Towards a mechanistic understanding of reciprocal drug\u2013microbiome interactions"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-3589","authenticated-orcid":false,"given":"Michael","family":"Zimmermann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6166-8640","authenticated-orcid":false,"given":"Kiran Raosaheb","family":"Patil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0797-9018","authenticated-orcid":false,"given":"Athanasios","family":"Typas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6473-4762","authenticated-orcid":false,"given":"Lisa","family":"Maier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"key":"BFMSB202010116_CR1","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/s41586-019-0965-1","volume":"568","author":"A Almeida","year":"2019","unstructured":"Almeida A, Mitchell AL, Boland M, Forster SC, Gloor GB, Tarkowska A, Lawley TD, Finn RD (2019) A new genomic blueprint of the human gut microbiota. 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