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Abstract

Studies as early as in the 70s showed that the gut and its intrinsic gut microbiota is a possible site of drug modification and later studies confirmed that human microbiota metabolism with its diverse set of genes can be a cause for drug side effects. Yet, our knowledge of the biochemical capabilities of gut bacteria to interact with or metabolize therapeutic drugs remains largely incomplete. To our knowledge, there has not been any systematic screen of xenobiotic-microbial interactions elucidating how wide-spread bacterial drug modification is across therapeutic drugs or the gut microbiota. In my PhD work, I tested, under anaerobic conditions, 450 bacteria-drug interactions covering 25 metabolically diverse gut bacteria and 18 structurally diverse FDA-approved drugs. This revealed almost 50 novel bioaccumulation or biotransformation links between 19 bacterial species and 10 drugs. The implicated bacteria are phylogenetically diverse, including commensals, probiotics and bacteria associated with diseases. The affected drugs span diverse indication areas, from asthma (montelukast) to depression (duloxetine and aripiprazole). As a case in point, the results from this bacteria-drug interaction study are followed upon in more details through investigation of interactions involving duloxetine – a widely used antidepressant. I found that duloxetine induces higher diversity in synthetic bacterial communities, and its bioaccumulation by community members affects the community dynamics. Following, I found that duloxetine affects the native metabolism of B. uniformis and C. saccharolyticum, in particular the purine metabolism. These interactions might in turn influence bacterial behavior in a community. To find the direct protein targets of duloxetine in C. saccharolyticum, I used click chemistry-based methods and proteomics. Two of the five strongly enriched binding proteins are part of a NADH:quinone dehydrogenase complex. Two potential underlying mechanisms for duloxetine interactions are suggested: i) Duloxetine inhibits NADH:quinone dehydrogenase by binding to its quinone binding site. The resulting NADH excess leads to a change in downstream pathways like purine metabolism. ii) Duloxetine binds competitively on the NADH binding site of NADH:quinone dehydrogenase and other proteins. In addition to discovering new xenobiotic interactions, the study highlights a new dimension to gut microbiota-drug interactions, namely bioaccumulation, which so far has been largely overlooked. My results suggest that bioaccumulation of drug compounds might be a common feature to many gut bacteria and thus have broad and far-reaching implications for drug dosage decisions and personalized medicine.