Bioaccumulation of therapeutic drugs by human gut bacteria

Abstract

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. Yet, the systematic mapping of the respective interactions has only started recently 1 and the main underlying mechanism proposed is chemical transformation of drugs by microbes (biotransformation). Here, we investigated the depletion of 15 structurally diverse drugs by 25 representative gut bacterial strains. This revealed 70 bacteria-drug interactions, 29 of which had not been reported before. Over half of the new interactions can be ascribed to bioaccumulation, that is bacteria storing the drug intracellularly without chemically modifying it, and in most cases without their growth being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using clickchemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the community composition through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioral response of Caenorhabditis elegans to duloxetine. Taken together, bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, likely in an individual manner.Therapeutic drugs can have a strong impact on the gut microbiome and vice versa 2-5 . The underlying drug-bacteria interactions can reduce microbial fitness 6 or alter the drug availability through biotransformation 7-14 . The latter can have either a positive or a negative impact on drug activity and efficacy. While drugs like lovastatin and sulfasalazine are chemically transformed by gut bacteria into their active forms, bacterial metabolism can inactivate drugs such as digoxin 15,16 , or cause toxic effects as in the case of irinotecan 17 .Furthering the diversity of susceptible drugs, over one hundred molecules were recently reported to be chemically modified by gut bacteria 1 . Yet, the mechanistic view on these interactions is largely confined to drug biotransformation 12,13 . Drug accumulation without metabolizationTo expand the knowledge of bacterial effect on drug availability, we systematically profiled interactions between 15 human-targeted drugs and 25 representative human gut bacterial strains (21 species; with additional subspecies or conspecific strains of Bifidobacterium longum, Escherichia coli and Bacteroides uniformis) (Supplementary Table 1). The bacterial species were selected to cover a broad phylogenetic and metabolic diversity representative of the healthy microbiota 18 (Extended Data Fig. 1a, Supplementary Table 1). On the drug side, 12 orally administered small molecule drugs (MW<500 Da), amenable to UPLC-UV-based quantificat...

Machine Learning Predicts Drug Metabolism and Bioaccumulation by Intestinal Microbiota

“…Experimental data describing the depletion of drugs by gut microbiota were compiled from several studies, with the majority from work by Zimmerman et al and Javdan et al [1][2][3]6,7,10,12]. Zimmerman et al incubated 271 drugs independently with 76 gut bacterial isolates anaerobically for 24 h. Drugs were labelled as being significantly (p < 0.05) depleted by at least one bacterial strain if ≥20% reduction in starting concentration occurred [1].…”

“…In this model, microbial metabolism and bioaccumulation were combined within the same class because the data from Zimmerman et al did not differentiate between the two mechanisms [1]. Drug accumulation by intestinal bacteria is a newly recognised concept, and as such sufficient data with which to predict metabolism and bioaccumulation as separate outcomes do not yet exist [3]. In the future, many more instances of bioaccumulation will likely be mapped, allowing distinction between metabolism and bioaccumulation.…”

“…Over 150 drugs are recognised as being susceptible to metabolism or bioaccumulation by intestinal microbiota [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. These direct effects on drug concentration can lead to significant inter-individual variability in pharmacokinetics, arising due to differences between individuals' gut microbiome compositions [16][17][18].…”

“…These direct effects on drug concentration can lead to significant inter-individual variability in pharmacokinetics, arising due to differences between individuals' gut microbiome compositions [16][17][18]. Microbial drug metabolism or bioaccumulation (termed henceforth as depletion) is often dependent upon the production of specific enzymes that may be variably expressed between patients [3,[19][20][21][22][23]. For example, digoxin is inactivated by strains of E. lenta that produce the cardiac glycoside reductase (CGR) enzyme [24].…”

“…In rare cases when microbial metabolism is explored, it is usually conducted to determine drugs' stability in the colonic environment rather than to study pharmacokinetic variability [7]. Due to its underexplored nature, there is currently no universally accepted method for the confirmation of microbial drug bioaccumulation [3]. Common methods used to quantify microbial drug metabolism involve incubating drugs in either human or animal faecal slurries, microbial cultures, and less commonly in intestinal fluids to measure drug degradation over a defined period (usually ≤24 h) [1,2,6].…”