Resource competition and metabolic cross-feeding are among the main drivers of microbial community assembly. Yet, the degree to which these two conflicting forces are reflected in the composition of natural communities has not been systematically investigated. Here we use genome-scale metabolic modeling to assess resource competition and metabolic cooperation potential in large co-occurring groups (up to 40 members) across thousands of habitats. Our analysis revealed two distinct community types, clustering at opposite ends in a trade-off between competition and cooperation. On one end, lie highly cooperative communities, characterized by smaller genomes and multiple auxotrophies. At the other end, lie highly competitive communities, featuring larger genomes, overlapping nutritional requirements, and harboring more genes related to antimicrobial activity. While the latter are mainly present in soils, the former are found both in free-living and host-associated habitats. Community-scale flux simulations showed that, while the competitive communities can better resist species invasion but not nutrient shift, the cooperative communities are susceptible to species invasion but resilient to nutrient change. In accord, we show, through analyzing an additional dataset, that colonization by probiotic species is positively associated with the presence of cooperative species in the recipient microbiome. Together, our analysis highlights the bifurcation between competitive and cooperative metabolism in the assembly of natural communities and its implications for community modulation.

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...