Dissecting the collateral damage of antibiotics on gut microbes

Abstract

24Antibiotics are used for fighting pathogens, but also target our commensal bacteria as a side 25 effect, disturbing the gut microbiota composition and causing dysbiosis and disease 1-3 . 26Despite this well-known collateral damage, the activity spectrum of the different antibiotic 27 classes on gut bacteria remains poorly characterized. Having monitored the activities of 28 >1,000 marketed drugs on 38 representative species of the healthy human gut microbiome 4 , 29 we here characterize further the 144 antibiotics therein, representing all major classes. We 30 determined >800 Minimal Inhibitory Concentrations (MICs) and extended the antibiotic 31 profiling to 10 additional species to validate these results and link to available data on 32 antibiotic breakpoints for gut microbes. Antibiotic classes exhibited distinct inhibition spectra, 33including generation-dependent effects by quinolones and phylogeny-independence by β-34 lactams. Macrolides and tetracyclines, two prototypic classes of bacteriostatic protein 35 synthesis inhibitors, inhibited almost all commensals tested. We established that both kill 36 different subsets of prevalent commensal bacteria, and cause cell lysis in specific cases. 37This species-specific activity challenges the long-standing divide of antibiotics into 38 bactericidal and bacteriostatic, and provides a possible explanation for the strong impact of 39 macrolides on the gut microbiota composition in animals 5-8 and humans 9-11 . To mitigate the 40 collateral damage of macrolides and tetracyclines on gut commensals, we exploited the fact 41 that drug combinations have species-specific outcomes in bacteria 12 and sought marketed 42 drugs, which could antagonize the activity of these antibiotics in abundant gut commensal 43 species. By screening >1,000 drugs, we identified several such antidotes capable of 44 protecting gut species from these antibiotics without compromising their activity against 45 relevant pathogens. Altogether, this study broadens our understanding of antibiotic action on 46 gut commensals, uncovers a previously unappreciated and broad bactericidal effect of 47 prototypical bacteriostatic antibiotics on gut bacteria, and opens avenues for preventing the48 collateral damage caused by antibiotics on human gut commensals.49 3 MAIN TEXT 50 Medication is emerging as major contributor for changes in the composition of the human gut 51 microbiota 4,13-15 . Such severe and long-lasting changes are associated, and in some cases 52 causatively linked, to dysbiosis and a wide range of diseases 16 . Although several non-53 antibiotic drugs may also have a previously unappreciated impact on the gut microbiome 54 composition 4,16,17 , antibiotics, developed to have broad spectra and thereby target very 55 diverse pathogens, are long known to take a heavy toll on our gut flora, causing a variety of 56 gastrointestinal side-effects 18 , including Clostridioides (former Clostridium) difficile infections. 57Recently more attention has been given to this collateral damage of antibiot...

Inflammatory bowel disease biomarkers of human gut microbiota selected via different feature selection methods

“…In IBD patients, while the moderations of the microbial abundances in the dysbiotic gut are observed to play critical key roles in the persistent inflammation, no single specific pathogenic species have been etiologically associated with IBD ( Yoo & Kim, 2016 ; Scher et al, 2015 ). In this respect, predicting host phenotypes based on taxonomy-informed feature selection and establishing an association between microbiome and disease states could help to identify potential taxonomic biomarkers of diseases ( Marcos-Zambrano et al, 2021 ; Maier et al, 2020 ).…”

Antibiotics create a shift from mutualism to competition in human gut communities with a longer-lasting impact on fungi than bacteria

“…We used 5 different broad-spectrum antibiotics which are commonly used to treat human diseases [45]. Recent work by Maier et al [46] addresses the issue that most knowledge of antibiotic drugs and their bacterial targets is based on pathogens and not the commensal microbiome. In a large screening of 144 different antibiotics and the 40 most common gut microbial strains, most antibiotics inhibited growth of all tested bacterial strains.…”

Towards a mechanistic understanding of reciprocal drug–microbiome interactions

“…Similar approaches could be applied to treat dysbiosis induced by human‐targeted drug treatments. Two recent studies co‐administered small molecule drugs with antibiotics to alleviate the effects of antibiotics on gut commensals (preprint: Maier et al , 2020; Garland et al , 2020), providing new ways to avoid or revert the collateral damage of drug treatment on healthy microbiomes.…”

“…However, it remains unclear whether this is true for a broader and/or more diverse population, and what are the links to antibiotic classes, initial microbiome composition and treatment duration. Similarly, our knowledge on the target spectra, mode of action, and resistance mechanisms of the different classes of antibiotics and their specific effect on gut commensal bacterial species is scarce (preprint: Maier et al , 2020). To gain mechanistic insights into these matters, assays, tools, and test systems from decades of antibiotic research on pathogens can be capitalized and adapted to study gut commensal species in pure culture, within microbial communities and within the host, especially at a systematic level (Fig 2) (Maier & Typas, 2017).…”