Anti-diarrheal drug loperamide induces dysbiosis in zebrafish microbiota via bacterial inhibition

BackgroundPerturbations of animal-associated microbiomes from chemical stress can affect host physiology and health. While dysbiosis induced by antibiotic treatments and disease are well known, chemical, non-antibiotic drugs have recently been shown to induce changes in microbiome composition, warranting further exploration. Loperamide is an opioid-receptor agonist drug widely prescribed drug for treating acute diarrhea in humans. Loperamide is also used as a tool to study the impact of bowel dysfunction in animal models by inducing constipation, but its effect on host-associated microbiota is poorly characterized. ResultsWe used conventional and gnotobiotic larval zebrafish models to show that in addition to host-specific effects, loperamide also has anti-bacterial activities that directly induce changes in microbiota diversity. This dysbiosis is due to changes in bacterial colonization, since germ-free zebrafish mono-reconventionalized with bacterial strains sensitive to loperamide are colonized up to 100-fold lower when treated with loperamide. Consistently, the bacterial diversity of gnotobiotic zebrafish colonized by a mix of representative bacterial strains is affected by loperamide treatment. ConclusionOur results demonstrate that loperamide, in addition to host effects, also induces dysbiosis in a vertebrate model, highlighting that established treatments can have underlooked secondary effects on microbiota structure and function. This study further provides a insights for future studies exploring how common medications directly induce changes in host-associated microbiota. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/537295v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@11c5492org.highwire.dtl.DTLVardef@f44f40org.highwire.dtl.DTLVardef@17eff8corg.highwire.dtl.DTLVardef@bb691a_HPS_FORMAT_FIGEXP M_FIG C_FIG