Impact of low-calorie sweeteners on gut bacteria is modulated by commonly used xenobiotics

The gut microbiota is implicated in adverse effects associated with low-calorie sweeteners. Yet, the direct impact of sweeteners on gut bacteria has not been systematically assessed. Here we report interactions between 25 phylogenetically diverse gut bacterial strains and 39 commercially used sweeteners. We tested these sweeteners individually and in combination with four commonly co-consumed compounds, viz., advantame, caffeine, vanillin, and duloxetine. Three quarters of the sweeteners individually impacted growth of at least one bacterial strain. Further, >100 interactions were found between sweeteners and the four co-consumed compounds. Isosteviol, a commonly used sweetener, and duloxetine, an antidepressant, synergistically inhibited Roseburia intestinalis, a bacterium linked to glucose homeostasis, and Parabacteroides merdae, a prevalent commensal linked to healthy microbiota. Proteomic, metabolomic, and genetic analyses indicate altered small molecule transport underpinning this sweetener-drug synergy. The isosteviol-duloxetine combination also modulated metabolism of a synthetic gut bacterial community leading to increased toxicity to HeLa cells and altered secretion of inflammation modulatory cytokines IL-6 and IL-8 by Caco-2 cells. Our data provides a mechanistic basis for sweetener-gut bacteria interaction and warrants considering their interaction with drugs in side-effect assessments.