Modulation of gut bacterial metabolism by commonly consumed sweeteners

The gut microbiota is implicated in adverse effects associated with artificial sweeteners. Yet, whether and how sweeteners directly impact gut bacteria is unclear. Here we report interactions between 25 phylogenetically diverse gut bacterial strains, and all commercially used 39 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 impacted growth of at least one bacterial strain. Further, >100 interactions were found between sweeteners and the co-consumed compounds. Notably, isosteviol, a commonly used sweetener, and duloxetine, an antidepressant, synergistically inhibited Roseburia intestinalis, a bacterium linked with glucose homeostasis. 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 pro-inflammatory cytokines IL-6 and IL-8 by Caco-2 cells. Our data provides a mechanistic basis for sweetener-microbiome link and warrants considering their interaction with drugs in side-effect assessments.