Interactions of Non-Nutritive Artificial Sweeteners with the Microbiome in Metabolic Syndrome

Abstract

Replacing sugar with non-nutritive artificial sweeteners (NAS) is a popular dietary choice for the prevention and management of metabolic syndrome and its comorbidities. However, evidence in human trials is conflicted regarding the efficacy of this strategy and whether NAS may counterintuitively promote, rather than prevent, metabolic derangements. The heterogeneity in outcomes may stem in part from microbiome variation between human participants and across research animal vivaria, leading to differential interactions of NAS with gut bacteria. An increasing body of evidence indicates that NAS can alter the mammalian gut microbiome composition, function, and metabolome, which can, in turn, influence host metabolic health. While there is evidence for microbiome-mediated metabolic shifts in response to NAS, the mechanisms by which NAS affect the gut microbiome, and how the microbiome subsequently affects host metabolic processes, remain unclear. In this viewpoint, we discuss data from human and animal trials and provide an overview of the current evidence for NAS-mediated microbial and metabolomic changes. We also review potential mechanisms through which NAS may influence the microbiome and delineate the next steps required to inform public health policies.

Keywords: diabetes; metabolic syndrome; metabolomics; metagenomics; microbiome; non-nutritive artificial sweeteners (NAS); obesity.

Figure 1.. Effects of NAS on the microbiome composition and function.

Studies investigating the association of NAS and mammalian microbiomes were retrieved using the search terms (Microbiome OR Microbiota) AND (Saccharin OR Sucralose OR Aspartame OR Acesulfame Potassium OR Neotame) on https://pubmed.ncbi.nlm.nih.gov/. Only research articles were selected. Studies in which the effect of NAS could not be isolated from that of an unrelated additive were excluded from analysis. Microbial features (taxa, functions, metabolites) included in this figure were significantly altered in at least three independent works, regardless of direction of the effect. An indicated feature was labeled as not significantly changed if it was clearly labeled as such in a study, or it was not included in a list reported by the authors as encompassing all significantly altered features. In experiments with dams consuming NAS, pups were exposed prenatally and through lactation, but were not directly supplemented with NAS. AceK, Acesulfame Potassium; ASP, Aspartame; NEO, Neotame; SAC, Saccharin; SCL, Sucralose; NC, Normal Chow; HFD, High Fat Diet; HFSD, High Fat/Sucrose Diet; DSS, Dextran Sulfate Sodium; AOM, Azoxymethane; FMT, Fecal Microbiota Transplant; MG, Metagenomics; GF, Germ-Free; F/M, Female/Male; ND, No Data/Not Determined. 1, FMT from offspring of dams consuming ASP; 2, FMT from mice consuming SAC + glucose; 3, FMT from mice consuming pure SAC and HFD; 4, FMT with fecal microbiome cultured with SAC.

Figure 2.. Putative mechanisms for microbiome modulation by NAS.

Gut bacteria can directly interact with NAS through several mechanisms, which may lead to growth promotion, inhibition, or community-wide effects.