Impacts of non-nutritive sweeteners on the human microbiome

Replacing sugar with non-nutritive sweeteners (NNS) is a common dietary strategy for reducing the caloric content and glycemic index of foods and beverages. However, the efficacy of this strategy in preventing and managing metabolic syndrome and its associated comorbidities remains uncertain. Human cohort studies suggest that NNS contribute to, rather than prevent, metabolic syndrome, whereas randomized controlled trials yield heterogeneous outcomes, ranging from beneficial to detrimental impacts on cardiometabolic health. The World Health Organization recently issued a conditional recommendation against using NNS, citing the need for additional evidence causally linking sweeteners to health effects. One proposed mechanism through which NNS induce metabolic derangements is through disruption of the gut microbiome, a link strongly supported by evidence in preclinical models. This review summarizes the evidence for similar effects in interventional and observational trials in humans. The limited available data highlight heterogeneity between trials, as some, but not all, find NNS consumption associated with microbiome modulation as well as metabolic effects independent of sweetener type. In other trials, the lack of microbiome changes coincides with the absence of metabolic effects. We discuss the hypothesis that the impacts of NNS on health are personalized and microbiome dependent. Thus, a precision nutrition approach may help resolve the conflicting reports regarding NNS impacts on the microbiome and health. This review also discusses additional factors contributing to study heterogeneity that should be addressed in future clinical trials to clarify the relationship between NNS, the microbiome, and health to better inform dietary guidelines and public health policies.