Artificial and natural non-nutritive sweeteners drive divergent gut and genetic responses across generations

Background The role of non-nutritive sweeteners (NNS) in the development of metabolic alterations and chronic non-communicable diseases is controversial. It is also unclear whether these alterations are transmitted to offspring or whether the gut microbiota is involved in these processes. This study aimed to compare, in mice, the effect of parental sucralose or stevia consumption on fecal microbiota diversity/composition and short-chain fatty acid (SCFA) concentrations in mice, as well as on the expression of Tlr4, Tnf, Tjp1 and Srebp1 in the liver and intestines. The study also aimed to determine whether these changes are transmitted to the F1 and F2 generations. Methods Forty-seven male and female mice were divided into three groups to receive water alone or water supplemented with sucralose or stevia (0.1 mg/ml) for 16 weeks (F0 generation). The F0 mice were then bred to produce the F1 generation, and the F1 mice were bred to produce the F2 generation. The F1 and F2 animals did not receive NNS. Results No changes in the glucose oral tolerance test were observed between in the F0 generation, while the glycemic response was mildly altered in the F1 and F2 male mice in the Sucralose group. Compositional changes in the fecal microbiota were greater in the F0 and F1 generations, particularly the Sucralose group. Animals from the F0 Sucralose and Stevia groups had lower SCFA concentrations, and this trait was passed on to next generations. In terms of gene expression, Tlr4 and Tnf were overexpressed in the intestine of the F0/F1 Sucralose group, while Srebp1 expression was lower in the liver of the F0 Sucralose group, a change that persisted in the F1 and F2 generations. Tlr4 and Tnf expression was higher in the F1 Stevia group and normalized in the F2. Conclusion Sucralose consumption affects glucose tolerance, the expression of liver Srebp1 and intestinal Tnf and Tlr4 , fecal microbiota composition and SCFA concentrations, and these changes are transmitted across generations. The effects of stevia are mainly observed in the F1 generation.