Drinking Water with Saccharin Sodium Alters the Microbiota-Gut-Hypothalamus Axis in Guinea Pig

SIMPLE SUMMARY: Saccharin sodium (SS) is one of the commonly used artificial sweeteners (AS) in the food industry, but the mechanisms mediating the physiological effects of sweeteners in the gut-brain axis is still unclear. The aim of this study was to explore the regulatory effect of SS on the microbiota-gut-hypothalamus axis on guinea pigs. We found that SS treatment may alter the growth and glucose metabolism of guinea pigs by activating sweet receptor signaling in the gut and growth hormone-releasing peptide (GHRP) hormone secretion. Besides, SS treatment increased the abundance of Firmicutes and Lactobacillasceae-Lactobacillus in the ileum, and subsequently increased levels of lactic acid and short-chain fatty acids (SCFAs). Adding 1.5 mM SS to drinking water alters the growth of guinea pigs by regulating the microbiota-hypothalamus-gut axis. This conclusion has theoretical implications for the comprehensive assessment of the biological effects of appropriate SS in the food industry. ABSTRACT: The effects of saccharin, as a type of sweetener additive, on the metabolism and development of mammals are still controversial. Our previous research revealed that saccharin sodium (SS) promoted the feed intake and growth of guinea pigs. In this experiment, we used the guinea pig model to study the physiological effect of SS in the microbiota-gut-hypothalamus axis. Adding 1.5 mM SS to drinking water increased the serum level of glucose, followed by the improvement in the morphology and barrier function of the ileal villus, such as SS supplementation which increased the villus height and villus height/crypt depth ratio. Saccharin sodium (SS) treatment activated the sweet receptor signaling in the ileum and altered GHRP hormone secretion. In the hypothalamus of SS and control (CN) group, RNA-seq identified 1370 differently expressed genes (796 upregulated, 574 downregulated), enriching into the taste signaling transduction, and neuroactive ligand–receptor interaction. LEfSe analysis suggested that Lactobacillaceae-Lactobacillus was the microbe with significantly increased abundance of ileum microorganisms in the SS-treated group, while Brevinema-Andersonii and Erysipelotrichaceae-Ilebacterium were the microbes with significantly increased abundance of the control. Furthermore, SS treatment significantly enhanced the functions of chemoheterotrophy and fermentation of ileal microflora compared to the CN group. Accordingly, SS treatment increased levels of lactic acid and short-chain fatty acids (acetic acid, propionic acid and N-valeric acid) in the ileal digesta. In summary, drinking water with 1.5 mM SS activated sweet receptor signaling in the gut and altered GHRP hormone secretion, followed by the taste signaling transduction in the hypothalamus.