Recent studies suggest that high-fructose diet induces neuroinflammation in mice1, yet the underlying mechanisms are unclear. Here, we explored the possible causal role of the gut microbiota in high-fructose diet-induced neuroinflammation. To this end, mice were fed a control or high-fructose diet with or without broad-spectrum antibiotics for 30 d. Our data showed that high-fructose diet-induced neuroinflammation depended on the presence of the gut microbiota, because neuroinflammation was completely eliminated by antibiotics, although high-fructose diet-induced intestinal barrier impairment was sustained in these mice. Short-chain fatty acids (SCFAs) are products of dietary components fermented by the gut microbiota. We found that high-fructose diet reduced the number of intestinal SCFAs-producing microbiota and fecal SCFAs. The activation of nucleotide-binding oligomerization domain protein-like receptors, pyrin-domain containing (NLRP)-6 inflammasome, a recently described essential mechanism of maintaining intestinal barrier and healthy gut microbiota2, was also inhibited in mice fed with fructose. Treatment of high-fructose diet-mice with SCFAs could activate NLRP6 inflammasome, maintain intestinal barrier integrity and reduce neuroinflammation. Mulberroside A is a natural polyhydroxylated stilbene compound isolated from the roots and twigs of Morus alba L. It is known for its antibacterial, anti-inflammatory, antioxidant and neuroprotective effects. We found that mulberroside A could reverse gut microbiota dysbiosis, increase the concentration of fecal SCFAs, activate NLRP6 inflammasome, maintain intestinal barrier integrity and reduce neuroinflammation. These results not only suggest that gut microbiota dysbiosis may provide a new pathogenic mechanism for fructose-induced neuroinflammation, but also indicate that mulberroside A may be a new therapeutic approach to prevent gut microbiota dysbiosis and neuroinflammation induced by high-fructose diet.
[1] Xu MX, Yu R, Shao LF, et al. Brain Behav Immun 2016; 58:69-81.
[2] Levy M, Thaiss CA, Zeevi D, et al. Cell 2015; 163:1428-43.