BACKGROUND: 6-Shogaol is a natural dietary phenolic extensively rich in edible and medicinal plants such as Zingiber officinale Roscoe and Brassica spp., utilized as tumor inhibitor and a promising anti-aging drug. Our previous study has revealed that 6-shogaol significantly prolonged healthy life of C. elegans. However, the interactions of 6-shogaol with the microbiota, gut and brain during natural aging process remain largely unexplored.
PURPOSE: This study aims to explore the anti-aging effects and potential mechanisms of microbiota-gut-brain axis mediated by 6-shogaol.
STUDY DESIGN AND METHODS: 18-month-old C57BL/6 mice were orally gavaged with 6-shogaol (10, 20 mg/kg.bw.) for 2 months. The autonomous exploratory, learning and memory capacities were investigated through behavioral tests. Furthermore, an integrated approach of untargeted, neurotransmitters-/SCFAs-targeted metabolomics and 16 s rRNA sequencing analysis was performed to reveal the underlying molecular mechanism of 6-shogaol in improving healthy aging, as well as histopathological staining, western blot and molecular docking analysis.
RESULTS: Declines of cognitive and memory capacities were significantly relieved by intervention of 6-shogaol in a dose-dependent manner during the natural aging process. Neurotransmitters-targeted metabolomics and histopathological staining indicated that 6-shogaol maintained the neurotransmitter homeostasis and protected hippocampus tissue. Untargeted and SCFAs-targeted metabolomics showed that butanoate metabolism was significantly upregulated by 6-shogaol. The observed metabolic regulatory effect of 6-shogaol was concomitant with augmentation of the intestinal barrier, as evidenced by the gut homeostasis, barrier integrity and up-regulated tight junction proteins. 16 s rRNA sequencing analysis revealed relative abundance of butyrate-producing microbiota (i.e., Muribaculaceae, Lachnospiraceae_NK4A136_group, Clostridium_sensu_stricto_1, Lachnospiraceae and Dubosiella) were significantly up-regulated, while the harmful bacteria of Clostridia_UCG-014, Turicibacter and Desulfovibrio were significantly inhibited in the 6-shogaol-fed group. Furthermore, 6-shogaol probably influenced aging trajectory of gut microbiota via regulating butyrate metabolism and type Ⅳ secretion system (T4SS).
CONCLUSION: This study explored the efficacy and mechanism of 6-shogaol in improving natural aging-associated declines of exploratory, learning and memory abilities via the bidirectional communication system connecting gut with brain in aging. Butyrate metabolism and butyrate-producing microbiota remodeled by 6-shogaol were probably the main contributors to the microbiota-gut-brain axis.
