Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Withaferin A maintained microbiome and metabolome features in A53T transgenic mice via multi-omics integrated analysis.
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Sun Xiaodong, Qin Bingqing, Guo Ai, Gui Jianjun, Weng Jingjing, Ye Junjie, Feng Shenglan, Sang Ming
Аннотация
BACKGROUND: Withaferin A (WFA), a naturally occurring compound, has shown promise as a therapeutic agent for Parkinson's disease (PD), a neurodegenerative disorder associated with motor and gastrointestinal dysfunctions. However, its effects on gut microbiota metabolism remain poorly understood.
PURPOSE: This study aimed to elucidate the neuroprotective mechanisms of WFA in a PD mouse model by investigating its regulation of gut microbiota composition, metabolic pathways, and correlations with brain spatial metabolomics.
METHODS: Human SNCA-transgenic (A53T) mice were treated with WFA and evaluated using behavioral tests, immunohistochemistry, Western blot, and ELISA to assess motor/cognitive functions and PD-related pathology. Gut microbiota composition was analyzed via 16S rRNA sequencing, while untargeted fecal metabolomics and brain spatial metabolomics were employed to identify metabolic alterations.
RESULTS: WFA significantly improved motor performance, alleviated cognitive deficits, restored intestinal barrier integrity, and reduced neuroinflammation. It elevated the abundance of anti-inflammatory gut bacteria (e.g., Bifidobacterium, Dubosiella, Akkermansia) and reversed 55 fecal metabolites linked to sphingolipid metabolism, serotonergic synapses, and neuroactive ligand- receptor interactions. Spatial metabolomics revealed WFA's regulation of sphingolipid signaling pathways, including sphingosine kinase (Sphk1), ceramidase, sphingosine 1-phosphate receptor (S1PR5), and endocannabinoid receptor CB2 expression. Correlation analysis indicated a link between brain metabolite content and gut microbiota abundance.
CONCLUSION: Our findings highlight a potential mechanism of WFA that repairs neurons by modulating the sphingolipid signaling pathway within the microbiota-gut-brain axis.
PURPOSE: This study aimed to elucidate the neuroprotective mechanisms of WFA in a PD mouse model by investigating its regulation of gut microbiota composition, metabolic pathways, and correlations with brain spatial metabolomics.
METHODS: Human SNCA-transgenic (A53T) mice were treated with WFA and evaluated using behavioral tests, immunohistochemistry, Western blot, and ELISA to assess motor/cognitive functions and PD-related pathology. Gut microbiota composition was analyzed via 16S rRNA sequencing, while untargeted fecal metabolomics and brain spatial metabolomics were employed to identify metabolic alterations.
RESULTS: WFA significantly improved motor performance, alleviated cognitive deficits, restored intestinal barrier integrity, and reduced neuroinflammation. It elevated the abundance of anti-inflammatory gut bacteria (e.g., Bifidobacterium, Dubosiella, Akkermansia) and reversed 55 fecal metabolites linked to sphingolipid metabolism, serotonergic synapses, and neuroactive ligand- receptor interactions. Spatial metabolomics revealed WFA's regulation of sphingolipid signaling pathways, including sphingosine kinase (Sphk1), ceramidase, sphingosine 1-phosphate receptor (S1PR5), and endocannabinoid receptor CB2 expression. Correlation analysis indicated a link between brain metabolite content and gut microbiota abundance.
CONCLUSION: Our findings highlight a potential mechanism of WFA that repairs neurons by modulating the sphingolipid signaling pathway within the microbiota-gut-brain axis.