Amomum villosum Lour. alleviates pre-eclampsia by inducing enrichment of Bifidobacterium bifidum through vanillic acid to inhibit placental ferroptosis
Peishi He, Haoqing He, Chang Su, Yarui Liu, Jiahan Wang, Yun Wu, Bing Wang, Shuhong Wang, Jie Zhao
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Amomum villosum Lour. (AVL), a traditional Chinese medicine, is widely used to pregnancy-related vomiting and prevent miscarriage. Pre-eclampsia (PE) is a severe pregnancy syndrome. Recent studies have demonstrated interactions between PE and the digestive system. However, it is uncertain that AVL against PE was associated with the gut. AIM OF THE STUDY: The current research examined the curative impact of AVL on PE and underly mechanisms based on the gut-placenta axis. MATERIALS AND METHODS: A water decoction of AVL (WOA) was extracted in boiling water, and then the decoction was converted into dried particles by freeze drying. An NG-nitro-L-arginine methyl ester (L-NAME)-induced PE mouse model was established and the preventative activity of WOA was evaluated. Furthermore, the gut microbial composition and structure were analyzed using 16S rRNA gene sequencing. Fecal microbiota transplantation (FMT) experiment was applied to confirm the efficacy of gut microbiota remodeled by WOA. RESULTS: WOA presented protective efficacy against PE. Notably, WOA induced a significant decrease in maternal hypertension and urine protein levels and promoted fetal intrauterine growth in a dose-dependent manner, thereby improving adverse pregnancy outcomes. Moreover, WOA modulated the angiogenic imbalance by decreasing the ratio between sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor) to repair placental injury and inhibited placental ferroptosis by increasing the protein levels of FPN1, FTH1, xCT, and GPX4. Tight junction proteins (ZO-1, Occludin, Claudin1) in the placenta and colon were significantly upregulated by WOA, leading to enhanced placental and gut barriers. WOA rescued intestinal dysbiosis by enriching Bifidobacterium and Akkermansia. Fecal microbiota transplantation (FMT) experiments revealed that the protection of WOA on placenta and gut were dependent on the gut microbial composition. Furthermore, supplementation with both Bifidobacterium bifidum (B. bifidum) and vanillic acid (VA, the major component of WOA) ameliorated PE symptoms. Intriguingly, results from both in vivo and in vitro analyses indicated that the B. bifidum population was enriched by VA. CONCLUSIONS: This research is the first to demonstrate that WOA prevents PE by enriching Bifidobacterium bifidum, strengthening the gut-placenta barrier, and inhibiting placental ferroptosis. Our findings provide compelling evidence for the vital involvement of the gut-placental axis in the protection of AVL on PE, presenting a novel target for the clinic.