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Integrated metagenomic and metabolomic analyses of the effects of total flavonoids of Rhizoma Drynariae on reducing ovariectomized-induced osteoporosis by regulating gut microbiota and related metabolites.

ABSTRACT:

TFRD has been widely used in China to treat osteoporosis (OP). However, the specific molecular mechanism of TFRD against OP has not been fully clarified. Our previous studies have also proved that TFRD could attenuate OP and the clinical equivalent dose of 67.5 mg/kg/d is the effective dose for TFRD treating OP. Therefore, this study used 67.5 mg/kg as the dosage of TFRD in combination with multi omics to investigate the mechanism of action of TFRD in the treatment of OP. The aim of this study was to further elucidate molecular mechanism of TFRD for treating OP based on metagenomic and metabolomic analyses. In this study, hematoxylin-eosin (H&E) staining, micro computed tomography (micro-CT) and bone mineral density (BMD) analysis were used to observe pharmacological effects of TFRD against ovariectomized (OVX)-induced OP. Subsequently, multiomics analysis including metagenomics, untargeted and short chain fatty acids (SCFAs) metabolomics were carried out to identify whether the anti-osteoporosis mechanism of TFRD correlated with gut microbiota and related metabolites. Our results indicate that TFRD could improve the microstructure and density of trabecular bone in OVX rats. 17 differential species, which mainly from Akkermansia, Bacteroides and Phascolarctobacterium genus, 14 related differential metabolites and acetic acid in SCFAs were significantly altered by OVX and reversed by TFRD. Furthermore, according to results of untargeted metabolomics analysis, it was found that several metabolic pathways such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and so on might play an important role in TFRD against OP. In order to further study the relationship between gut microbiota and related metabolites, spearman correlation analysis was used, and showed that gut microbiota such as Akkermansia muciniphila might be closely related to several metabolites and metabolic pathways. These findings suggest that TFRD treatment could reduce the effects of OVX-induced OP by altering.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS11866 | MetaboLights | 2025-05-12

REPOSITORIES: MetaboLights

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Integrated metagenomic and metabolomic analyses of the effects of total flavonoids of Rhizoma Drynariae on reducing ovariectomized-induced osteoporosis by regulating gut microbiota and related metabolites.

Li Qiuyue Q Wu Xuelin X Niu Xinyu X Yu Zhangjingze Z Fang Shengjie S Chu Xuelei X Zhu Jia J Song Qinghui Q Hou Chengzhi C Wei Xu X

PloS one 20250214 2

PMID: 39951448

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Project description:Background: Primary osteoporosis has increasingly become one of the risk factors affecting human health, and the clinical effect and action mechanism of traditional Chinese medicine in the treatment of primary osteoporosis have been widely studied. Previous studies have confirmed that in traditional Chinese medicine , Drynaria rhizome has a role in improving bone density. In this study, TMT-based proteomic analysis was conducted to derive potential targets for Drynaria rhizome treatment in postmenopausal osteoporosis. Methods: The model group (OVX) and experimental group (OVXDF) for menopausal osteoporosis were established using the universally acknowledged ovariectomy method, and the latter group received intragastric administration of 8.1 g /kg-1 of Drynaria rhizome for 12 weeks. After 12 weeks, femurs of rats selected for this study were examined with a bone mineral density (BMD) test, Micro-CT, ELISABiochemical testing, hematoxylin and eosin (HE) staining, and immunohistochemistry. A certain portion of the bone tissue was studied with a TMT-based proteomic analysis and functional and pathway enrichment analysis. Finally, key target genes were selected for Western blotting for validation. Results: The comparison of the OVXDF and OVX groups indicated that Drynaria rhizome could improve bone density. In the TMT-based proteomic analysis, the comparison of these two groups revealed a total of 126 differentially expressed proteins (DEPs), of which 62 were upregulated and 64 were downregulated. Further, by comparing the differential genes between the OVXDF and OVX groups and between the OVX and SHAM groups, we concluded that the 27 differential genes were significantly changed in the rats selected for the osteoporosis model after Drynaria rhizome intragastric administration. The gene ontology (GO) enrichment analysis of DEPs showed that molecular function was mainly involved in biological processes, such as glucose metabolism, carbohydrate metabolism, immune responses, and aging. A Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEPs revealed that multiple differential genes were enriched in the estrogen and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Relationships with nitrogen metabolism, glycerophospholipid metabolism, secretion systems, and tumor diseases were also observed. Western blotting was consistent with the analysis. Conclusions: We used TMT-based proteomics to analyze the positive effects of TCM Drynaria rhizome, which can regulate related proteins through the unique roles of multiple mechanisms, targets, and pathways. This treatment approach can regulate oxidative stress, improve lipid metabolism, reduce the inflammatory response mechanism, and improve bone density. These benefits highlight the unique advantages of TCM in the treatment of primary osteoporosis.

Project description:Purpose: Alcohol-induced damage to bone microstructure leads to alcoholic osteopenia (AOP). While prior studies have demonstrated alcohol's negative impact on bone density, the mechanisms by which alcohol induces osteoporosis through immune pathways, gut microbiota dysbiosis, and metabolic alterations remain insufficiently characterized. Given that alcohol is primarily absorbed in the upper gastrointestinal tract, the research aims to elucidate the role of spatial distribution disorders in gut microbiota and metabolites in the pathogenesis of alcohol-induced osteoporosis and to evaluate the potential of microbiota supplementation and targeted immunosuppressants as therapeutic strategies for related bone diseases. Methods: Eight-week-old male C57BL/6 mice were used to establish an osteoporosis model via the force-feeding method. Bone loss was validated using micro-computed tomography (micro-CT). Segmented intestinal samples and fecal samples were analyzed by 16S rRNA sequencing and metabolomics. Mechanistic studies were conducted by supplementing R. intestinalis, prostaglandin D2 (PGD2), and its specific immune inhibitor, Ramatroban. Analytical methods included tartrate-resistant acid phosphatase (TRAP) staining, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). For statistical analysis, paired t-tests were used for comparisons between two groups, while one-way analysis of variance (ANOVA) followed by Tukey's post hoc test was employed for multiple group comparisons.Results: Alcohol disrupts the spatial complexity of intestinal segments and fecal microbiota in mice, causing metabolic dysregulation and ultimately leading to elevated PGD2 levels. This, in turn, triggers Th17/Treg immune imbalance and osteoclast activation, resulting in bone loss. Supplementation with the probiotic R. intestinalis or inhibition of PGD2 can significantly improve bone density and alleviate inflammation.Conclusion: Due to the complex spatial distribution of gut microbiota, fecal or colonic microbiota alone cannot fully represent the entire gut environment. The microbiota and metabolites in the lower gastrointestinal tract are better indicators of the host's systemic metabolic status, while the sensitive changes in microbial diversity in the upper gastrointestinal tract also play a significant role in disease progression. This study demonstrates that alcohol-induced elevation of prostaglandin D2 (PGD2) is a key pathogenic factor in alcohol-induced osteoporosis (AOP). PGD2 accelerates bone loss by promoting osteoclast formation through the activation of Th17 cells. Furthermore, this study highlights the importance of investigating the spatial distribution of gut microbiota and metabolites, providing potential targets and novel strategies for the precise treatment of AOP and other diseases associated with external stimuli.

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Dataset Information

Integrated metagenomic and metabolomic analyses of the effects of total flavonoids of Rhizoma Drynariae on reducing ovariectomized-induced osteoporosis by regulating gut microbiota and related metabolites.

Dataset's files

Publications

Integrated metagenomic and metabolomic analyses of the effects of total flavonoids of Rhizoma Drynariae on reducing ovariectomized-induced osteoporosis by regulating gut microbiota and related metabolites.

Similar Datasets

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