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Parabacteroides distasonis Improving osteoporosis progression through glycerophospholipid metabolism_blood

ABSTRACT:

Backround&Aim: Dysbiosis of gut microbiota is closely related to the pathogenesis of osteoporosis (OP). This study aimed to identify probiotic candidates and gut-derived metabolites capable of ameliorating osteoporosis via modulation of bone metabolism.

Methods: Ovariectomized (OVX) rats were used to model PMOP. Multi-omics analyses, including 16S rDNA sequencing, metagenomics, and untargeted metabolomics, were conducted to characterize gut microbiota(GM) and metabolic alterations following icariin (ICA) administration. Probiotic candidates enriched by ICA treatment were screened based on microbial and metabolic profiles. The effects of P. distasonis (LPD) were evaluated via oral gavage and fecal microbiota transplantation (FMT) in pseudo-germ-free OVX rats. Fecal samples from PMOP patients were analyzed using qPCR to assess LPD abundance. In vitro assays were performed to examine the osteogenic and anti-resorptive activities of glycerophospholipid metabolites derived from LPD.

Results: ICA administration improved bone microarchitecture and mechanical strength in OVX rats, restored intestinal barrier integrity, and altered GM composition. Multi-omics analysis identified Parabacteroides distasonis as a key bacterium enriched by ICA. Oral gavage of LPD and FMT from ICA-treated donors ameliorated bone loss in pseudo-germ-free OVX rats. Quantitative PCR of fecal samples confirmed reduced LPD abundance in PMOP patients. Metabolomic profiling revealed that ICA and LPD elevated circulating levels of phosphatidylcholine (PC), lysophosphatidylethanolamine (Lyso PE), and lysophosphatidylcholine (Lyso PC), which were positively correlated with bone formation markers. In vitro, these metabolites enhanced osteoblast differentiation and suppressed osteoclastogenesis.

Conclusions: ICA exerts anti-osteoporotic effects via GM modulation, in part through enrichment of LPD and its glycerophospholipid metabolites. These findings highlight LPD as a promising probiotic candidate and support the therapeutic potential of targeting the gut-bone axis in PMOP.

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

PROVIDER: MTBLS12803 | MetaboLights | 2025-08-01

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12803_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS12803_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12803_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12803_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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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.

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.

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Parabacteroides distasonis Improving osteoporosis progression through glycerophospholipid metabolism_blood

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