Effects of Icariin on Modulating Gut Microbiota and Regulating Metabolite Alterations to Prevent Bone Loss in Ovariectomized Rat Model

Abstract

Postmenopausal osteoporosis (PMOP) is an estrogen deficiency-induced bone loss, which has been shown an association with an altered gut microbiota (GM). Gut microbiota-bone axis has been recognized as a crucial mediator for bone homeostasis. Icariin (ICA) is an effective agent to delay bone loss by regulating the bone homeostasis. Thus, we hypothesize that ICA can prevent bone loss by modulating GM and regulating metabolite alterations. The effects of ICA on bone metabolism improvement in ovariectomized (OVX) rats and their relationships with the GM and fecal metabolites were investigated. Micro-computed tomography (micro-CT) and hematoxylin-eosin (HE) staining showed a typical bone boss in OVX group, while ICA or estradiol (E2) administration exhibited positive effects on bone micro-architecture improvement. The GM such as Actinobacteria, Gammaproteobacteria, Erysipelotrichi, Erysipelotrichales, Enterobacteriales, Actinomycetales, Ruminococcus and Oscillospira significantly correlated to serum bone Gla-protein (BGP), receptor activator of nuclear factor-κB (RANK), receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG) and tartrate resistant acid phosphatase (TRACP). Further t-test revealed a substantial variation of the GM and fecal metabolites in different treatments. Among them, Lachnoclostridium, Butyricimonas, Rikenella, Paraprevolla, Adlercreutzia, Enterorhabdus, Anaerovorax, Allobaculum, Elusimicrobium, Lactococcus, Globicatella and Lactobacillus were probably the key microbial communities driving the change of bile acid, amino acid and fatty acid, thereby leading to an improvement of PMOP. The significant up-regulation of L-Saccharopine, 1-Aminocyclohexadieneacid and linoleic acid after ICA administration suggested important contributions of amino acid and fatty acid metabolisms in the prevention and treatment of PMOP. Taken together, our study has provided new perspectives to better understand the effects of ICA on PMOP improvement by regulating GM and the associated fecal metabolites. Our findings contribute to develop ICA as a potential therapy for PMOP.

Phytosterols Protect against Osteoporosis by Regulating Gut Microbiota

“…Several studies have reported that Bilophila and Ruminococcus are closely related to cholesterol, which is strongly associated with bone health. , High cholesterol increases osteoclast activity and decreases osteoblast function, especially in bone residential cells . Meanwhile, it has been reported that Ruminococcus correlates with serum indexes of bone homeostasis and inflammation while Ruminococcus protects intestinal mucus from degradation against the entry of harmful substances into the blood in ethanol-induced osteoporosis . We found that the relative abundance of Ruminococcus correlated negatively with TC concentration, which was significantly decreased in our study.…”

“…35 Meanwhile, it has been reported that Ruminococcus correlates with serum indexes of bone homeostasis and inflammation while Ruminococcus protects intestinal mucus from degradation against the entry of harmful substances into the blood in ethanol-induced osteoporosis. 37 We found that the relative abundance of Ruminococcus correlated negatively with TC concentration, which was significantly decreased in our study. In contrast, bone parameters are positively correlated with the relative abundance of Ruminococcus.…”

Evaluation of Biological Mechanisms of Quanduzhong Capsule for Treating Osteoporosis by Integrating Untargeted Metabolomics and Network Pharmacology

“…Estrogen deficiency can stimulate RAKNL expression and extend osteoclasts' lifespans while shortening osteoblasts'. 30 Enrichment analysis of pathways containing 25 differential metabolites revealed five pathways: unsaturated fatty acid biosynthesis, arachidonic acid metabolism, glycerophospholipid metabolism, steroid biosynthesis pathway, and primary bile acid biosynthesis. Only the first two pathways had p -values <0.05 with −log ( p ) > 2; consequently, arachidonic acid metabolism and unsaturated fatty acid biosynthesis were selected for analysis.…”

Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism

“…Notably, previous research demonstrated that Allobaculum may be a key microbial community that drives the metabolism of bile acid, amino acid, and fatty acid, thereby improving postmenopausal OP. 47 In addition, Zhou et al reported that Allobaculum is a specific bacteria associated with calcium absorption in osteoporotic rats, which may participate in improved BMD and bone microarchitecture. 48 To ulteriorly identify the specific microbial taxa that exhibited the largest differences between OVX + NS and OVX + MLT groups and were associated with MLT treatment, we performed linear discriminant analysis Effect Size (LEfSe) and Cladogram (based on maximum relative abundance difference in each level) analyses, which determined 8 strains of bacteria enriched in MLT-treated mice, while seven strains were enriched in OVX + NS mice (Figure 6I,J).…”