Natural bioactive compounds in estrogen deficiency-induced osteoporosis: Classification and an integrated gut microbiota-metabolite-immune-bone framework

Table 1 Microbiota-dependent classification of natural bioactive compounds in estrogen deficiency-induced osteoporosis

Category	Representative compounds or interventions	Microbiota dependency	Major gut-derived mediators	Dominant bone-related mechanisms	Evidence level	Ref.
Phytoestrogens and estrogen-like compounds	Puerarin, genistein, daidzein, S-equol, calycosin, 8-prenylnaringenin	Mixed: Direct estrogen receptor modulation plus microbial biotransformation	S-equol, SCFAs, estrobilome-related β-glucuronidase/sulfatase activity	ERα/ERβ signaling, reduced osteoclastogenesis, associated with greater intestinal barrier integrity, decreased systemic inflammation	Moderate preclinical evidence; limited human intervention evidence	[15,24,25,27-29]
Polyphenols, flavonoids, and terpenoids	Flavan-3-ols, ginkgolide B, taraxasterol, Moringa oleifera leaf constituents, quercetin, resveratrol, curcumin	Moderate to high; many compounds require microbial metabolism or reshape microbiota	Phenolic metabolites, SCFAs, altered bile acid and indole metabolites	Antioxidant and anti-inflammatory effects, RANKL/OPG regulation, NF-κB/NFATc1 suppression, MAPK and NLRP3 modulation	Moderate preclinical evidence; mostly OVX animal studies with 16S/metabolomicsevidence	[11,12,30-33]
Polysaccharides, oligosaccharides, and dietary fibers	Dendrobium officinale polysaccharides, Polygonatum polysaccharides, algal oligosaccharides, dietary fiber-rich foods	High; generally act as prebiotic substrates rather than directly absorbed bone-active molecules	Butyrate, acetate, propionate, isovalerate, SCFA-producing bacteria	Enhanced tight junction proteins, Treg induction, reduced inflammation, Wnt/β-catenin activation, improved osteoblastogenesis	Moderate to high when FMT or metabolite evidence is included	[16,35,49,51]
Probiotics, postbiotics, and defined bacterial strains	Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus sakei CVL-001, Parabacteroides distasonis, Clostridium sporogenes	Direct microbiota- targeted intervention	Butyrate, indole propionic acid, bacterial components, TLR2/GPCR-related signals	Th17/Treg rebalancing, reduced IL-17/TNF-α, improved gut barrier, suppressed RANKL-induced osteoclastogenesis	Moderate preclinical evidence; limited evidence for clinical skeletal efficacy	[13,36-40]
Fermented foods and dietary-pattern interventions	Fermented soybeans, Bacillus subtilis-rich foods, quinoa, tryptophan-restricted intermittent diet	High; effects depend on dietary substratesand microbialecological remodeling	Biotin, SCFAs, soyisoflavone metabolites, altered tryptophan metabolites	Improved BMD and trabecular microarchitecture, reduced M1 macrophage polarization, induced osteoclast apoptosis, improved metabolic status	Preliminary-to-moderate preclinical evidence	[35,42,43]
Complex herbal formulations and natural extracts	Roucongrong Pill, Jiaru fuling traditional Chinese medicine formulas, deer velvet antler protein extract	Variable; often multi-component and multi-pathway	SCFAs, steroid-related metabolites, taurine/hypotaurine metabolites, lipid and nucleotide metabolites	Multi-target regulation of gut microbiota, immune balance, steroid hormone biosynthesis, osteoclast inhibition, osteoblast support	Preliminary or hypothesis-generating evidence; causal attribution remains insufficient	[14,34,44,45]

Interventions were classified according to their predominant gut microbiota-dependent effects and bone-related mechanisms. Evidence levels were qualitatively assessed based on available in vitro, animal, and human studies; categories may overlap. SCFAs: Short-chain fatty acids; OVX: Ovariectomy; FMT: Fecal microbiota transplantation; BMD: Bone mineral density; ER: Estrogen receptor.