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

Table 2 Mechanistic modules linking natural bioactive compounds, gut microbiota, and bone remodeling

Mechanistic module	Upstream trigger or intervention	Key microbial or metabolic mediators	Immune/endocrine/cellular pathway	Skeletal consequence	Main uncertainty	Ref.
Gut barrier-bone module	Estrogen deficiency, dysbiosis, natural compound intervention	LPS, microbial-associated molecular patterns, tight junction proteins	TLR4/NF-κB activation, systemic inflammation, TNF-α and IL-6 release	Increased osteoclastogenesis when barrier is impaired; bone protection when barrier is restored	Whether barrier repair is primary or secondary to microbiota remodeling	[8,15,16,32,36-38]
SCFA-mediated immune-bone module	Prebiotics, polysaccharides, probiotics, fiber-rich diets	Butyrate, acetate, propionate, SCFA-producing bacteria	FFAR2/3 signaling, Treg induction, reduced Th17 response, Wnt/β-catenin activation	Reduced bone resorption and enhanced bone formation	Optimal SCFA profile, dose, and target cell specificity remain unclear	[16,37,38,49,51]
Tryptophan-indole metabolite module	Tryptophan metabolism, defined bacteria, dietary restriction	IPA, IAA, IA, biotin-associated microbial changes	PXR/P65, AhR/NF-κB, AKT/NFATc1/ROS, M1 macrophage polarization, osteoclast apoptosis	Suppressed osteoclast formation and improved trabecular bone microarchitecture	Context-dependent effects of tryptophan restriction and indole metabolites need clarification	[40,43,46,47]
Bile acid-bonemodule	Natural compounds, estrogen deficiency, gut microbiota remodeling	Primary and secondarybile acids, DCA, TGR5-related signals	TGR5/NF-κB, BMSC differentiation, inflammation regulation	Reduced inflammatory bone loss and improved bone remodeling	Human relevance and bile acid subtype-specific effects remain insufficiently defined	[29,49]
Estrobolome-phytoestrogen module	Menopause, phytoestrogen intake, long-term medication	β-glucuronidase/sulfatase activity, S-equol, estrogen recycling metabolites	ERβ signaling, estrogenavailability, intestinal deconjugation, enterohepatic circulation	Potential preservation of bone mass and reduction of bone turnover	Equol-producer status and medication-induced estrobolome changes are under-tested clinically	[24,27,28,41]
TMAO-PERK/mitochondrial stressmodule	Choline/carnitine metabolism, dysbiosis, TMAO exposure	TMAO, TMA-producing bacteria, FMO3 activity	PERK/ATF4/ATF5, ER stress, mitochondrial unfolded protein response, osteoblast proteostasis	Either bone damage or protection depending on dose, source, and metabolic context	Direction of effect is contradictory and likely context-dependent	[48,53]
miRNA/extracellular vesicle module	Gut dysbiosis, natural bioactive compounds, microbial metabolites	Host fecal miRNAs, BMSC-derived exosomal miRNAs, circulating EV-miRNAs	Post-transcriptional regulation of osteogenesis, adipogenesis, immune polarization, and osteoclastogenesis	Potential bridge between microbial signals and bone marrow cell fate	Still emerging; causal links in natural compound studies are largely missing	[17-23,54]

SCFAs: Short-chain fatty acids; IPA: Indole-3-propionic acid; IA: Indoleacrylic acid; IAA: Indole-3-acetic acid; LPS: Lipopolysaccharide.