Next-generation probiotics and engineered BEVs for precision therapeutics in osteoporosis

Osteoporosis, characterized by reduced bone density and increased fracture risk, faces limitations with conventional therapies due to adverse effects and poor gut microbiota modulation. Emerging strategies leveraging probiotics and bacterial extracellular vesicles (BEVs) offer novel therapeutic potential by targeting the gut-bone axis. Engineered probiotics and next-generation formulations enhance osteoprotection via immunomodulation, metabolite production (e.g., SCFAs), and neuroendocrine regulation. BEVs, as biocompatible nanocarriers, enable targeted delivery of osteogenic factors while circumventing colonization challenges. Synthetic biology advances facilitate precision engineering of probiotics and BEVs, improving therapeutic efficacy and scalability. This review highlights pre-clinical and clinical progress, challenges in standardization and safety, and future directions for microbiome-based interventions to revolutionize osteoporosis management. Integrating engineered probiotics with BEV technology promises transformative approaches for bone health restoration.

1 Introduction

Osteoporosis (OP) is a chronic bone disease that is characterized by a decrease in bone mineral density and a deterioration in bone structure, leading to an increased risk of fractures, especially in postmenopausal women (1). While conventional treatments, including bisphosphonates, selective estrogen receptor modulators (SERMs), and calcium and vitamin D supplementation, have been shown to effectively reduce fracture risk, they are often associated with adverse side effects, such as gastrointestinal disturbances, atypical fractures, and osteonecrosis of the jaw (2, 3). Moreover, these treatments do not address the gut dysbiosis commonly observed in individuals with osteoporosis (4–6). This highlights the urgent need for the accelerated development of novel pharmacological interventions that minimize side effects. Such advancements have the potential to reshape the treatment landscape for osteoporosis in the near future.

Live beneficial bacteria, known as probiotics, are often used as a complementary therapy (7). Over 1,000 clinical trials have investigated probiotics for diverse pathologies, including gastrointestinal, metabolic and chronic diseases (colorectal cancer (8), multiple sclerosis (9); rheumatoid arthritis (10)), with mixed therapeutic outcomes. Currently, probiotics such as Lactobacillus reuteri (11), Lactobacillus paracasei (12), Bifidobacterium longum (13) and Akkermansia muciniphila (AKK) (14) have been shown to be potential targets for the treatment of osteoporosis. While promising, clinical efficacy is often constrained by poor gut colonization, inter-strain variability, dosage inconsistencies, and dynamic host-microbe interactions (15). To address these limitations, synthetic biology has emerged as a pivotal tool for engineering probiotics with enhanced therapeutic precision and functionality.

Next-Generation Probiotics (NGPs) leverage synthetic circuits to sense microenvironmental cues and dynamically deliver therapeutic payloads, such as enzymes for metabolic disorders (e.g., phenylketonuria, hyperammonemia) or anti-inflammatory molecules (16–18). These engineered systems also serve as in situ diagnostics, secreting therapeutic proteins in response to disease biomarkers (19).

Bacterial-derived extracellular vesicles (BEVs), phospholipid bilayer nanostructures measuring 40−200 nm in diameter (20), represent emerging nanoscale delivery platforms in biomedicine due to their tiny structure, mild toxicity and good biocompatibility (21). They are engineered to target bone tissue and can carry a variety of substances, including miRNAs, DNA, proteins, cytokines and other factors that regulate the progression of osteoporosis (22). In contrast to the low productivity of mammalian EVs (MEVs), BEVs derived from high-density batch-cultured probiotics possess a rapid proliferative capacity, allowing them to be mass-produced and tailored to synthetic biology (23). Particularly within the gut-bone regulatory network, BEV-mediated therapeutic strategies show remarkable capacity to modulate the onset and progression of OP.

We summarize the progress of both key common and rare probiotics in pre-clinical and clinical studies related to osteoporosis and explore the potential clinical applications of the latest engineering toolbox for bone health.

2 Osteoporosis

Osteoporotic fractures, a hallmark of systemic skeletal fragility, disproportionately affect the hip and vertebrae but impose the greatest socioeconomic burden through non-hip, non-vertebral fractures, which account for the majority of incident cases (8, 9). Hip fractures—characterized by acute pain, immobility, and high short-term mortality—pre-dominantly occur in women over 80 years, with global incidence showing marked geographical disparities (> 10-fold variation) and an estimated 2.7 million cases in 2010, half of which were potentially preventable through osteoporosis mitigation (10, 20, 21). Vertebral fractures, the most prevalent osteoporotic fractures, often evade clinical detection yet serve as critical predictors of subsequent fragility fractures, including hip fractures (14–16). While their heterogeneous presentation (ranging from asymptomatic to debilitating) complicates epidemiological analysis, standardized diagnostic criteria are emerging to refine their classification and clinical relevance (18, 19).

Notably, secular trends in fracture epidemiology reveal diverging patterns: Hip fracture rates have declined in North America but risen in Asia, whereas non-hip fractures exhibit less consistent trajectories (21–23). These shifts likely reflect complex interactions between lifestyle changes, urbanization, obesity trends, and screening practices. Despite advances in understanding, unmet needs persist in fracture prevention and global equity in osteoporosis care, particularly given the substantial morbidity, mortality, and economic costs linked to underdiagnosed vertebral fractures (13, 17).

2.1 Bone remodeling and age-related pathophysiology

The adult skeleton comprises cortical and trabecular bone, with site-specific pre-dominance: Vertebrae are rich in trabecular bone, while long bones primarily consist of cortical bone. Bone remodeling—a tightly coupled process of resorption and formation—occurs in discrete remodeling units. Orchestrated by osteoclast-mediated resorption followed by osteoblast-driven formation, this cycle renews the skeleton over ∼10 years while maintaining equilibrium in healthy adults (24, 25) In contrast, bone modeling, pre-dominant during skeletal development, decouples resorption and formation to optimize bone geometry in response to mechanical stress, persisting in adulthood under loading conditions (26, 27).

Genetic factors account for 50–85% of bone mineral density (BMD) variance, with genome-wide association studies (GWAS) identifying > 100 loci linked to bone strength and fracture risk. While most loci exert small polygenic effects, monogenic disorders have elucidated critical pathways (e.g., RANK/RANKL/OPG, Wnt signaling) governing bone remodeling and structural integrity (28).

2.2 Effects of osteoporosis drugs on bone remodeling and modeling

Osteoporosis drugs exert their effects on bone through distinct mechanisms, targeting either bone resorption or formation. Antiresorptive drugs primarily inhibit osteoclast recruitment and activity, reducing the rate of bone remodeling and allowing for a modest increase in bone mineral density (BMD) (29). By decreasing the number of remodeling units, these drugs reduce the negative remodeling balance, leading to increased secondary mineralization and preservation of bone mass and structure.

Denosumab, a monoclonal antibody targeting receptor activator of nuclear factor κB ligand (RANKL), has shown particular efficacy in improving cortical bone structure by increasing thickness and decreasing porosity. This effect may be due to its enhanced pharmacokinetic properties compared to bisphosphonates, allowing better accessibility to cortical bone (30).

Anabolic drugs stimulate bone formation through both remodeling and modeling processes. Teriparatide, a recombinant parathyroid hormone, promotes modeling-based bone formation on cancellous, endosteal, and periosteal surfaces, particularly in the early stages of treatment. However, the majority of its anabolic effects in cancellous bone are achieved through remodeling with overfilling of remodeling units (31, 32). In cortical bone, treatment with teriparatide may initially increase total bone area and cortical porosity, forming hypomineralized new bone. Despite these early changes, long-term treatment has been associated with increased bone strength and localized cortical thickness at mechanically loaded sites (33, 34).

Romosozumab, a monoclonal antibody targeting sclerostin, an osteocyte-derived inhibitor of bone formation, exhibits unique anabolic effects. Early treatment with romosozumab induces large increases in bone formation in cancellous and endocortical bone, accompanied by a sustained reduction in bone resorption. These effects lead to significant improvements in trabecular bone volume, microarchitecture, and cortical thickness after 12 months of treatment (35). Although animal studies suggest increased modeling bone formation in response to sclerostin inhibition, the relative contributions of remodeling and modeling to bone formation in humans remain to be fully elucidated (34).

2.3 Adverse effects of osteoporosis pharmacotherapies

Therapeutic interventions for osteoporosis, while effective in fracture prevention, are associated with distinct adverse effect profiles that necessitate careful risk-benefit evaluation. Bisphosphonates, including alendronate and zoledronate, are linked to gastrointestinal complications such as esophagitis and gastric ulceration, particularly with oral formulations, due to delayed mucosal healing exacerbated by gastroesophageal reflux (36, 37). Intravenous zoledronate frequently induces transient acute-phase reactions (30% incidence), characterized by myalgia, fever, and cytokine-driven inflammation, which typically resolve within days (38, 39). Although early studies suggested a potential association with atrial fibrillation, subsequent meta-analyses found no statistically significant risk (40–42). Ocular adverse events, including uveitis (0.8–1.1%), occur rarely but warrant patient counseling, as symptoms often emerge within days post-infusion and respond to topical therapies (43–45). Prolonged bisphosphonate use elevates the risk of atypical femoral fractures (AFFs), with adjusted relative risks of 1.70 (95% CI 1.22–2.37) in cohort studies, disproportionately affecting Asian populations and escalating with treatment duration beyond 3–5 years (46–48). Osteonecrosis of the jaw (ONJ), though rare in osteoporosis (0.01–0.001%), rises significantly in oncology settings (1–15%) due to high-dose regimens, comorbid therapies (e.g., glucocorticoids, antiangiogenics), and invasive dental procedures (49–52). Pathophysiological mechanisms involve suppressed bone remodeling, osteocyte apoptosis, and immune modulation via γδ T-cell dysregulation (53–56).

Denosumab, a RANKL inhibitor, demonstrates comparable antifracture efficacy but carries risks of hypocalcemia, necessitating pre-treatment vitamin D optimization (57). While AFFs (1:10,000) and ONJ remain uncommon in osteoporosis, extended use (7–10 years) correlates with incremental ONJ incidence, albeit far lower than in malignancy cohorts (57). Teriparatide, the sole anabolic agent, exhibits favorable tolerability with transient nausea and dizziness reported; rodent osteosarcoma findings have not translated to human risk (58, 59). Selective estrogen receptor modulators (SERMs), notably raloxifene, reduce vertebral fractures but increase thromboembolic events and fatal stroke risk, offsetting benefits in non-osteoporotic populations (60, 61).

Mitigation strategies emphasize pre-therapeutic dental evaluations to minimize ONJ risk, vigilance for prodromal AFF symptoms (e.g., thigh pain), and individualized duration limits for antiresorptives (62, 63). Clinicians must weigh skeletal benefits against context-specific harms, particularly in patients with comorbidities or extended treatment histories.

2.4 Pathogenesis of osteoporosis

2.4.1 Gut microbiota in osteoporosis

The gut microbiota (GM), a diverse consortium of over 1,000 microbial species, emerges as a pivotal regulator of skeletal homeostasis. Comparative studies in germ-free (GF) mice reveal elevated trabecular bone mineral density (BMD), underscoring the GM’s role in physiological bone remodeling (64). Mechanistically, GM depletion attenuates osteoclastogenesis via reduced T-cell proliferation and proinflammatory cytokines (TNF-α, IL-6), while butyrate—a microbial-derived short-chain fatty acids (SCFAs)—enhances bone formation by stimulating osteocalcin secretion and Wnt10b signaling through Treg-CD8 + T cell crosstalk (65, 66). Intriguingly, butyrate supplementation rescues the anabolic effects of intermittent parathyroid hormone (iPTH) in microbiome-depleted models, restoring trabecular bone volume (67). Conversely, continuous PTH (cPTH)-induced bone loss requires GM-mediated expansion of pro-osteoclastic TNF + T and Th17 cells, highlighting the microbiota’s dual role in bone dynamics (68). These findings position GM modulation as a therapeutic frontier for osteoporosis (OP).

2.4.2 Autophagy dysregulation: a nexus of bone cell dysfunction in osteoporosis

Autophagy, a conserved cellular recycling process, critically balances bone formation and resorption. In osteocytes, fluid shear stress enhances autophagic flux, preserving cellular viability under mechanical strain (69). Conversely, RANKL-induced osteoclast differentiation necessitates autophagy activation; its pharmacological inhibition (e.g., via chloroquine) mitigates glucocorticoid-driven bone loss by modulating RANKL/OPG ratios (70). Aging exacerbates OP pathogenesis through declined autophagy in bone marrow mesenchymal stem cells (BMMSCs), skewing differentiation toward adipogenesis via ROS/p53 pathways (71). Mitophagy defects further impair BMMSC function, linking mitochondrial dysfunction to senescent phenotypes (72). Thus, autophagy modulation represents a dual-edged yet promising target for OP intervention.

2.4.3 Cellular senescence and the aging skeleton

Cellular senescence, marked by irreversible cell-cycle arrest and senescence-associated secretory phenotype (SASP) production, accumulates in aged bone microenvironments. Senescent osteoblasts, osteocytes, and immune cells exhibit elevated p16Ink4a expression, correlating with trabecular deterioration (73). Senolytic strategies—genetic ablation or pharmacological agents like ruxolitinib—reduce senescent burden, improving bone microstructure and strength in aged models (74). GM dysbiosis in senescence-accelerated mice parallels β-galactosidase upregulation and IL-17A-mediated BMMSC dysfunction, implicating microbial-metabolic crosstalk in age-related OP (71). Iron overload exacerbates senescence via ROS overproduction, reversible by chelators like Desferal^®, which restore BMMSC osteogenic capacity (75). Targeting senescence thus offers a viable route to counteract OP progression.

2.4.4 Therapeutic horizons: bridging mechanisms to clinical translation

Emerging therapies exploit GM modulation, autophagy enhancement, and senolysis to restore bone homeostasis. Probiotics and SCFAs supplementation may rectify GM dysbiosis, while autophagy inducers (e.g., rapamycin analogs) could rejuvenate BMMSC function (64). Senolytics, though nascent, show pre-clinical efficacy in eliminating senescent cells and mitigating SASP-driven bone loss (76). Animal models, particularly ovariectomy (OVX) and glucocorticoid-induced OP, remain indispensable despite limitations in replicating human pathophysiology (64, 77). Standardizing these models and integrating multi-omics approaches will accelerate translational breakthroughs.

3 Probiotics

Probiotics, when administered at physiologically effective concentrations, confer health benefits to the host organism, positioning them as a key focus of public health research (78). The expanding comprehension of dynamic crosstalk between enteric microbiota and host immune homeostasis has propelled investigations into probiotics’ immune-homeostatic regulatory functions, now constituting a pivotal research frontier in immunometabolism (79). Over the past several decades, the impact of probiotics on human health has been extensively studied by researchers, as well as the food and drug industries.

The concept of probiotics was initially associated primarily with beneficial bacteria. However, recent advancements have expanded the definition of probiotics to include not only bacteria but also other microorganisms, such as yeasts (80). Probiotics, including combined Bifidobacterium, Saccharomyces boulardii sachets, and Bifid.Triple Viable Capsules, are widely used in the treatment of diarrhea and various other diseases, particularly in children. A notable example is Saccharomyces boulardii, a yeast extensively studied for its positive effects on gastrointestinal health (81). Industrial-scale probiotic production pre-dominantly utilizes lactic acid bacteria (LAB) genera (Leuconostoc, Lactobacillus, Lactococcus, Streptococcus, and Enterococcus), spore-forming Bacillus species, Bifidobacterium spp., Propionibacterium strains, and select non-pathogenic Escherichia coli (E. coli) variants (82). The enteroprotective mechanisms of probiotics operate through enhancing mucosal barrier integrity via stimulation of enterocyte mitogenesis, and maintaining selective paracellular transport through stabilization of intercellular junction complexes (83). Furthermore, Probiotics further strengthen the gut’s defenses by stimulating the production and secretion of antimicrobial peptides (84).

Lactic acid bacteria (LAB), a ubiquitous cluster of Gram-positive, non-pathogenic 2microorganisms, are prevalent in the human gut and fermented foods, and they are generally regarded as safe. Lactobacilli, a prominent subgroup of LAB, are frequently used in functional foods to regulate glucose and lipid metabolism, maintain gut microbial balance, and enhance host immune function (85, 86). Well-known strains include Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactococcus lactis, Bifidobacterium longum, Bifidobacterium infantis and Streptococcus thermophilus (87). These bacteria have a long history in food fermentation, enhancing quality, flavor, texture, and promoting beneficial biological activities. For example, fermentation with Lactobacillus plantarum WLPL01 increases the organic acid content and reduces the bitterness of Artemisia (88). Additionally, fermentation with Bifidobacterium infantis significantly altered the volatile and non-volatile components of barley juice and improved its antioxidant capacity (89). The advent of metabolomics technology has markedly heightened interest in the study of LAB-secreted bioactive compounds, including SCFAs, bacteriocins, and extracellular polysaccharides (EPS), due to their acknowledged significance in host physiology. The critical role of LAB in mammalian biology has been confirmed by studies conducted on sterile mice and antibiotic-treated mouse models (90, 91). Mechanistically, LAB execute their probiotic functions through three fundamental pathways: Alleviation of oxidative stress, preservation of intestinal epithelial barrier architecture, and homeostatic regulation of gut microbial ecology (86).

3.1 Genetic engineering paradigms in lactic acid bacteria

Plasmid-based systems remain foundational for LAB engineering yet face intrinsic constraints including low transformation efficiency due to Gram-positive cell wall barriers, strain-specific restriction-modification systems, and plasmid instability (92). Shuttle vectors like pTRKH2 and pLEM415-ldhL-mRFP1 circumvent these limitations through E. coli-LAB compatibility, enabling high-copy replication and functional gene expression tracking in vivo (93, 94). However, antibiotic selection pressures risk genomic mutation and microbiome dysbiosis, motivating chromosomal integration strategies. Early approaches utilized Rec-independent insertion (pTRK327) or homology-directed systems (pTRK685/pGK12) for stable gene insertion (95, 96).

The Cre-lox system advanced precision editing by enabling site-specific recombination, though its utility is constrained by off-target effects and screening complexity (97). CRISPR-Cas platforms now dominate LAB engineering through multiplexed editing capabilities. Pioneering work in Lactobacillus reuteri demonstrated Cas9-mediated double-strand break repair with homology-directed templates, while innovations like the all-in-one pNZDual plasmid reduced metabolic burden in Lactococcus lactis (98, 99). CRISPRi further enables tunable gene regulation, synergizing with the well-characterized NICE system for nisin-inducible protein secretion (100, 101). These tools collectively facilitate proteome optimization and metabolic pathway engineering while mitigating escape mutations through lethal selection (102, 103).

3.2 Precision probiotics

The burgeoning field of probiotics has transitioned from generalized formulations toward precision therapeutics, driven by the recognition of individual variability in gut microbiota composition, host physiology, and microbial interaction networks (13, 42, 43). Conventional probiotics, while beneficial for broad-spectrum dysbiosis, often fail to address patient-specific pathologies due to heterogeneous factors such as age, dietary habits, and immune responses. Precision probiotics address this gap by leveraging strain-specific molecular mechanisms—effector proteins, metabolites, and host-microbe signaling pathways—to restore targeted dysbiotic states.

Notable examples illustrate this mechanistic specificity: Precision strategies exploit molecular effectors such as Lactobacillus helveticus and Bifidobacterium longum-derived Runx2/BMP-2 upregulation to enhance osteogenesis (104, 105), andLactobacillus plantarum mediated elevation of vitamin D receptor coupled with cytoprotective autophagy induction, synergistically promoting osteoblast activity (106, 107) while Faecalibacterium prausnitzii reinforces intestinal barrier integrity via butyrate production, mitigating inflammatory conditions (48). Similarly, Bacillus amyloliquefaciens demonstrates anti-osteoporosis effects mediated by the increased IGF-1 levels (108). These findings underscore the necessity of multi-omics integration (genomics, proteomics, metabolomics) and machine learning algorithms to decode strain-host synergies, enabling predictive selection of probiotics aligned with individual microbial ecosystems.

Advancements in computational biology facilitate patient stratification based on microbial biomarkers and clinical phenotypes, allowing tailored therapeutic regimens. AI-driven models analyze genomic signatures, metabolite profiles, and host metadata to predict colonization efficacy and monitor disease progression dynamically (45, 49). However, challenges persist in standardizing omics data across diverse cohorts and establishing universal functionality biomarkers. Collaborative efforts bridging clinical microbiology, bioinformatics, and systems biology are critical to realizing precision probiotics’ translational potential.

3.3 AI/ML-Driven advancements in probiotic research

Artificial intelligence (AI) and machine learning (ML) are revolutionizing probiotic development by enhancing precision across in vitro, in silico, in vivo, and clinical research paradigms. These technologies accelerate strain identification, functional characterization, and therapeutic optimization while minimizing human error and resource expenditure (109, 110).

3.3.1 Strain screening and functional decoding

AI models like ABIOME simulate gut ecosystems using adaptive regression algorithms (MARS), identifying synergistic probiotic combinations while detecting antagonistic interactions (e.g., competitive amino acid depletion between L. reuteri and Saccharomyces boulardii) (111, 112). Concurrently, ML predicts excipient compatibility, optimizing formulations—such as 111 pharmaceutical agents enhancing L. paracasei viability (113).

ML algorithms enable high-throughput discrimination of probiotic candidates from non-probiotic microbes. Platforms like iProbiotics employ SVM classifiers and k-mer feature selection to achieve species-specific probiotic identification (110), while ANN models demonstrate 90% accuracy in tRNA sequence-based classification (112). Beyond taxonomy, ML integrates multi-omics data—such as transcriptomic networks of Lactobacillus reuteri—to elucidate strain-specific mechanisms (e.g., antimicrobial gene clusters) (114). Such in silico predictions synergize with in vitro assays; for instance, supervised ML screening of 144 LAB strains identified four Lactobacillus isolates with potent antimicrobial activity (115).

3.3.2 Pre-clinical and clinical integration

In preclinical models, AI enhances pathological analysis efficiency, exemplified by deep learning-driven histopathological interpretation in murine colitis (116) and tumor phenotyping in lung adenocarcinoma (114). Clinically, AI/ML holds promise for stratifying patient populations and predicting therapeutic outcomes. A landmark study applied ML to 70,000 IBD patients, achieving robust prediction of disease progression and risk scores (117). While randomized trials validate probiotic efficacy—Bacillus subtilis against S. aureus colonization (118), microbiota modulation in T2D (119)—AI-augmented clinical frameworks remain underexplored.

Bridging AI with multi-omics and clinical metadata will refine predictive models for personalized probiotic therapies. Prioritizing AI-driven trial designs could optimize dosing regimens, monitor real-time microbiota shifts, and forecast host responses, ultimately accelerating translational outcomes.

3.3.3 AI/ML-Driven probiotics for osteoporosis: decoding molecular mechanisms to clinical translation

The anti-osteoporotic properties of probiotics stem from molecular interactions mediated by surface proteins and metabolites. Clinically robust lactic acid bacteria (LAB) exhibit bile tolerance (via transporter activity) (120) and high adaptability to gastrointestinal stressors (acid, osmolarity) (121), while their surface proteins govern mucosal adhesion (immunomodulation) (78) and pathogen exclusion (122). A paradigm is L. rhamnosus GG, whose P40/P75 proteins enhance intestinal barrier integrity by activating epidermal growth factor receptors (EGFR) (123). These proteins synergize with bacteriocins (lactacin B, bifidocin) and SCFAs to suppress pathogens (S. aureus, H. pylori), modulate gut ecology, and ultimately ameliorate osteoporosis through microbiota-bone axis regulation (124, 125).

Despite omics technologies (genomics, proteomics, metabolomics) mapping these interactions, clinical translation remains hindered by data complexity (126). AI/ML bridges this gap by decoding multidimensional patterns: DeepFilter resolves uncharacterized bacterial proteomes via spectral analysis (127); ML models predict diet-driven shiftsin Lactobacillus and Ruminococcus populations (128); and CNN-based TaxoNN correlates microbiome profiles with osteoporosis risk (129).

Although direct studies on AI-guided probiotic screening for osteoporosis remain in their nascent stages, and no direct literature currently exists on AI/ML-based strain selection for osteoporosis treatment, interdisciplinary approaches suggest novel pathways with translational potential. By transforming data into predictive biomarkers, AI/ML holds promise for enabling precision selection of probiotics with optimized stability, therapeutic efficacy, and bone-protective potential in the future, paving the way for tailored microbiome interventions in osteoporosis management.

3.4 Challenges

Despite their therapeutic promise, probiotics face clinical implementation barriers due to host non-responsiveness (36% efficacy in diarrhea trials) and heterogeneous outcomes driven by individual variations in diet, genetics, and microbiota composition (130). Personalized approaches require integration of multi-omics data (genomics, proteomics, metabolomics) and clinical metadata to identify microbial biomarkers and replenish underrepresented taxa—a process hindered by invasive sampling methods and incomplete gut microbiome profiling (131, 132).

4 Probiotic-driven mechanisms in osteoporosis modulation

4.1 Association between gut microbiota and bone formation

The human skeleton undergoes continuous remodeling through coupled actions of osteoclasts, which resorb aged bone, and osteoblasts, which deposit new bone. Tight regulation of this balance is critical to prevent pathological changes in bone mass or quality (133). Emerging evidence implicates the gut microbiome as a novel modulator of skeletal homeostasis, potentially through microbial metabolites that influence systemic pathways (134, 135).

It is through the modulation of tryptophan metabolism that gut bacteria play a crucial role in skeletal homeostasis. Bacterial indoleamine-2,3-dioxygenase-1 (IDO-1) initiates tryptophan catabolism, producing kynurenine (an aryl hydrocarbon receptor (Ahr) ligand that promotes regulatory T-cell (Treg) differentiation and interleukin-22 (IL-22) secretion by group 3 innate lymphoid cells (ILC3s), thereby modulating inflammatory responses) (136). Mice fed a tryptophan-deficient diet exhibited altered gut microbiota composition and compromised intestinal immunity, underscoring the importance of tryptophan-derived metabolites in immune-bone crosstalk (136). While these findings highlight microbial metabolic influence, the precise origins and identities of Ahr ligands remain unresolved.

Insulin-like growth factor 1 (IGF-1) represents another critical mediator of the gut-bone axis. Germ-free (GF) mice colonized with specific pathogen-free (SPF) microbiota showed elevated serum IGF-1 levels—produced pre-dominantly in liver and adipose tissue—accompanied by increased bone formation and resorption markers (137). Conversely, antibiotic-induced microbiota depletion reduced IGF-1 production and suppressed osteogenesis, reinforcing microbiota-dependent regulation of bone metabolism (137).

Hydrogen sulfide (H2S), generated by both host gastrointestinal cells and gut microbes, further contributes to skeletal homeostasis. GF mice demonstrated diminished serum and intestinal H2S levels, suggesting microbial origin of systemic H2S (137). Dysregulated H2S impairs calcium flux via altered sulfhydration of TRP calcium channels, disrupting kinase signaling essential for osteoblast/osteoclast differentiation from bone marrow mesenchymal stem cells (138, 139).

Clinical evidence supports these mechanistic insights. Mendelian randomization studies link Clostridiales and Lachnospiraceae taxa to bone mass alterations (140). In a cohort of 181 participants, Clostridium Cluster XIVa (Firmicutes phylum) abundance correlated with osteopenia/osteoporosis prevalence (140). Similarly, postmenopausal women with osteoporosis/osteopenia exhibited reduced gut microbiota diversity and elevated Lachnospira pectinoschiza (Lachnospiraceae family) levels compared to controls (140). These findings collectively position gut microbiota composition as a potential biomarker and therapeutic target for bone disorders.

4.2 Probiotic-mediated attenuation of inflammatory and oxidative pathways in osteoporosis

The gastrointestinal tract, housing the body’s largest immune cell repertoire, plays a pivotal role in bone metabolism through cytokine-mediated regulation of bone remodeling (141, 142). Emerging evidence reveals that intestinal dysbiosis, particularly antibiotic-induced microbiota alterations, modulates systemic inflammation by reducing lipopolysaccharide (LPS) levels and associated inflammatory cascades (143). This gut-bone axis presents promising therapeutic targets, with probiotics demonstrating multifaceted regulatory capacities.

Mechanistically, probiotic-derived bacteriocins attenuate inflammatory responses through COX-2-mediated modulation of NLRP3 inflammasome and NF-κB signaling pathways (144). Such anti-inflammatory actions not only preserve tissue integrity but also suppress osteoclast differentiation, counteracting the RANKL/OPG imbalance characteristic of osteoporosis-associated dysbiosis (38). Notably, specific probiotic strains exhibit strain-specific benefits: Lactobacillus rhamnosus enhances mucosal immunity through IgA-mediated pathogen exclusion (145, 146), while EPS-producing Bifidobacterium 35624 preferentially inhibits osteoclast precursor fusion through IL-17 regulation (147).

The aging process exacerbates bone loss through redox imbalance mechanisms. Postmenopausal estrogen decline impairs antioxidant defenses (reduced superoxide dismutase, folate, and GSH-Px activity), leading to ROS accumulation that disrupts bone homeostasis via MAPK, NF-κB, and Wnt/β-catenin pathway dysregulation (148–151) Crucially, gut microbiota composition modulates mitochondrial biogenesis through CREB-dependent glutathione synthesis, with Firmicutes/Bacteroidetes ratio alterations potentially exacerbating ROS-mediated bone resorption (152). Probiotic metabolites like urolithin A demonstrate therapeutic potential by simultaneously reducing osteoclast NLRP3 inflammasome activation (via caspase-1 and GSDMD suppression) and enhancing antioxidant capacity (153–155). After discussing the immunomodulatory role of probiotics, let’s now turn to their impact on the neuroendocrine system, which also has significant implications for bone health.

4.3 Neuroendocrine modulation

The bidirectional brain-gut axis integrates neural, endocrine, and immune pathways between the central nervous system and gastrointestinal tract (156, 157). Sensory neurons, gut hormones (e.g., 5-HT, GABA), and microbial metabolites mediate this crosstalk, with emerging evidence linking these interactions to bone homeostasis through osteocyte modulation (158–163). Probiotics demonstrate dual regulatory capacity: They restore gut microbiota equilibrium while influencing enteric nervous system activity, vagal signaling, and hypothalamic-pituitary-adrenal (HPA) axis dynamics—mechanisms potentially relevant to bone metabolism via neurotransmitter-mediated osteocyte regulation (164–167) (Figure 1).

FIGURE 1

Figure 1. Probiotics modulate bone formation via gut-brain axis and neurotransmitters. NCC, enterochromaffin cell; TPH1, tryptophan hydroxylase 1; SCFA, short chain fatty acid; IAA, indoleacetic acid; 5-HT, 5-hydroxytryptamine; CNS, central nervous system; HPA axis, hypothalamic–pituitary–adrenal axis; SNS, sympathetic nervous system. Created in BioRender. Wenshuo, D. (2025) https://BioRender.com/nt3qm3r.

4.3.1 Serotonergic modulation

Gut-derived serotonin (g5-HT), synthesized from tryptophan in enterochromaffin cells, exerts site-specific effects on bone remodeling. Microbial metabolites critically modulate this pathway: Short-chain fatty acids upregulate tryptophan hydroxylase 1 (TPH1) to enhance g5-HT production, while specific gut bacteria (e.g., Clostridium, Bacteroides) metabolize tryptophan into indole derivatives that suppress g5-HT levels (168–174). This microbial-g5-HT crosstalk influences osteoblastogenesis through 5-HT1B receptor activation, with altered serotonin transporter (SERT) expression potentially disrupting bone-microbiome homeostasis.

4.3.2 Adrenergic modulation

Norepinephrine (NE) from sympathetic neurons interacts with gut microbiota through cAMP-PKA-pCREB signaling, with elevated NE levels correlating with bone density suppression (175–177). Germ-free models reveal microbiota-dependent NE synthesis, as Clostridium colonization restores cecal NE concentrations (178). This microbial-neuroendocrine interplay suggests probiotics may modulate sympathetic tone through HPA axis regulation, though mechanistic details require further elucidation.

4.4 Endocrine modulation

Insulin-like growth factor 1 (IGF-1) serves as a central regulator of bone homeostasis through dual mechanisms: Stimulating osteoblast-mediated matrix synthesis and suppressing osteoclastic resorption (179). Emerging evidence highlights probiotics as potent modulators of IGF-1 bioactivity, offering therapeutic potential for osteoporosis. IGF-1 enhances bone anabolism by upregulating type I collagen synthesis, alkaline phosphatase activity, and osteocalcin expression while inhibiting collagen degradation (180, 181). Systemically, it coordinates mineral metabolism through renal phosphate reabsorption and calcitriol-mediated intestinal calcium/phosphate absorption (182).

Notably, specific gut microbiota strains exhibit strain-dependent capacity to activate the growth hormone/IGF-1 axis. Lactobacillus plantarum strains differentially enhance growth parameters in juvenile mammals, with LpWJL demonstrating superior efficacy in elevating hepatic IGF-1 expression and butyrate synthesis (183, 184). Mechanistic studies reveal that Lactobacillus reuteri attenuates diabetic bone loss via Wnt10b/IGF-1 crosstalk (185) while Bacillus amyloliquefaciens restores growth in malnourished models by amplifying nutrient absorption and mucosal immunity through GH/IGF-1 activation (108). SCFAs-producing taxa (e.g., Rikenellaceae, Clostridiales) further synergize this axis (186).

Of particular interest, Bifidobacterium species exhibit robust osteogenic effects. B. longum subsp. infantis CCFM1269 significantly elevates serum IGF-1 (P < 0.05) and osteogenic markers (OPG, osteocalcin) across sex and age groups, accompanied by increased IGFBP3 levels—a critical determinant of IGF-1 bioavailability (187).

4.5 Microbiota-derived metabolites modulation

4.5.1 SCFAs and bone metabolism

SCFAs—primarily carboxylic acids with short hydrocarbon chains—are synthesized by the gut microbiota and can translocate from the gastrointestinal tract into systemic circulation. Once in circulation, SCFAs serve as pivotal signaling molecules in metabolism, immunity, and endocrine regulation (188–191, 192). Although early research mainly focused on the interactions of SCFAs with organs such as the liver, brain, pancreas, and kidneys, emerging evidence now suggests that SCFAs also play an important role in regulating bone metabolism (137, 191).

4.5.2 Mechanisms by which SCFAs regulate bone metabolism

The mechanisms through which SCFAs regulate bone metabolism encompass the following: (1) Facilitating intestinal calcium absorption: SCFAs serve as an energy source for intestinal epithelial cells, maintaining barrier integrity. They enhance intestinal villus structure, increase epithelial surface area, and promote calcium absorption by improving the paracellular pathway and reducing pH in the intestinal lumen, which increases mineral solubility and supports bone formation (188, 193). (2) Modulating IGF-1 regulation: Another fundamental mechanism (137). (3) Regulating phytoestrogens: Gut bacteria, such as Bifidobacterium and Lactobacillus, metabolize phytoestrogens into compounds that bind estrogen receptors, promoting osteoblast proliferation, differentiation, and inhibiting osteoclast activity, thereby increasing bone mineral density (187, 194–196). (4) Inhibition of histone deacetylase (HDAC) activity: Butyrate exhibits HDAC inhibitory effects, facilitating the development of Foxp3 + regulatory T cells (Tregs), and contributing to immune system homeostasis (197, 198). (5) Interaction with G protein-coupled receptors (GPCRs): SCFAs modulate bone metabolism by reducing intracellular cyclic adenosine monophosphate (cAMP) levels, activating immune responses, promoting Treg proliferation, suppressing intestinal inflammation, and inhibiting osteoclast differentiation (199). (6) Regulation of 5-HT synthesis and release: SCFAs and secondary bile acids (2BAs) regulate 5-HT synthesis and release from enterochromaffin cells (ECCs), which interact with osteocytes to suppress osteoblast proliferation primarily through the activation of 5-HT1B receptors on preosteoblasts (200). (7) Vitamin D production and parathyroid hormone (PTH) secretion: Promote vitamin D production while inhibiting parathyroid hormone (PTH) secretion (201).

4.5.3 Phytoestrogen metabolism

Recent research has highlighted several nutrients with potential to alleviate osteoporosis, with phytoestrogens being particularly notable (202, 203). Phytoestrogens are polyphenolic compounds found in plants such as soybean and flaxseed. They resemble mammalian estrogens structurally and can exert estrogen-like effects in biological systems (204). These compounds are primarily categorized into isoflavones, ellagitannin, and lignans, which undergo metabolism by gut bacteria to form more biologically active compounds like equol, urolithin, and enterolipin (205).

These metabolites exhibit enhanced estrogenic/antiestrogenic and antioxidant activities in comparison to their precursors (206). Furthermore, they possess anti-inflammatory, anti-proliferative, and pro-apoptotic effects (207). Studies have demonstrated that intestinal bacteria such as Bifidobacterium and Lactobacillus can metabolize isoflavones into equol, which mimics estrogen activities (208, 209). Equol bind to estrogen receptors ERα and ERβ, stimulates the differentiation of mesenchymal stem cells into immature osteoblasts, impedes the differentiation and activation of osteoclasts, induces their apoptosis, and restores the equilibrium between bone formation and resorption (210–213). Ellagitannin can be converted by gut bacteria, like Clostridium leptum and Ruminococcus bromii, into urolithin, a compound with antioxidant properties that may reduce inflammation, promote bone formation, and inhibit bone resorption (214–216). Additionally, Clostridium, Klebsiella, and Collinia participate in the conversion of lignans into enterolipins (especially enterodiol and enterolactone), which regulate hormone levels, particularly estrogen, and promote bone health (196, 217). However, it is important to note that the complex structure of the gut microbiota is critical for proper lignan metabolism. For instance, Eggerthella lenta does not independently convert secoisolariciresino (SECO) to enterolactone but does so in co-culture with Blautia producta (218, 219).

4.6 Gene expression modulation

Genes associated with bone calcification and remodeling - including SPARC (secreted protein acidic and cysteine-rich), the osteogenic master transcription factor RUNX2, and bone morphogenetic protein 2 (BMP-2) - are critical regulators of skeletal development (Figure 2). Emerging evidence indicates that probiotic interventions can modulate their expression to influence osteoporosis progression (105, 220). Specifically, SPARC functions as a calcium-binding matrix protein that facilitates bone mineralization through transcriptional activation of calcification-related targets during tissue repair and remodeling processes (221, 222).

FIGURE 2

Figure 2. The signaling pathway of the probiotics and pathogens in the pathogenesis and probiotics therapies for osteoporosis. SPSRC, Secreted protein acidic and rich in cysteine; BMP-2, Bone morphogenetic protein 2; SCFA, short-chain fatty acids; RANKL, Receptor Activator of nuclear factor-kappa B ligand;APC, Antigen presenting cells; IFN-γ, Interferon-γ; IL-1, Interleukin -1; IL-2, Interleukin-2; IL-6, Interleukin-6;IL-17, Interleukin-17; TNF, Tumor Necrosis Factor; MMPs, Matrix metalloproteinases; COX-2, Cyclooxygenase-2; Pi, Phosphorus; NFAT, Nuclear factor of activated T cells; L. reuteri, Limosilactobacillus reuteri; IGF-1, Insulin-like growth factor 1. Created in BioRender. Wei, A. (2025) https://BioRender.com/e75e579.

Clinical investigations by Parvaneh et al. revealed that Bifidobacterium longum supplementation upregulated SPARC and BMP-2 expression, corresponding with increased serum osteocalcin (a bone formation marker) and decreased C-terminal telopeptide of type I collagen (CTX, a bone resorption indicator) (105). The Wnt signaling pathway, particularly through its key ligand Wnt10b, further contributes to osteoblast regulation and bone homeostasis (223). Mechanistically, probiotics enhance osteogenic Wnt10b production via butyrate-mediated differentiation of regulatory T cells (Tregs) (224). Supporting this pathway, Zhang et al. demonstrated that Lactobacillus reuteri administration prevented Wnt10b signaling suppression and maintained osteoblast activity in type 1 diabetic mice, establishing a direct association between Wnt10b dysregulation and diabetic osteoporosis progression.

5 Conventional probiotics

Emerging pre-clinical studies delineate a paradigm shift in osteoporosis management through targeted microbial modulation. Conventional probiotics (Lactobacillus, Bifidobacterium) demonstrate conserved osteoprotective mechanisms across animal models, including suppression of osteoclastogenesis via TNF-α/IL-1β inhibition and enhancement of intestinal barrier integrity through ZO-1/occludin upregulation (225–227). These findings align with Saccharomyces species’ capacity to attenuate bone resorption through RANKL/IL-17 axis modulation (228), and Bacillus strains’ dual action in T-cell polarization rebalancing and vitamin D metabolism potentiation (229, 230).

5.1 Lactobacillus

Although representing a minor proportion of gut microbiota (< 10% in duodenum, < 1% in colon) (231, 232), Lactobacillus species emerge as critical modulators of bone homeostasis through their unique acid tolerance and S-layer protein-mediated intestinal colonization (233, 234). Clinical evidence underscores their therapeutic potential: A landmark randomized trial (n = 249) demonstrated that tri-strain Lactobacillus supplementation preserved lumbar bone mass in postmenopausal women via WNT pathway modulation (WNT16, sFRP4, Wnt10b) (235), establishing a paradigm for microbiota-targeted interventions.

5.1.1 Mechanistic interplay between lactobacilli and skeletal system

Lactobacilli orchestrate bone remodeling through three synergistic axes. First, their capacity to produce short-chain fatty acids enhances mineral bioavailability, exemplified by Lactobacillus plantarum-mediated 10% elevation in Caco-2 calcium absorption through vitamin D receptor upregulation and transcellular transport potentiation (107, 236). Second, lactobacilli reinforce intestinal barrier integrity via species-specific mechanisms: L. plantarum induces dose-dependent tight junction reorganization in colonic epithelia (237–239), while L. rhamnosus ameliorates mucosal damage through Th17/Treg balance restoration and inflammatory cytokine suppression (240). Third, direct osteogenic modulation occurs via strain-dependent signaling—L. helveticus upregulates Runx2/BMP-2 expression and serum osteocalcin levels (105), whereas L. plantarum stimulates pyrazine synthesis to activate osteogenic genes (OSX, osteocalcin) (106, 241).

5.1.2 Clinical heterogeneity and therapeutic implications

Divergent clinical outcomes highlight the complexity of lactobacilli-bone interactions (Table 1). While L. reuteri NCIMB 30242 significantly elevated serum 25(OH)D in adults (242), its effects on bone density remain context-dependent. Notably, a 12-month RCT of L. reuteri 6,475 in osteopenic elderly women demonstrated improved trabecular bone mineral density (Tb.BMD: + 2.1% vs. −1.8% in placebo, P = 0.03) through gut microbiota modulation (a Faecalibacterium, ↓ Escherichia; q < 0.05) (11), yet a subsequent multi-omics analysis by Li et al. on the same cohort revealed non-responders exhibited detrimental microbial shifts, including enrichment of Escherichia coli (log2FC = 3.7, adjusted P = 0.04) and upregulated biofilm formation (e.g., arcA, csgA; P < 0.01), suggesting non-canonical pathways (243). Intriguingly, L. acidophilus-natto combinations paradoxically increased femoral calcium despite reducing serum levels, emphasizing tissue-specific bioavailability (236). These discrepancies underscore the necessity to delineate strain-specific pharmacodynamics and host-microbe crosstalk.

TABLE 1

Table 1. Effect of probiotic supplementation on clinical trials.

5.2 Bifidobacterium

As keystone commensals within gut microbiota, Bifidobacterium species (B. longum, B. adolescentis, B. bifidum) demonstrate emerging potential in osteoporosis intervention through multimodal biological pathways (244). Clinical evidence reveals that B. longum supplementation enhances vitamin D bioavailability and calcium absorption, with a phase III trial demonstrating significant elevation of serum vitamin D3 and reduction of procalcitonin in postmenopausal women receiving Bifidobacterium-calcitriol co-therapy versus controls (229, 245, 246). These effects are mechanistically linked to TLR2-dependent osteoclast inhibition mediated by B. bifidum-derived exopolysaccharides (247), alongside immunomodulatory capacity to suppress proinflammatory cytokine networks (248).

5.2.1 Prebiotic synergy and ecological modulation

The therapeutic landscape extends beyond direct probiotic administration to encompass prebiotic strategies that selectively enrich endogenous Bifidobacterium populations. Phytochemical interventions—notably grape seed anthocyanins and konjac oligosaccharides—exert osteoprotective effects by reshaping microbial ecology. These compounds enhance Bifidobacterium abundance while suppressing opportunistic pathogens, concurrently restoring intestinal barrier integrity and bone marrow immune homeostasis (230, 249). Such findings position plant-derived prebiotics as ecological modulators that amplify the osteoanabolic potential of commensal bifidobacteria.

5.3 Saccharomyces

Emerging evidence positions Saccharomyces species—notably S. boulardii and S. cerevisiae—as novel modulators of osteoimmunological balance through pleiotropic mechanisms. The S. boulardii CNCM I-745 strain demonstrates potent anti-osteoclastic activity by suppressing RANKL/IL-17/TNFα signaling cascades, effectively attenuating inflammatory bone resorption (228). This immunometabolic modulation extends to direct interference with osteoclast differentiation through bone marrow monocyte interactions, establishing a dual therapeutic axis against pathological bone loss.

5.3.1 Bioactive components and translational potential

Beyond classical probiotic functions, Saccharomyces-derived compounds exhibit targeted osteoprotection. β-Glucans from S. cerevisiae demonstrate systemic bone metabolism regulation, with pre-clinical studies highlighting their capacity to mitigate alveolar bone deterioration in metabolic disorder contexts (250). Notably, yeast hydrolyzates restore sex hormone equilibrium and trabecular microarchitecture, suggesting utility in postmenopausal osteoporosis management (251) A breakthrough innovation lies in yeast-conjugated gallium (YG), which synergizes enhanced bone mineral density with reduced osteoclast activity (evidenced by suppressed TRACP-5b), while circumventing elemental toxicity through organic complexation (252, 253).

5.4 Bacillus

As resilient Gram-positive probiotics, Bacillus species (B. coagulans, B. subtilis) emerge as potent modulators of osteoimmune homeostasis through multifaceted mechanisms (254, 255). Clinical evidence reveals that B. coagulans supplementation enhances bone mineral density, particularly in weight-bearing skeletal regions, via dual immunometabolic pathways: Suppression of bone-resorptive cytokines and potentiation of vitamin D biosynthesis (256). This vitamin D elevation—uncoupled from serum calcium fluctuations—suggests tissue-specific endocrine modulation rather than systemic mineral regulation.B. subtilis further expands this therapeutic repertoire by rebalancing T-cell polarization, specifically through Th17 suppression and Treg population expansion, thereby attenuating osteoclastogenic inflammatory cascades (IL-17, IL-6, TNF-α) (220, 256, 257).

While conventional probiotics have shown therapeutic promise, recent advancements in synthetic biology have enabled the engineering of next-generation probiotics with enhanced functionalities.

6 Next-generation probiotics

6.1 Revolutionizing probiotic therapeutics through synthetic biology

The integration of synthetic biology tools into probiotic engineering represents a paradigm shift in developing next generation biotherapeutics. By reprograming microbial chassis to dynamically sense pathological signals and execute therapeutic responses, researchers are advancing live biotherapeutic systems capable of treating metabolic disorders with unprecedented precision (19, 258). Notably, synthetic biology-engineered probiotics have demonstrated clinical potential in addressing homocystinuria, osseointegration, tumor microenvironment, and inflammatory bowel disease through targeted enzyme delivery and metabolite regulation (259–262).

These next-generation probiotics (NGPs) combine therapeutic enzyme expression with sophisticated biosensing circuits, enabling real-time detection and mitigation of disease biomarkers within the gastrointestinal microenvironment (263). However, their translational implementation faces critical biological barriers. The gut ecosystem imposes dual challenges through both physicochemical stressors and microbial competition, where commensal microbiota outcompetes therapeutic strains for nutritional resources while creating colonization resistance (264). Furthermore, maintaining microbial viability and functional stability within the intestinal lumen’s dynamic conditions remains a pivotal hurdle for sustained therapeutic efficacy.

6.2 Escherichia coli Nissle 1917 (EcN): a versatile platform for engineered biotherapeutics

First isolated during a World War I shigellosis outbreak, E. coli Nissle 1917 (EcN) demonstrated intrinsic resistance to enteric pathogens, later validated for its immunomodulatory, anti-inflammatory, and antimicrobial properties (265, 266). Marketed as Mutaflor^®, EcN is clinically proven to alleviate acute diarrhea in pediatric populations (267) and ulcerative colitis (UC) symptoms comparably to mesalazine (268). Its efficacy stems from anti-inflammatory cytokine induction and competitive exclusion of pathogens via microcin H47 secretion (269, 270). These traits, combined with genomic stability and a long safety profile, position EcN as a robust chassis for NGPs (271).

6.2.1 Genetic toolbox and biocontainment strategies

EcN’s fully annotated genome (272) and cryptic plasmids (pMUT1/2) enable stable heterologous expression without antibiotic selection (273, 274). Chromosomal integration further enhances genetic stability (275), while conjugation-based systems improve transformation efficiency (276). To address biocontainment concerns, CRISPR-Cas9 kill switches and temperature-sensitive circuits ensure controlled proliferation and environmental safety (277). These advancements support EcN’s application in drug delivery (278), biosensing (279), and inflammatory disease mitigation (280).

6.2.2 Therapeutic applications of engineered EcN

EcN’s modularity enables tailored therapies for diverse domains. In oncology, engineered strains enhance antitumor immunity through L-arginine-mediated T-cell infiltration (281) or STING pathway activation via cyclic di-AMP delivery (282). Anti-infective strategies leverage pathogen-specific mechanisms, including tetrathionate-responsive microcins against Salmonella (122) and bile salt hydrolase-mediated inhibition of C. difficile sporulation (258). Emerging applications span neuromodulation (GABA production via gadB overexpression for neuropsychiatric disorders) (283) and ethanol detoxification through metabolic pathway engineering (284).These advances highlight EcN’s versatility as a therapeutic platform, with multiple candidates progressing toward FDA approval.

However, current clinical research remains largely confined to pre-clinical studies and early phase trials. Despite demonstrating promising experimental efficacy, substantial barriers persist before widespread clinical adoption can be realized.

Illustrating this translational challenge, Synlogic’s EcN-based engineered strain SYNB1934—developed for phenylketonuria—achieved a 34% reduction in plasma phenylalanine during its Phase II trial (NCT04534842) (285). Nevertheless, its pivotal Phase III study (NCT05764239) was terminated in 2024 due to suboptimal efficacy.

Ongoing efforts aim to address unmet needs in homocystinuria and enteric hyperoxaluria using the EcN platform. For SYNB8802 (targeting hyperoxaluria), pre-clinical work by Lubkowicz et al. successfully modeled and predicted clinically relevant urinary oxalate reductions (> 20%) (286). Yet, while its Phase I trial (NCT04629170) has completed, results remain unpublished. Similarly, the Phase I trial of SYNB1353 for homocystinuria (NCT05462132) demonstrated a statistically significant 26% reduction in plasma methionine (AUC_0–24)(p < 0.05) in methionine-loaded healthy volunteers (260). This preliminary finding warrants validation in homocystinuria patients, and further Phase II studies are planned.

Despite EcN’s versatile therapeutic adaptability and the clinical advancement of multiple candidates, collective data reveal unresolved translational barriers that challenge the platform’s broader applicability.

6.3 Emerging non-conventional probiotics

Novel probiotic candidates such as Akkermansia muciniphila, Faecalibacterium duncaniae, Bacteroides fragilis, and Bacillus clausii are gaining attention for their therapeutic potential in inflammatory and metabolic disorders (287–290). These species contribute to gut homeostasis through distinct mechanisms, notably via the biosynthesis of SCFAs including acetate, propionate, and butyrate. A. muciniphila enhances metabolic health by stimulating glucagon-like peptide-1 (GLP-1) secretion, a mechanism linked to improved glycemic regulation in murine models (291). Genomic characterization of this species has further identified redundant mucinase genes, suggesting an evolutionary adaptation for mucin degradation and niche colonization (292)

F. duncaniae, a dominant butyrogenic commensal, exerts anti-inflammatory effects by IL-10-secreting, Foxp3-expressing T regulatory cells, thereby attenuating mucosal inflammation (288). Similarly, Bacillus clausii modulates glucose fermentation dynamics through propionate production, influencing host metabolic pathways (293). Within the Bacteroides genus, species such as B. fragilis, B. thetaiotaomicron, and B. vulgatus exhibit competitive fitness in the gut ecosystem via polysaccharide utilization loci (PULs), enabling efficient catabolism of complex dietary fibers (294, 295). However, their clinical application is complicated by strain-specific virulence factors; for instance, enterotoxigenic B. fragilis variants are implicated in colorectal carcinogenesis through bacteriocin and toxin production (296).

To harness their therapeutic potential, targeted gene editing—such as deletion of virulence determinants or heterologous expression of carbohydrate-active enzymes—may enhance safety and colonization efficacy. Nevertheless, developing organism-specific genetic toolkits remains a critical hurdle for engineering these phylogenetically diverse candidates.

6.4 Evolutionary advancements in microbial therapeutics

This mechanistic convergence underpins the therapeutic potential of next-generation probiotics like Anaerostipes caccae, a spore-forming Lachnospiraceae member that optimizes butyrate production and oxygen tolerance (297, 298). Comparative pre-clinical analyses reveal A. caccae’s superior biodurability and metabolic versatility. Long-term supplementation in avian models demonstrated sustained trabecular preservation through bone marrow immunomodulation, outperforming conventional probiotics in aging-related bone loss attenuation (299). Synergistic formulations with lactulose amplify butyrate synthesis, achieving dual osteoprotective and anti-allergic effects in gnotobiotic systems—a therapeutic breadth unmatched by first-generation probiotics (300).

6.5 Advancing genetic toolkits for engineering non-conventional probiotics

The therapeutic potential of non-conventional probiotics remains constrained by the scarcity of organism-specific genetic engineering platforms. While synthetic biology strategies established for model probiotics offer a foundational framework, their adaptation to phylogenetically diverse species requires systematic optimization. For instance, Akkermansia muciniphila—a mucinolytic specialist producing immunomodulatory SCFAs—has been engineered using a codon-optimized Himar1 transposase system (301, 302). This approach enabled the creation of a transposon mutagenesis library, revealing that mucin degradation machinery is critical for both glycan metabolism and gastrointestinal colonization (292).

CRISPR-based systems have demonstrated species-specific challenges and opportunities. In Clostridium butyricum, initial attempts to enhance butyrate yields via heterologous Streptococcus pyogenes Cas9 faced toxicity limitations (303). By contrast, leveraging the endogenous Type I-B CRISPR-Cas system improved editing efficiency, achieving a 60% increase in butyrate production through targeted knockout of spo0A and aldh genes (304). Similarly, Bacteroides spp.—dominant gut colonizers harboring both metabolic versatility and pathogenic potential—exhibit diverse native CRISPR systems (Type I-B, III-B, II-C) that could be repurposed to silence virulence factors or xenogeneic elements (305, 306).

Beyond genetic manipulation, understanding host-microbe interactions remains pivotal. Innovative platforms like the Gut Microbiome Physiome (GuMI) system have elucidated how butyrate-producing strains modulate inflammatory pathways, including TLR3/4 downregulation (307). Future efforts to expand the genetic toolbox for NGPs should prioritize both precision genome editing and functional validation within physiologically relevant models, ultimately enabling tailored expression of therapeutic biomolecules.

6.6 Reassessing probiotic safety and translational challenges

Despite their therapeutic promise, probiotic interventions carry non-trivial risks ranging from subclinical inefficacy to severe adverse events. A landmark Dutch trial administering multispecies probiotics to acute pancreatitis patients reported higher incidence of bowel ischemia and mortality compared to placebo—a cautionary outcome that significantly impacted clinical probiotic research trajectories (308, 309). Beyond acute complications, chronic issues such as D-lactic acidosis from LAB-derived metabolites can induce neurocognitive impairments, while post-antibiotic probiotic use may paradoxically delay microbiome reconstitution (310, 311). Safety concerns are compounded by risks of bacteremia, horizontal antibiotic resistance transfer, and unintended ecological disruption in antibiotic-treated hosts (312, 313).

These challenges underscore the need for precision engineering in NGPs. Advanced genetic tools could mitigate risks by eliminating virulence factors and enhancing strain stability (314). For instance, Novome Biotechnologies employs synthetic biology to engineer Bacteroides strains with tailored polysaccharide utilization loci, coupled with prebiotic porphyran supplementation to create selective metabolic niches (308, 315). Such synbiotic strategies may overcome colonization barriers that frequently undermine therapeutic efficacy in late-stage trials (316). By integrating strain optimization with ecological engineering, researchers can address both safety and functionality gaps in probiotic development.

7 Bacterial extracellular vesicles (BEVs): emerging therapeutic agents in OP management

7.1 Biogenesis and functional diversity of BEVs

BEVs, bilayered spherical nanostructures (20–400 nm diameter), encapsulate diverse cargo including glycoproteins, enzymes, nucleic acids, and metabolites, enabling their roles in immunomodulation, microbial colonization, and metabolic cooperation (317, 318). Initially identified in Gram-negative bacteria in the 1960s (319), BEVs were later recognized in Gram-positive species in the 1990s (320). Their biogenesis mechanisms differ markedly between bacterial classifications: Gram-negative bacteria produce outer membrane vesicles (OMVs) via membrane blebbing or explosive cell lysis (EOMV/OIMV), while Gram-positive counterparts generate cytoplasmic membrane vesicles (CMVs) through programed cell lysis pathways (23, 321, 322). Compositionally, OMVs are enriched with outer membrane proteins influenced by cell wall dynamics, whereas CMVs and EOMV/OIMV harbor peptidoglycan, nucleic acids, and cytoplasmic components due to their lytic origins (18, 217). A critical distinction lies in the exclusive presence of lipopolysaccharide (LPS) in Gram-negative BEVs, a feature linked to both therapeutic potential and systemic toxicity (23, 321).

7.2 BEVs as therapeutic platforms for OP

BEVs represent a promising experimental therapeutic strategy for systemic bone diseases such as OP, leveraging their cell-free nature, nanosized architecture, biocompatibility, and non-replicative properties. Compared to parental probiotics, BEVs may offer enhanced safety and efficacy potential in modulating the “gut-bone” axis—a critical pathway involving intestinal metabolites, immune regulation, and endocrine signaling (323, 324). Notably, BEVs derived from probiotics like Akkermansia muciniphila, Lactobacillus spp., and Bifidobacterium spp., which demonstrate pre-clinical anti-osteoporotic effects in models, represent potential candidates for OP treatment that require further validation.

OP fracture treatment demands a holistic approach addressing bone loss, microenvironment repair, and mechanical stabilization. Pre-clinical studies suggest that BEVs can synergize with mesoporous inorganic biomaterials (325, 326), metallic scaffolds (327, 328), and hydrogels (329) to enhance fracture repair. As dual-purpose nanocarriers in experimental settings, BEVs have shown potential to simultaneously deliver anti-resorptive agents and promote osteogenic differentiation, addressing both systemic OP and localized fracture healing in animal models..

7.3 BEVs in osteoporosis: mechanisms and engineering advances

BEVs derived from probiotic or attenuated bacterial strains show pre-clinical promise in bone disease therapeutics by circumventing LPS-mediated toxicity. For instance, Proteus mirabilis (PM)-derived BEVs were shown to suppress osteoclastogenesis by elevating reactive oxygen species (ROS), disrupting mitochondrial membrane potential, and modulating apoptosis-related proteins (Bax, Bcl-2, Caspase-3) (330). In ovariectomized (OVX) mice, PM-BEV administration mitigated bone loss, highlighting their experimental osteoprotective potential (330).

Engineering strategies further enhance BEV functionality. Liu et al. engineered BEVs expressing BMP-2 and CXCR4 fused to ClyA surface proteins, which promoted BMSC osteogenic differentiation in OVX models (331). To address poor bone targeting, bone-homing peptides were anchored to Lactobacillus rhamnosus GG-derived EVs (LGG-EVs), enabling miRNA delivery to bone microenvironments while inhibiting osteoclastogenesis (332). Similarly, anti-miR-6359-loaded exosomes modified with EXOmotif (CGGGAGC) demonstrated precise osteoclast precursor targeting (333). These pre-clinical innovations underscore the versatility of engineered BEVs in balancing efficacy and safety, but remain to be translated clinically.

7.4 Engineering strategies for functionalizing bacterial extracellular vesicles (BEVs)

7.4.1 Physical engineering approaches

7.4.1.1 Membrane fusion

Liposome-mediated fusion stands as a versatile method to enhance BEV functionality. Simple incubation at 37°C enables EV-liposome fusion (334), while polyethylene glycol (PEG) facilitates efficient hybridization (335). For example, fusion of CXCR4-engineered MEVs with antagomir-188-loaded liposomes yielded hybrid nanoparticles with dual bone-targeting and therapeutic capabilities (336). Similarly, Lin et al. demonstrated CRISPR-Cas9 delivery to mesenchymal stem cells (MSCs) via MEV-liposome hybrids (334), highlighting the potential for BEVs to integrate gene-editing tools.

7.4.1.2 Membrane coating

Nanoparticle encapsulation through membrane coating enhances BEV functionality while preserving targeting specificity. Chen et al. engineered BEVs to coat indocyanine green (ICG)-loaded mesoporous silica nanoparticles (MSNs), achieving targeted dendritic cell delivery (337). Hybrid membrane systems, such as BEV-cancer EV (CEV) fusions, further combine tumor-targeting properties with immunogenicity for precision drug delivery (338). These platforms exemplify how BEV-coated nanoparticles could bridge therapeutic and diagnostic applications.

7.4.1.3 Electroporation

Electroporation enables efficient cargo loading without compromising vesicle integrity. Optimized conditions (400 V, 125 μF in potassium phosphate buffer) successfully introduced siRNA into MEVs for neuron-specific delivery via Lamp2B-RVG targeting (339) Applied to BEVs, this method could load antiresorptive or anabolic agents for osteoporosis therapy. Notably, Zha et al. demonstrated VEGF plasmid delivery via progenitor cell-derived MEVs to enhance bone repair (340), suggesting electroporation’s adaptability for BEV-based regenerative strategies.

7.4.2 Chemical engineering approaches

Chemical modification strategies for BEVs are broadly classified into covalent and non-covalent methods, each offering distinct advantages in precision, stability, and applicability. Covalent approaches leverage robust chemical bonds to permanently functionalize BEV surfaces, while non-covalent strategies prioritize flexibility and simplicity for transient interactions. Below, we dissect these methodologies and their implications for BEV engineering.

7.4.2.1 Covalent modifications

Covalent engineering exploits stable chemical bonds to anchor functional moieties onto BEV membranes. Click chemistry, for instance, enables site-specific conjugation of targeting peptides or imaging probes through bioorthogonal reactions, minimizing off-target effects (341). Huang et al. demonstrated this principle by tethering quantum dots to MEVs using DNA hinges, achieving precise labeling without compromising vesicle integrity (342). Similarly, aldehyde-amine condensation and amidation reactions facilitate aptamer conjugation, transforming BEVs into smart platforms for precision therapeutics (343). Bioconjugation strategies further capitalize on BEV-specific surface markers, such as CD63, to anchor functional peptides like CP05, thereby enhancing cargo-loading efficiency (344). However, the limited identification of BEV-specific markers—compared to MEVs, which express well-characterized tetraspanins (e.g., CD9, CD81) and TSG101 (345)—remains a bottleneck. Additionally, the long-term biocompatibility and immunogenicity of covalently modified BEVs warrant rigorous investigation to ensure clinical viability.

7.4.2.2 Non-covalent strategies

Non-covalent modifications offer reversible and rapid functionalization, ideal for applications requiring dynamic interactions. Hydrophobic insertion, a widely adopted method, exploits the amphiphilic nature of BEV membranes. For example, DSPE-PEG derivatives conjugated to targeting ligands (e.g., RGD, folate) spontaneously integrate into lipid bilayers, enhancing BEV homing to specific tissues (346). Electrostatic interactions provide another avenue: Cationic polymers or lipids bind to the anionic BEV surface, enabling hybrid nanoparticle formation. Nakase et al. utilized cationic lipids to fuse pH-sensitive peptides with MEVs, improving cytoplasmic delivery (347), while Sawada et al. engineered cationic pullulan-based nanogels to boost EV uptake efficiency (348). Receptor-ligand interactions further exemplify non-covalent precision. By exploiting natural binding pairs—such as transferrin (Tf) and its receptor (TfR)—Yang et al. isolated TfR + MEVs using magnetic nanoparticles, showcasing a strategy adaptable for BEV-specific targeting (349). Despite their simplicity, non-covalent methods may suffer from lower stability compared to covalent approaches, necessitating context-dependent optimization.

7.5 Administration strategies

Current BEV delivery approaches include oral, intravenous, and bioactive material-combined routes. Oral administration, though non-invasive, faces hurdles such as gastric acid degradation and intestinal variability. Surface modifications, such as dopamine polymerization, protect BEVs from acidic environments, enhancing gastric stability in pre-clinical settings (350).

Intravenous delivery, while potentially efficient, risks systemic toxicity; localized injections and hydrogel encapsulation are being developed as strategies toprolong retention and minimize off-target effects (351, 352). Integration with bioactive materials represents a promising experimental frontier in BEV applications. Liang Ma et al. combined nanotopographical titanium-cultured sEVs with 3D-printed polyetheretherketone scaffolds, significantly enhancing bone regeneration in rabbit femoral defects models (353). Similarly, hypoxia-responsive EVs (hypo-EVs) embedded in hydrogels promoted cranial defect repair in rats, leveraging the hypoxic bone microenvironment (354). These advances demonstrate the pre-clinical-stage synergistic potential of BEV-material hybrids in tissue engineering, necessitating future clinical validation.

7.6 Translational challenges and strategies for BEVs therapeutics

7.6.1 Biosafety: Balancing efficacy and risk mitigation

The clinical advancement of bacterial extracellular vesicles (BEVs) hinges on rigorous biosafety validation. While pre-clinical studies confirm the absence of acute toxicity in BEV-administered models (355, 356), concerns persist regarding residual immunogenic components such as lipopolysaccharides (LPS). Strategies to enhance biocompatibility include genetic modifications targeting LPS biosynthesis (msbA, lpxM deletions) (357), leveraging non-pathogenic Gram-positive species or engineered probiotics (e.g., Escherichia coli Nissle 1917) (358), and physicochemical purification via lysozyme/pH treatments (359, 360). Encapsulation with pH-responsive biomaterials (e.g., calcium phosphate) further refines targeted delivery while minimizing systemic exposure (361). Comprehensive pharmacokinetic profiling—encompassing biodistribution, cellular uptake, and clearance mechanisms—remains critical to establish therapeutic windows and long-term safety thresholds.

7.6.2 Standardization: toward reproducible BEV therapeutics

Heterogeneity in BEV production and isolation protocols poses significant reproducibility challenges. Variations in bacterial culture parameters (nutrient availability, pH, temperature) directly modulate vesicle yield and cargo composition (362, 363), while quantification methods based on protein content or nanoparticle counts introduce analytical inconsistencies (77, 364). Although commercial isolation kits improve accessibility, limitations in purity and cost-efficiency necessitate standardized workflows. Alignment with frameworks such as the MISEV guidelines (20, 365), coupled with advanced characterization tools (e.g., nanotracking analysis, proteomic profiling), could harmonize inter-laboratory practices and enhance data comparability.

7.6.3 Scalability: bridging laboratory innovation to industrial feasibility

Fermentation technologies offer a scalable platform for BEV production, yet industrial translation faces bottlenecks. Heterologous protein expression in recombinant strains often requires suboptimal low-temperature induction (366, 367), conflicting with large-scale fermentation efficiency. Hypervesiculating mutants (e.g., nlpL, rmpM knockouts) (368, 369) and optimized bioreactor conditions (e.g., fed-batch strategies, dissolved oxygen control) (370, 371) present viable pathways to amplify vesicle yields. Future efforts must integrate synthetic biology with bioprocess engineering to achieve cost-effective, GMP-compliant manufacturing—a prerequisite for clinical adoption.

8 Conclusion and future perspectives

OP management faces persistent challenges with conventional therapies due to adverse effects and inadequate modulation of gut-bone crosstalk. NGPs and BEVs represent promising experimental transformative strategies that address these limitations through precision-targeted mechanisms. NGPs, enhanced by synthetic biology, hold potential to enable dynamic delivery of osteoprotective metabolites (e.g., SCFAs, phytoestrogens), immunomodulation, and neuroendocrine regulation, while circumventing colonization barriers inherent to traditional probiotics. BEVs, as biocompatible nanocarriers, offer experimental, scalable, non-replicative platforms for bone-specific delivery of therapeutic cargo (miRNAs, cytokines, osteogenic factors), synergizing with biomaterials to enhance fracture repair. Despite encouraging pre-clinical promise, significant challenges in strain-specific efficacy, biosafety, and industrial scalability necessitate standardized protocols and rigorous clinical validation. Future research must prioritize multi-omics integration to decode host-microbe interactions, optimize genetic toolkits for non-conventional probiotics, and advance hybrid BEV-scaffold systems. By bridging microbial therapeutics with bone bioengineering, these innovations hold immense potential to restore skeletal homeostasis, offering safer, personalized alternatives to reshape osteoporosis care.

Future directions should prioritize multifactorial strategies: Optimizing synthetic probiotics to enrich therapeutic strains, elucidating senescence-autophagy interplay in BMMSC aging, and advancing BEV engineering for dual osteoanabolic/anti-resorptive effects. Bridging these mechanistic insights with robust clinical validation is essential to unlock next-generation therapies, transforming OP management from symptomatic relief to pathophysiology-driven precision medicine.

Author contributions

JW: Writing – original draft, Writing – review & editing. WD: Writing – original draft, Writing – review & editing. KS: Writing – original draft, Writing – review & editing. YZ: Writing – original draft, Writing – review & editing. QL: Writing – original draft, Writing – review & editing. CQ: Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

Acknowledgments

We are grateful to Q. Luo and Q. Chen for their insightful discussions and critical feedback during manuscript preparation.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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