Alliances of the gut and bone axis.

Gut hormones secreted from enteroendocrine cells following nutrient ingestion modulate metabolic processes including glucose homeostasis and food intake, and several of these gut hormones are involved in the regulation of the energy demanding process of bone remodelling. Here, we review the gut hormones considered or known to be involved in the gut-bone crosstalk and their role in orchestrating adaptions of bone formation and resorption as demonstrated in cellular and physiological experiments and clinical trials. Understanding the physiology and pathophysiology of the gut-bone axis may identify adverse effects of investigational drugs aimed to treat metabolic diseases such as type 2 diabetes and obesity and new therapeutic candidates for the treatment of bone diseases.

New insights into dairy management and the prevention and treatment of osteoporosis: The shift from single nutrient to dairy matrix effects-A review.

Dairy is recognized as a good source of calcium, which is important for preventing osteoporosis. However, the relationship between milk and bone health is more complex than just calcium supplementation. It is unwise to focus solely on observing the effects of a single nutrient. Lactose, proteins, and vitamins in milk, as well as fatty acids, oligosaccharides, and exosomes, all work together with calcium to enhance its bioavailability and utilization efficiency through various mechanisms. We evaluate the roles of dairy nutrients and active ingredients in maintaining bone homeostasis from the perspective of the dairy matrix effects. Special attention is given to threshold effects, synergistic effects, and associations with the gut-bone axis. We also summarize the associations between probiotic/prebiotic milk, low-fat/high-fat milk, lactose-free milk, and fortified milk with a reduced risk of osteoporosis and discuss the potential benefits and controversies of these dairy products. Moreover, we examine the role of dairy products in increasing peak bone mass during adolescence and reducing bone loss in old age. It provides a theoretical reference for the use of dairy products in the accurate prevention and management of osteoporosis and related chronic diseases and offers personalized dietary recommendations for bone health in different populations.

The regulative effect and repercussion of probiotics and prebiotics on osteoporosis: involvement of brain-gut-bone axis.

Osteoporosis (OP) is a systemic disease characterized by decreased bone mass and degeneration of bone microstructure. In recent years, more and more researches have focused on the close relationship between gut microbiota (GM) and the occurrence and progression of OP, and the regulation of probiotics and prebiotics on bone metabolism has gradually become a research hotspot. Based on the influence of brain-gut-bone axis on bone metabolism, this review expounds the potential mechanisms of probiotics and prebiotics on OP from next perspectives: regulation of intestinal metabolites, regulation of intestinal epithelial barrier function, involvement of neuromodulation, involvement of immune regulation and involvement of endocrine regulation, so as to provide a novel and promising idea for the prevention and treatment of OP in the future.

The impacts of oral and gut microbiota on alveolar bone loss in periodontitis.

Periodontitis, a chronic infectious disease, primarily arises from infections and the invasion of periodontal pathogens. This condition is typified by alveolar bone loss resulting from host immune responses and inflammatory reactions. Periodontal pathogens trigger aberrant inflammatory reactions within periodontal tissues, thereby exacerbating the progression of periodontitis. Simultaneously, these pathogens and metabolites stimulate osteoclast differentiation, which leads to alveolar bone resorption. Moreover, a range of systemic diseases, including diabetes, postmenopausal osteoporosis, obesity and inflammatory bowel disease, can contribute to the development and progression of periodontitis. Many studies have underscored the pivotal role of gut microbiota in bone health through the gut-alveolar bone axis. The circulation may facilitate the transfer of gut pathogens or metabolites to distant alveolar bone, which in turn regulates bone homeostasis. Additionally, gut pathogens can elicit gut immune responses and direct immune cells to remote organs, potentially exacerbating periodontitis. This review summarizes the influence of oral microbiota on the development of periodontitis as well as the association between gut microbiota and periodontitis. By uncovering potential mechanisms of the gut-bone axis, this analysis provides novel insights for the targeted treatment of pathogenic bacteria in periodontitis.

Pivotal Role of Intestinal Microbiota and Intraluminal Metabolites for the Maintenance of Gut-Bone Physiology.

Intestinal microbiota, and their mutual interactions with host tissues, are pivotal for the maintenance of organ physiology. Indeed, intraluminal signals influence adjacent and even distal tissues. Consequently, disruptions in the composition or functions of microbiota and subsequent altered host-microbiota interactions disturb the homeostasis of multiple organ systems, including the bone. Thus, gut microbiota can influence bone mass and physiology, as well as postnatal skeletal evolution. Alterations in nutrient or electrolyte absorption, metabolism, or immune functions, due to the translocation of microbial antigens or metabolites across intestinal barriers, affect bone tissues, as well. Intestinal microbiota can directly and indirectly alter bone density and bone remodeling. Intestinal dysbiosis and a subsequently disturbed gut-bone axis are characteristic for patients with inflammatory bowel disease (IBD) who suffer from various intestinal symptoms and multiple bone-related complications, such as arthritis or osteoporosis. Immune cells affecting the joints are presumably even primed in the gut. Furthermore, intestinal dysbiosis impairs hormone metabolism and electrolyte balance. On the other hand, less is known about the impact of bone metabolism on gut physiology. In this review, we summarized current knowledge of gut microbiota, metabolites and microbiota-primed immune cells in IBD and bone-related complications.

From Cells to Environment: Exploring the Interplay between Factors Shaping Bone Health and Disease.

The skeletal system is an extraordinary structure that serves multiple purposes within the body, including providing support, facilitating movement, and safeguarding vital organs. Moreover, it acts as a reservoir for essential minerals crucial for overall bodily function. The intricate interplay of bone cells plays a critical role in maintaining bone homeostasis, ensuring a delicate balance. However, various factors, both intrinsic and extrinsic, can disrupt this vital physiological process. These factors encompass genetics, aging, dietary and lifestyle choices, the gut microbiome, environmental toxins, and more. They can interfere with bone health through several mechanisms, such as hormonal imbalances, disruptions in bone turnover, direct toxicity to osteoblasts, increased osteoclast activity, immune system aging, impaired inflammatory responses, and disturbances in the gut-bone axis. As a consequence, these disturbances can give rise to a range of bone disorders. The regulation of bone's physiological functions involves an intricate network of continuous processes known as bone remodeling, which is influenced by various intrinsic and extrinsic factors within the organism. However, our understanding of the precise cellular and molecular mechanisms governing the complex interactions between environmental factors and the host elements that affect bone health is still in its nascent stages. In light of this, this comprehensive review aims to explore emerging evidence surrounding bone homeostasis, potential risk factors influencing it, and prospective therapeutic interventions for future management of bone-related disorders.

Gut-organ axis: a microbial outreach and networking.

Human gut microbiota (GM) includes a complex and dynamic population of microorganisms that are crucial for well-being and survival of the organism. It has been reported as diverse and relatively stable with shared core microbiota, including Bacteroidetes and Firmicutes as the major dominants. They are the key regulators of body homeostasis, involving both intestinal and extra-intestinal effects by influencing many physiological functions such as metabolism, maintenance of barrier homeostasis, inflammation and hematopoiesis. Any alteration in GM community structures not only trigger gut disorders but also influence other organs and cause associated diseases. In recent past, the GM has been defined as a 'vital organ' with its involvement with other organs; thus, establishing a link or a bi- or multidirectional communication axis between the organs via neural, endocrine, immune, humoral and metabolic pathways. Alterations in GM have been linked to several diseases known to humans; although the exact interaction mechanism between the gut and the organs is yet to be defined. In this review, the bidirectional relationship between the gut and the vital human organs was envisaged and discussed under several headings. Furthermore, several disease symptoms were also revisited to redefine the communication network between the gut microbes and the associated organs.

Loss of Intestinal Alkaline Phosphatase Leads to Distinct Chronic Changes in Bone Phenotype.

BACKGROUND: The gut is becoming increasingly recognized as the source of various systemic diseases, and recently, it has been linked to bone metabolism via the so-called gut-bone axis. The microbiome and gut-derived mediators are thought to impact upon bone metabolism, and administration of probiotics has been shown to have beneficial effects in bone. The gut brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in controlling calcium absorption, inhibiting lipopolysaccharides, and other inflammatory mediators responsible for endotoxemia and appears to preserve the normal gut microbiota. Interestingly, IAP-deficient mice (AKP3-/-) also display a significant decrease in fecal Lactobacillus, the genus shown to be beneficial to bone. MATERIALS AND METHODS: IAP mRNA levels in mouse bone were measured using quantitative real-time polymerase chain reaction. Femurs of IAP-knockout (KO) and wild-type (WT) mice were analyzed by microcomputed tomography and histopathology. Serum levels of alkaline phosphatase, calcium, and phosphorus were measured. Target cell response upon exposure to serum from IAP-KO and WT mice was quantified using primary bone marrow macrophages. RESULTS: IAP was not significantly expressed in bones of WT or KO animals. IAP (alkaline phosphatase 3) expression in bone was vanishingly low compared to the duodenum (bone versus duodenum, 56.9 ± 17.7 versus 25,430.3 ± 10,884.5 relative expression, P = 0.01). Bone histology of younger IAP-KO and WT animals was indistinguishable, whereas older IAP-deficient mice showed a distinctly altered phenotype on histology and computed tomography scan. Younger KO mice did not display any abnormal levels in blood chemistry. Older IAP-KO animals showed an isolated increase in serum alkaline phosphatase levels reflecting an environment of active bone formation (IAP-WT versus IAP-KO, 80 ± 27.4 U/I versus 453 ± 107.5 U/I, P = 0.004). There was no significant difference in serum calcium or phosphorus levels between KO and WT mice. Serum from IAP-KO mice induced a significantly higher inflammatory target cell response. CONCLUSIONS: Through its multiple functions, IAP seems to play a crucial role in connecting the gut to the bone. IAP deficiency leads to chronic changes in bone formation, most likely through dysbiosis and systemic dissemination of proinflammatory mediators.

Association of dietary live microbe intake with prevalence of osteoporosis in US postmenopausal women: a cross-sectional study.

The association between live microbe intake and osteoporosis in postmenopausal women remains unknown. The research findings indicated that an increased intake of live microbes through dietary sources was associated with a low prevalence of osteoporosis among postmenopausal women. PURPOSE: To investigate the relationship between the consumption of live microbes in the diet and osteoporosis in postmenopausal women. METHODS: A cross-sectional investigation using data obtained from the National Health and Nutrition Examination Survey was conducted. Participants were classified into three groups by using the dietary live microbe classification system developed by Sanders. Dual x-ray absorptiometry was used to measure body mineral density, and osteoporosis was diagnosed according to the World Health Organization criteria. We conducted a crude and adjusted multivariate logistic regression analysis, and utilized the restricted cubic splines model to assess the correlation between the consumption of live microbes in the diet and osteoporosis in postmenopausal women. RESULTS: A total of 1378 women who had undergone menopause were enrolled in the study. After controlling for potential covariates, individuals with a high consumption of live microbes in their diet exhibited a notably low prevalence of osteoporosis in comparison to those with a low intake of dietary live microbes (odd ratio: 0.46, 95% confidence interval: 0.23, 0.93, P = 0.03). Subgroup analysis showed the stability of the results, and restricted cubic splines showed an approximate L-shape curve. CONCLUSIONS: In this research, a higher consumption of live microbes in the diet was linked to a low prevalence of osteoporosis in postmenopausal women.

Diets intervene osteoporosis via gut-bone axis.

Osteoporosis is a systemic skeletal disease that seriously endangers the health of middle-aged and older adults. Recently, with the continuous deepening of research, an increasing number of studies have revealed gut microbiota as a potential target for osteoporosis, and the research concept of the gut-bone axis has gradually emerged. Additionally, the intake of dietary nutrients and the adoption of dietary patterns may affect the gut microbiota, and alterations in the gut microbiota might also influence the metabolic status of the host, thus adjusting bone metabolism. Based on the gut-bone axis, dietary intake can also participate in the modulation of bone metabolism by altering abundance, diversity, and composition of gut microbiota. Herein, combined with emerging literatures and relevant studies, this review is aimed to summarize the impacts of different dietary components and patterns on osteoporosis by acting on gut microbiota, as well as underlying mechanisms and proper dietary recommendations.

Gut-bone axis research: unveiling the impact of gut microbiota on postmenopausal osteoporosis and osteoclasts through Mendelian randomization.

Background: Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known as the gut-bone axis, has garnered widespread attention. Methods: We employed a two-sample Mendelian randomization approach to assess the associations between gut microbiota with osteoclasts and postmenopausal osteoporosis, respectively. Single nucleotide polymorphisms associated with the composition of gut microbiota were used as instrumental variables. By analyzing large-scale multi-ethnic GWAS data from the international MiBioGen consortium, and combining data from the eQTLGen consortium and the GEFOS consortium, we identified microbiota related to osteoclasts and postmenopausal osteoporosis. Key genes were further identified through MAGMA analysis, and validation was performed using single-cell data GSE147287. Results: The outcomes of this study have uncovered significant associations within the gut microbiome community, particularly with the Burkholderiales order, which correlates with both an increase in osteoclasts and a reduced risk of postmenopausal osteoporosis. with an odds ratio (OR) of 0.400, and a P-value of 0.011. Further analysis using single-cell data allowed us to identify two key genes, FMNL2 and SRBD1, that are closely linked to both osteoclasts and osteoporosis. Conclusion: This study utilizing Mendelian randomization and single-cell data analysis, provides new evidence of a causal relationship between gut microbiota and osteoclasts, as well as postmenopausal osteoporosis. It was discovered that the specific microbial group, the Burkholderiales order, significantly impacts both osteoporosis and osteoclasts. Additionally, key genes FMNL2 and SRBD1 were identified, offering new therapeutic strategies for the treatment of postmenopausal osteoporosis.

Targeting the gut microbiota-related metabolites for osteoporosis: The inextricable connection of gut-bone axis.

Osteoporosis is a systemic skeletal disease characterized by decreased bone mass, destruction of bone microstructure, raised bone fragility, and enhanced risk of fractures. The correlation between gut microbiota and bone metabolism has gradually become a widespread research hotspot in recent years, and successive studies have revealed that the alterations of gut microbiota and its-related metabolites are related to the occurrence and progression of osteoporosis. Moreover, several emerging studies on the relationship between gut microbiota-related metabolites and bone metabolism are also underway, and extensive research evidence has indicated an inseparable connection between them. Combined with latest literatures and based on inextricable connection of gut-bone axis, this review is aimed to summarize the relation, potential mechanisms, application strategies, clinical application prospects, and existing challenges of gut microbiota and its-related metabolites on osteoporosis, thus updating the knowledge in this research field and providing certain reference for future researches.

Korean red ginseng extract prevents bone loss in an oral model of glucocorticoid induced osteoporosis in mice.

The gut microbiota and barrier function play important roles in bone health. We previously demonstrated that chronic glucocorticoid (GC)-induced bone loss in mice is associated with significant shifts in gut microbiota composition and impaired gut barrier function. Korean Red Ginseng (KRG, Panax Ginseng Meyer, Araliaceae) extract has been shown to prevent glucocorticoid-induced osteoporosis (GIO) in a subcutaneous pellet model in mice, but its effect on gut microbiota and barrier function in this context is not known. The overall goal of this study was to test the effect of KRG extract in a clinically relevant, oral model of GIO and further investigate its role in modulating the gut-bone axis. Growing male mice (CD-1, 8 weeks) were treated with 75 µg/mL corticosterone (∼9 mg/kg/day) or 0.4% ethanol vehicle in the drinking water for 4 weeks. During this 4-week period, mice were treated daily with 500 mg/kg/day KRG extract dissolved in sterile water or an equal amount of sterile water via oral gastric gavage. After 4 weeks of treatment, we assessed bone volume, microbiota composition, gut barrier integrity, and immune cells in the bone marrow (BM) and mesenteric lymph nodes (MLNs). 4 weeks of oral GC treatment caused significant distal femur trabecular bone loss, and this was associated with changes in gut microbiota composition, impaired gut barrier function and altered immune cell composition. Importantly, KRG extract prevented distal femur trabecular bone loss and caused significant alterations in gut microbiota composition but had only modest effects on gut barrier function and immune cell populations. Taken together, these results demonstrate that KRG extract significantly modulates the gut microbiota-bone axis and prevents glucocorticoid-induced bone loss in mice.

Fructooligosaccharides act on the gut-bone axis to improve bone independent of Tregs and alter osteocytes in young adult C57BL/6 female mice.

Targeting the gut-bone axis with probiotics and prebiotics is considered as a promising strategy to reduce the risk of osteoporosis. Gut-derived short chain fatty acids (SCFA) mediate the effects of probiotics on bone via Tregs, but it is not known whether prebiotics act through a similar mechanism. We investigated how 2 different prebiotics, tart cherry (TC) and fructooligosaccharide (FOS), affect bone, and whether Tregs are required for this response. Eight-wk-old C57BL/6 female mice were fed with diets supplemented with 10% w/w TC, FOS, or a control diet (Con; AIN-93M) diet, and they received an isotype control or CD25 Ab to suppress Tregs. The FOS diet increased BMC, density, and trabecular bone volume in the vertebra (~40%) and proximal tibia (~30%) compared to the TC and control diets (Con), irrespective of CD25 treatment. Both prebiotics increased (P < .01) fecal SCFAs, but the response was greater with FOS. To determine how FOS affected bone cells, we examined genes involved in osteoblast and osteoclast differentiation and activity as well as genes expressed by osteocytes. The FOS increased the expression of regulators of osteoblast differentiation (bone morphogenetic protein 2 [Bmp2], Wnt family member 10b [Wnt10b] and Osterix [Osx]) and type 1 collagen). Osteoclasts regulators were unaltered. The FOS also increased the expression of genes associated with osteocytes, including (Phex), matrix extracellular phosphoglycoprotein (Mepe), and dentin matrix acidic phosphoprotein 1 (Dmp-1). However, Sost, the gene that encodes for sclerostin was also increased by FOS as the number and density of osteocytes increased. These findings demonstrate that FOS has a greater effect on the bone mass and structure in young adult female mice than TC and that its influence on osteoblasts and osteocytes is not dependent on Tregs.

Microbiota and Resveratrol: How Are They Linked to Osteoporosis?

Osteoporosis (OP), which is characterized by a decrease in bone density and increased susceptibility to fractures, is closely linked to the gut microbiota (GM). It is increasingly realized that the GM plays a key role in the maintenance of the functioning of multiple organs, including bone, by producing bioactive metabolites such as short-chain fatty acids (SCFA). Consequently, imbalances in the GM, referred to as dysbiosis, have been identified with a significant reduction in beneficial metabolites, such as decreased SCFA associated with increased chronic inflammatory processes, including the activation of NF-κB at the epigenetic level, which is recognized as the main cause of many chronic diseases, including OP. Furthermore, regular or long-term medications such as antibiotics and many non-antibiotics such as proton pump inhibitors, chemotherapy, and NSAIDs, have been found to contribute to the development of dysbiosis, highlighting an urgent need for new treatment approaches. A promising preventive and adjuvant approach is to combat dysbiosis with natural polyphenols such as resveratrol, which have prebiotic functions and ensure an optimal microenvironment for beneficial GM. Resveratrol offers a range of benefits, including anti-inflammatory, anti-oxidant, analgesic, and prebiotic effects. In particular, the GM has been shown to convert resveratrol, into highly metabolically active molecules with even more potent beneficial properties, supporting a synergistic polyphenol-GM axis. This review addresses the question of how the GM can enhance the effects of resveratrol and how resveratrol, as an epigenetic modulator, can promote the growth and diversity of beneficial GM, thus providing important insights for the prevention and co-treatment of OP.

Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes.

CONTEXT: Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE: The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS: We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS: GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION: Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis.

Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.

Microbial Tryptophan Metabolites Ameliorate Ovariectomy-Induced Bone Loss by Repairing Intestinal AhR-Mediated Gut-Bone Signaling Pathway.

Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut-bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole-3-propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)-induced postmenopausal osteoporosis mice in an AhR-dependent manner. Mechanistically, intestinal AhR activation by Trp metabolites, especially IAA, effectively repairs intestinal barrier function by stimulating Wnt/ß-catenin signaling pathway. Consequently, enhanced M2 macrophage by supplementation with IAA and IPA secrete large amount of IL-10 that expands from intestinal lamina propria to bone marrow, thereby simultaneously promoting osteoblastogenesis and inhibiting osteoclastogenesis in vivo and in vitro. Interestingly, supplementation with Trp metabolites exhibit negligible ameliorative effects on both gut homeostasis and bone loss of OVX mice with intestinal AhR knockout (VillinCreAhrfl/fl). These findings suggest that microbial Trp metabolites may be potential therapeutic candidates against osteoporosis via regulating AhR-mediated gut-bone axis.

Genus_Ruminococcus and order_Burkholderiales affect osteoporosis by regulating the microbiota-gut-bone axis.

Background: This study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments. Methods: We conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1ß, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed. Results: A positive correlation was observed between g_Ruminococcus1 and the risk of osteoporosis, while O_Burkholderiales showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the O_Burkholderiales was significantly reduced, while the abundance of g_Ruminococcus was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of O_Burkholderiales is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of g_Ruminococcus shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors. Conclusion: O_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis.

The Brain-Gut-Bone Axis in Neurodegenerative Diseases: Insights, Challenges, and Future Prospects.

Neurodegenerative diseases are global health challenges characterized by the progressive degeneration of nerve cells, leading to cognitive and motor impairments. The brain-gut-bone axis, a complex network that modulates multiple physiological systems, has gained increasing attention owing to its profound effects on the occurrence and development of neurodegenerative diseases. No comprehensive review has been conducted to clarify the triangular relationship involving the brain-gut-bone axis and its potential for innovative therapies for neurodegenerative disorders. In light of this, a new perspective is aimed to propose on the interplay between the brain, gut, and bone systems, highlighting the potential of their dynamic communication in neurodegenerative diseases, as they modulate multiple physiological systems, including the nervous, immune, endocrine, and metabolic systems. Therapeutic strategies for maintaining the balance of the axis, including brain health regulation, intestinal microbiota regulation, and improving skeletal health, are also explored. The intricate physiological interactions within the brain-gut-bone axis pose a challenge in the development of effective treatments that can comprehensively target this system. Furthermore, the safety of these treatments requires further evaluation. This review offers a novel insights and strategies for the prevention and treatment of neurodegenerative diseases, which have important implications for clinical practice and patient well-being.