Osteoporotic bone defects significantly affect patient health and quality of life. The gut-bone axis plays a crucial role in osteoporosis, and disruptions in gut microbiota are linked to systemic inflammation and compromised bone metabolism. Irisin, a myokine, has shown potential in protecting against osteoporosis, but its mechanisms of action on the gut-bone axis remain unclear. This study aimed to investigate the role of irisin in mitigating osteoporotic bone defects by examining its effects on gut microbiota, related metabolites, and intestinal barrier integrity.

An osteoporosis model was created using ovariectomized (OVX) mice. The mice were divided into Sham, OVX, and r-irisin groups. Mice in the r-irisin group received intraperitoneal injections of 100 μg/kg irisin twice weekly for five weeks. Bone parameters were analyzed by micro-CT and histological staining. Gut microbiota composition was examined via 16S rDNA sequencing. Intestinal cytokines and barrier proteins were measured using immunohistochemistry and ELISA. Fecal metabolomic profiling was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and correlations between gut microbiota, metabolites, and bone metabolism markers were evaluated.

Irisin treatment improved bone mineral density (BMD), bone volume/tissue volume (BV/TV), trabecular bone thickness (Tb.Th), and trabecular number (Tb.N), and reduced trabecular separation (Tb.Sp) in OVX mice. It enhanced new bone formation and collagen deposition. Irisin restored intestinal barrier integrity by increasing tight junction protein expression and reducing inflammatory cytokines in intestinal tissues. It also modulated gut microbiota diversity, reducing Firmicutes and increasing Verrucomicrobiota abundance. Key fecal metabolites, including atractylon (r = - 0.60, P < 0.01) and enterodiol (r = + 0.83, P < 0.01), showed strong correlations with BMD.

Irisin mitigates osteoporotic bone defects by enhancing bone formation, restoring intestinal barrier integrity, modulating gut microbiota composition, and influencing fecal metabolites. These preclinical findings highlight irisin's potential to mitigate osteoporosis via the gut-bone axis.

The target and mechanism of oral traditional Chinese medicine (TCM) have been important research directions for a long time. The close relationship between osteoporosis and gut microbiota (GM) has been confirmed. However, the relevance of oral TCM and the "Gut-Bone Axis" is still poorly understood.

Twenty-one SPF C57BL/6J female mice were divided into sham (Sham), ovariectomized (OVX), and Zuo-Gui-Wan-treated (ZGW, 1.4 g/kg) groups. The osteoporosis mouse model was established through ovariectomy. After eight weeks of Zuo-Gui-Wan treatment via gavage, serum calcium, phosphorus, ALT, AST, CREA, and other biochemical indicators were measured. Subsequently, Micro-CT, HE staining, and analysis of gut microbiota were conducted to further explore the potential mechanism.

The anti-osteoporotic effects of ZGW were confirmed through micro-CT, histological, and biochemical tests in an OVX-induced osteoporosis mouse model. ZGW treatment also alters the diversity and composition of the gut microbiota and altered the Firmicutes/Bacteroidetes ratio. Further analysis reveals a correlation between specific bacterial groups and serum indicators. Mfuzz clustering analysis and metagenomeSeq analysis identified important microbiota species that were rescued or modulated by ZGW treatment.

These findings suggest that changes in gut microbiota abundance may be linked to ZGW's ability to improve osteoporosis. This study provides new insights into how ZGW treats osteoporosis, though further research is needed to clarify the mechanisms by which specific gut microbiota influence bone health.

Emerging insights in osteoimmunology have enabled researchers to explore in depth the role of immune modulation in regulating bone health. Bone is one of the common sites of metastasis notably in case of breast cancer, prostate cancer and several other cancer types. High calcium ion concentration and presence of several factors within the mineralized bone matrix including TGF-β, BMP etc., aid in tumor growth and proliferation. Accumulating evidence has substantiated the role of the gut-microbiota (GM) in tumorigenesis, further providing a strong impetus for the growing "immune-cancer-gut microbiota" relationship. Recent advancements in research further highlight the importance of the intra-tumor microbiota in conjunction with GM in cancer metastasis. Intratumoral microbiota owing to their ability to cause genetic instability, mutations, and epigenetic modifications within the tumor microenvironment, has been recognized to affect cancer cell physiology. The host microbiota and immune system crosstalk shapes the innate and adaptive arms of the immune system, which is the key player in cancer progression. In this review, we aim to decipher the role of microorganisms mediating bone metastasis by shedding light on the immuno-onco-microbiome (IOM) axis. We discussed the feasible cancer therapeutic interventions based on the modulation of the microbiome-immune cell axis which includes prebiotics, probiotics, and postbiotics. Here, we leverage the conceptual framework based on the published articles on microbiota-based therapies to target bone metastases. Understanding this complicated nexus will provide insights into fundamental factors governing bone metastases which will subsequently help in managing this malignancy with better efficacy.

Previous studies have suggested a potential association between the gut microbiota and arthritis. However, the causal links between the gut microbiota and various types of arthritis, as well as the potential mediating role of inflammatory proteins, remain unclear. Mendelian randomization was used to explore the causal relationships between gut microbiota, inflammatory proteins, and various forms of arthritis (osteoarthritis, rheumatoid and psoriatic arthritis, and ankylosing spondylitis [AS]). The inverse variance-weighted method was the primary analytical approach used. Furthermore, we examined the mediating role of inflammatory proteins in the pathway linking the gut microbiota to arthritis. Sensitivity analyses were performed to verify the robustness of the findings, and enrichment analyses were conducted to investigate the biological functions and pathways involved. We identified 11 positive and 14 negative causal effects linking the genetic liability of the gut microbiota to arthritis. Similarly, 9 positive and 8 negative causal effects between inflammatory proteins and arthritis were identified. Notably, an increased abundance of the order Bacillales (odds ratio [OR] = 1.199, 95% confidence interval [CI] = 1.030-1.394, P = 0.019) and higher interleukin-7 levels (OR = 1.322, 95% CI = 1.004-1.741, P = 0.046) significantly elevated the risk of AS. Furthermore, interleukin-7 mediated 13.8% of the effect caused by the order Bacillales, with a mediation effect size of β = 0.025 (95% CI = 0.001-0.064). Sensitivity and supplementary analyses revealed no significant evidence of horizontal pleiotropy or heterogeneity. Overall, our findings demonstrate causal links between the gut microbiota, inflammatory proteins, and four arthritis types, highlighting the gut microbiota as a potential therapeutic target. Crucially, interleukin-7 not only strongly correlated with AS but also partially mediated the effect exerted by the gut microbiota on AS, suggesting that managing the gut microbiota to modulate inflammatory proteins could serve as an effective therapeutic strategy for arthritis.

Recent studies have established associations between the gut microbiota (GM) and thyroid diseases (TDs). However, their causal relationships remain elusive.

To investigate this causality, we conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data from MiBioGen and FinnGen, with GM as the exposure and six TDs as outcomes.

We identified 32 microbial taxa linked to the risk of six TDs. The Clostridium innocuum group, Ruminiclostridium5, and Lachnoclostridium exhibited protective effects against nontoxic diffuse goiter (NDG). Conversely, an increased risk of NDG was associated with Ruminococcaceae UCG002, Alistipes, Methanobrevibacter, Marvinbryantia, and Ruminococcaceae UCG014. Bifidobacterium and Sutterella were protective against nontoxic multinodular goiter (NMG), while the Ruminococcus gauvreauii group and Rikenellaceae RC9 gut group heightened NMG risk. Protective effects against nontoxic single thyroid nodule (NSTN) were observed with Defluviitaleaceae UCG011, Ruminococcus1, and Ruminococcaceae UCG010, whereas increased risk was linked to Alistipes, the Ruminococcus gauvreauii group, and Lachnospiraceae UCG010. Ruminiclostridium9, Victivallis, and Butyricimonas offered protection against thyrotoxicosis with Graves' Disease (GD), while the Eubacterium rectale group, Desulfovibrio, Bifidobacterium, Collinsella, Oscillospira, and Catenibacterium were risk factors. For thyrotoxicosis with Plummer Disease (PD), protective taxa included Butyricimonas and Lachnospira, whereas Dorea, Eggerthella, Odoribacter, Lactobacillus, Intestinimonas, and Phascolarctobacterium increased risk. Lastly, Parasutterella was protective against thyrotoxicosis with toxic single thyroid nodule (TSTN), while increased risk was associated with Sutterella, Oscillibacter, and Clostridium sensu stricto1.

Our findings support a causal relationship between specific GM and TDs at the genetic level, laying the foundation for future research into potential mechanisms and the identification of novel therapeutic targets.

While some studies have suggested a link between gut microbiota (GM) and abortion, the causal relationship remains unclear.

To explore the causal relationship between GM and abortion, including spontaneous abortion (SA) and habitual abortion (HA), we performed a two-sample Mendelian randomization (MR) analysis. We used summary statistics data from MiBioGen and FinnGen for genome-wide association studies (GWAS), with GM data as the exposure variable and abortion data as the outcome variable.

In the absence of heterogeneity and horizontal pleiotropy, the inverse-variance weighted (IVW) method identified five genetically predicted GM genera linked to the risk of abortions. Lactococcus was negatively correlated with the risk of SA, whereas the Eubacterium fissicatena group was positively correlated with the risk of SA. Genetic predictions of Coprococcus3 and Odoribacter were linked to a reduced risk of HA, while the Eubacterium ruminantium group was associated with an increased risk of HA.

Our study suggests a genetic causal relationship between specific GM and two types of abortions, improving our understanding of the pathological relationship between GM and abortion.

Several studies have reported a potential association between the gut microbiota (GM) and scoliosis. However, the causal relationship between GM and scoliosis and the role of inflammatory factors (IFs) as mediators remain unclear. This study aimed to analyze the relationship between GM, IFs, and scoliosis. We investigated whether IFs act as mediators in pathways from the GM to scoliosis. Additionally, using reverse Mendelian randomization (MR) analysis, we further investigated the potential impact of genetic predisposition to scoliosis on the GM and IFs. In this study, we searched for publicly available genome-wide association study aggregate data and utilized the MR method to establish bidirectional causal relationships among 211 GM taxa, 91 IFs, and scoliosis. To ensure the reliability of our research findings, we employed 5 MR methods, with the inverse variance weighting approach serving as the primary statistical method, and assessed the robustness of the results through various sensitivity analyses. Additionally, we investigated whether IFs mediate pathways from GM to scoliosis. Three negative causal correlations were observed between the genetic predisposition to GM and scoliosis. Additionally, both positive and negative correlations were found between IFs and scoliosis, with 3 positive and 3 negative correlations observed. IFs do not appear to act as mediators in the pathway from GM to scoliosis. In conclusion, this study demonstrated a causal association between the GM, IFs, and scoliosis, indicating that IFs are not mediators in the pathway from the GM to scoliosis. These findings offer new insights into prevention and treatment strategies for scoliosis.

Osteoporosis (OP) and cardiovascular disease (CVD) are major global public health issues, especially exacerbated by the challenges of an aging population. As these problems intensify, the associated burden on global health is expected to increase significantly. Despite extensive epidemiological investigations into the potential association between OP and CVD, establishing a clear causal relationship remains elusive.

Instrumental variables were selected from summary statistics of the IEU GWAS database. Five different components of BMD (heel BMD, LS BMD, FA BMD, FN BMD, and TB BMD) were used as OP phenotypes. CHD, MI, and stroke were selected to represent CVD. Multiple analysis methods were used to evaluate the causal relationship between CVD and OP comprehensively. In addition, sensitivity analyses(Cochran's Q test, MR-Egger intercept test, and "leave one out" analysis) were performed to verify the reliability of the results.

The MR showed a significant causal relationship between CHD on heel BMD and TB BMD; in the reverse analysis, there was no evidence that OP has a significant causal effect on CVD. The reliability of the results was confirmed through sensitivity analysis.

The study results revealed that CHD was causally associated with Heel BMD and TB BMD, while in the reverse MR analysis, the causal relationship between OP and CVD was not supported. This result posits CHD as a potential etiological factor for OP and prompts that routine bone density assessment at traditional sites (forearm, femoral neck, lumbar spine) using DAX may inadequately discern underlying osteoporosis issues in CHD patients. The recommendation is to synergistically incorporate heel ultrasound or DAX for total body bone density examinations, ensuring clinical diagnostics are both precise and reliable. Moreover, these findings provide valuable insights for public health, contributing to the development of pertinent prevention and treatment strategies.

This study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments.

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-1β, 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.

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.

O_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis.

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with poor prognosis. Previous studies have implicated the gut microbiota in CCA, but evidence for causal mechanisms is lacking.

To investigate the causal relationship between gut microbiota and CCA risk.

We performed a two-sample mendelian randomization study to evaluate potential causal associations between gut microbiota and CCA risk using genome-wide association study summary statistics for 196 gut microbial taxa and CCA. Genetic variants were used as instrumental variables. Multiple sensitivity analyses assessed result robustness.

Fifteen gut microbial taxa showed significant causal associations with CCA risk. Higher genetically predicted abundance of genus Eubacteriumnodatum group, genus Ruminococcustorques group, genus Coprococcus, genus Dorea, and phylum Actinobacteria were associated with reduced risk of gallbladder cancer and extrahepatic CCA. Increased intrahepatic CCA risk was associated with higher abundance of family Veillonellaceae, genus Alistipes, order Enterobacteriales, and phylum Firmicutes. Protective effects against CCA were suggested for genus Collinsella, genus Eisenbergiella, genus Anaerostipes, genus Paraprevotella, genus Parasutterella, and phylum Verrucomicrobia. Sensitivity analyses indicated these findings were reliable without pleiotropy.

This pioneering study provides novel evidence that specific gut microbiota may play causal roles in CCA risk. Further experimental validation of these candidate microbes is warranted to consolidate causality and mechanisms.

Depression frequently occurs in patients with liver cirrhosis, yet the reasons for this correlation are not fully understood. Dysbiosis of gut microbiota has been implicated in depression through the gut-brain axis via the vagus nerve. This study explored the potential role of the gut-liver-brain axis via the vagus nerve in depression-like phenotypes in mice with liver cirrhosis. These mice underwent common bile duct ligation (CBDL), a method used to stimulate liver cirrhosis. To assess depression-like behaviors, behavioral tests were conducted 10 days following either sham or CBDL surgeries. The mice with CBDL displayed symptoms such as splenomegaly, elevated plasma levels of interleukin-6 and tumor necrosis factor-α, depression-like behaviors, decreased levels of synaptic proteins in the prefrontal cortex (PFC), disrupted gut microbiota balance, and changes in blood metabolites (or lipids). Additionally, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Significantly, these changes were reversed in CBDL mice by performing a subdiaphragmatic vagotomy. Intriguingly, depression-like phenotypes in mice with CBDL were improved after a single injection of arketamine, a new antidepressant. These results suggest that CBDL-induced depression-like phenotypes in mice are mediated through the gut-liver-brain axis via the subdiaphragmatic vagus nerve, and that arketamine might offer a new treatment approach for depression in liver cirrhosis patients.

Previous observational studies have provided cumulative data linking gut microbiota to myasthenia gravis (MG). However, the causal link between the two remains unexplored. Hence, the current study was performed to explore the causal link between them.

Mendelian randomization (MR) analysis was conducted using the summary statistics of 211 gut microbiota taxa and the largest genome-wide association studies (GWAS) for MG currently available. The inverse variance-weighted (IVW), MR-Egger, weighted median, and weighted mode methods were employed to ascertain the causal influence. Sensitivity studies utilizing several methodologies were then used to assess the robustness of the findings. Lastly, to evaluate reverse causality, a reverse MR analysis was performed.

Seven suggestive causal associations between the gastrointestinal microbiota and MG were identified based on the outcomes of the MR analysis. Specifically, phylum Actinobacteria (OR: 0.602, 95% CI: 0.405-0.896, p = 0.012), class Gammaproteobacteria (OR: 0.587, 95% CI: 0.357-0.968, p = 0.037), and families Defluviitaleaceae (OR: 0.695, 95% CI: 0.485-0.996, p = 0.047), Family XIII (OR: 0.614, 95% CI: 0.412-0.916, p = 0.017), and Peptococcaceae (OR: 0.698, 95% CI: 0.505-0.964, p = 0.029) had suggestive protective effects on MG, while order Mollicutes RF9 (OR: 1.424, 95% CI: 1.015-1.998, p = 0.041) and genus Faecalibacterium (OR: 1.763, 95% CI: 1.220-2.547, p = 0.003) were suggestive risk factors for MG. The outcomes indicate that neither heterogeneity nor horizontal pleiotropy had any discernible impact. Nevertheless, this reverse analysis did not reveal any apparent effect of MG on the gut microbiota composition.

The MR investigation has substantiated the suggestive causal connection between gut microbiota and MG, which may provide helpful insights for innovative therapeutic and preventative approaches for MG. Further randomized controlled trials are needed to elucidate the gut microbiota's precise role and therapeutic potential in the pathogenesis of MG.