Rheumatoid arthritis is a widely prevalent autoimmune bone disease that imposes a significant burden on global healthcare systems due to its increasing incidence. In recent years, attention has focused on the interaction between gut homeostasis and the immune system, particularly in relation to bone health. Dysbiosis, which refers to an imbalance in the composition and function of the gut microbiota, has been shown to drive immune dysregulation through mechanisms such as the release of pro-inflammatory metabolites, increased gut permeability, and impaired regulatory T cell function. These factors collectively contribute to immune system imbalance, promoting the onset and progression of Rheumatoid arthritis. Dysbiosis induces both local and systemic inflammatory responses, activating key pro-inflammatory cytokines such as tumor necrosis factor-alpha, Interleukin-6, and Interleukin-17, which exacerbate joint inflammation and damage. Investigating the complex interactions between gut homeostasis and immune regulation in the context of Rheumatoid arthritis pathogenesis holds promise for identifying new therapeutic targets, revealing novel mechanisms of disease progression, and offering innovative strategies for clinical treatment.

Postmenopausal osteoporosis (PMOP) is a metabolic bone disease driven by estrogen deficiency, primarily manifesting as reduced bone mass and heightened fracture risk. Its development is intricately linked to the balance between Th17 and Treg cells. Recent studies have highlighted the significant role of gut homeostasis in PMOP. The gut microbiota profoundly impacts bone health by modulating the host’s immune system, metabolic pathways, and endocrine functions. In particular, the regulation of Th17 and Treg cell balance by gut homeostasis plays a pivotal role in the onset and progression of PMOP. Th17 cells secrete pro-inflammatory cytokines that stimulate osteoclast activity, accelerating bone resorption, while Treg cells counteract this process through anti-inflammatory mechanisms, preserving bone mass. The gut microbiota and its metabolites can influence Th17/Treg equilibrium, thereby modulating bone metabolism. Furthermore, the integrity of the gut barrier is critical for systemic immune stability, and its disruption can lead to immune dysregulation and metabolic imbalances. Thus, targeting gut homeostasis to restore Th17/Treg balance offers a novel therapeutic avenue for the prevention and treatment of PMOP.

Gout is an arthritis characterized by the deposition of urate crystals, often accompanied by robust inflammatory responses. The gut microbiome profoundly influences gout pathogenesis, progression, and management by affecting uric acid metabolism, immune responses, and intestinal barrier function. Studies reveal that gut microorganisms exert a dual role in gout development. Gout patients typically exhibit increased harmful bacterial abundance and reduced beneficial species. Harmful bacteria and associated metabolites can influence systemic uric acid levels by regulating excretion and synthesis, thereby promoting gout manifestations. Conversely, beneficial bacteria interact with the host immune system to inhibit inflammation and modulate the inflammatory state of joints. Furthermore, the gut microbiome can significantly impact gout treatment efficacy through its influence on drug metabolism and absorption. Research highlighting the gut-joint-inflammation axis offers novel therapeutic strategies for gout, suggesting that future approaches may involve microbiome modulation to enhance clinical outcomes.

Age-related osteoporosis arises from the interplay between impaired bone remodeling, immune remodeling, and chronic low-grade inflammation during aging. Beyond local degeneration in bone tissue, alterations in the gut microbiota, mucosal barrier, and autonomic nervous regulation may reshape the bone marrow immune environment and amplify osteoclastogenic responses. This review integrates evidence linking the gut, neural regulation, and the bone marrow immune microenvironment. It summarizes their potential contributions to age-related bone loss and provides a conceptual framework for understanding disease mechanisms, improving risk stratification, and optimizing intervention strategies.

Osteoporosis is one of the most prevalent metabolic bone diseases worldwide, and current pharmacological options are limited by adverse effects and are poorly suited to long-term use, underscoring the need for novel therapeutic targets. Bifidobacterium, one of the most representative beneficial bacterial genera in the human gut, has been linked to bone mineral density, and supplementation with specific strains improves bone metabolic parameters in animal models of osteoporosis. This narrative review examines the molecular mechanisms through which Bifidobacterium may protect bone via the gut–bone axis, encompassing four interconnected dimensions: reinforcement of the intestinal barrier, modulation of the immune network, remodeling of the gut microbiota, and production of bone-protective metabolites. The review makes three principal contributions. First, it establishes a four-tier mechanistic framework of Bifidobacterium-mediated regulation of osteoporosis in which the evidence is stratified into three categories—direct evidence from Bifidobacterium-specific studies, indirect evidence from other probiotics, and general mechanisms of gut microbiota-regulated bone metabolism—thereby strengthening the rigor of each argument and explicitly distinguishing evidence derived from Bifidobacterium-specific studies from that based on other probiotics or general gut-microbiota mechanisms throughout the review. Second, it systematically compares the osteoprotective efficacy of different Bifidobacterium strains (Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium adolescentis, etc.), highlighting the central importance of strain specificity. Third, it evaluates the strength of the evidence and identifies knowledge gaps for each mechanistic pathway. Most current evidence derives from cross-sectional studies and animal models; causal relationships await validation in large-scale prospective cohort studies and randomized controlled trials. In addition, functional disparities among strains and heterogeneity across clinical studies remain the core bottleneck in translating these fundamental findings into clinical practice.