Mechanisms of gut homeostasis regulating Th17/Treg cell balance in PMOP

Abstract

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.

Keywords: PMOP; Th17/Treg cell balance; gut homeostasis; gut microbiome; mechanism study.

Figure 1

Immunopathological Mechanism of PMOP. B cells differentiate into osteoclasts, leading to bone loss. In the estrogen-deficient state, hypoxia-inducible factor-1α signaling is activated in B cells, enhancing RANKL expression and promoting osteoclastogenesis, thereby inducing PMOP. T cells normally exhibit bone-protective functions in basal bone metabolism. However, following ovariectomy, CD4+ and CD8+ T cells become activated and secrete RANKL and other osteoclastic factors. Treg cells secrete IL-10, TGF-β, and other anti-resorptive cytokines, whereas Th17 cells produce IL-17, which stimulates osteoclastogenesis. Additionally, IL-17 triggers mesenchymal stem cells to release osteoclast differentiation factors. Thus, estrogen modulates bone metabolism by regulating the balance between Th17 and Treg cells.

Figure 2

Gut Homeostasis and Immune Regulation. Gut homeostasis plays a pivotal role in maintaining immune equilibrium. Disruption of the gut microbiota and damage to the intestinal barrier can lead to immune dysregulation, characterized by the abnormal activation of innate immune cells, including dendritic cells and macrophages. This activation induces the production of elevated levels of pro-inflammatory cytokines, such as IL-12, IL-23, and type I interferons, while anti-inflammatory cytokines, including TGF-β and IL-10, are suppressed. Activated antigen-presenting cells, like dendritic cells and macrophages, present microbial antigens to CD4+ T helper cells, driving their differentiation into various pro-inflammatory T cell subsets, including Th1, Th2, and Th17.

Figure 3

Gut Homeostasis Regulates Th17/Treg Balance and Influences PMOP. (A) The gut microbiota modulates the balance between Th17 and Treg cells, as well as cytokine levels, affecting the development and progression of PMOP. (B) Microbial-derived metabolites from the gut regulate multiple immune cells, causing an imbalance between osteoblasts and osteoclasts, which contributes to PMOP. (C) Intestinal barrier damage increases permeability and disrupts tight junctions, triggering inflammation and promoting osteoclast differentiation, thereby accelerating the onset and progression of PMOP.