Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis

Abstract

Postmenopausal osteoporosis (PMO) is a prevalent metabolic bone disease characterized by bone loss and structural destruction, which increases the risk of fracture in postmenopausal women. Owing to the high morbidity and serious complications of PMO, many efforts have been devoted to its prophylaxis and treatment. The intestinal microbiota is the complex community of microorganisms colonizing the gastrointestinal tract. Probiotics, which are dietary or medical supplements consisting of beneficial intestinal bacteria, work in concert with endogenous intestinal microorganisms to maintain host health. Recent studies have revealed that bone loss in PMO is closely related to host immunity, which is influenced by the intestinal microbiota. The curative effects of probiotics on metabolic bone diseases have also been demonstrated. The effects of the intestinal microbiota on bone metabolism suggest a promising target for PMO management. This review seeks to summarize the critical effects of the intestinal microbiota and probiotics on PMO, with a focus on the molecular mechanisms underlying the pathogenic relationship between bacteria and host, and to define the possible treatment options.

Figure 1

Regulators of the gut microbiota and mechanisms by which the gut microbiota regulates bone metabolism. Shaped by both host and environmental factors, the gut microbiota regulates bone metabolism through various pathways, including the immune system, endocrine system, and influences on calcium balance.

Figure 2

Genetic background acts on PMO bone loss. Genetic regulation affects bone loss in PMO by shaping the gut microbiota and determining basal bone mass as well as the distribution of APCs.

Figure 3

Intestinal microbial diversity in PMO is regulated by estrogen and probiotics. Healthy status can maintain gut microbial diversity and beneficial bacteria, which can activate Tregs to sustain immune homeostasis that is resistant to pathogens (a). Estrogen deficiency reduces gut microbial diversity and beneficial bacteria, while increased pathogens induce inflammation (b). Probiotics can prevent pathogens and increase gut microbial diversity by producing extracellular substances (c).

Figure 4

Intestinal epithelial barrier function in PMO is regulated by estrogen and probiotics. Sufficient estrogen can prompt the expression of tight junction (TJ) proteins through the Raf-MEK1/2-ERK1/2 pathway to enhance the gut epithelial barrier (a), while this active effect on TJ is weakened by estrogen deficiency (b). Under estrogen deficiency, pathogen-induced pro-inflammatory cytokines such as TNF-α and IFN-γ reduce the production of TJ proteins through both the Raf-MEK1/2-ERK1/2 and MLKs-MKK3/6-p38 pathways and compromise the gut epithelial barrier (b). The positive action of IL-17 on TJ proteins (thin green arrows in b) fails to completely compensate for the adverse effect of TNF-α and IFN-γ. Probiotics can enhance the gut epithelial barrier by regulating the production and distribution of TJ proteins and affecting the growth and movement of intestinal epithelial cells (c).

Figure 5

Host immune responses in PMO are regulated by estrogen and intestinal microbiota. Both beneficial gut bacteria and sufficient estrogen activate Tregs, which produce TGF-β to prevent osteoclastogenesis and induce osteoclast apoptosis; estrogen prompts osteoblast formation to improve bone mass and structure (a). Estrogen deficiency reduces osteoblast formation; the invasion of pathogens activates CD4+T cells including TH17, which mainly produce TNF-α to promote osteoclastogenesis, leading to bone loss and microstructural destruction (b). Probiotics can regulate immune responses by secreting small molecules such as SCFAs and histamine (c).