The Role of Intestinal Flora in the Regulation of Bone Homeostasis

Abstract

Intestinal flora located within the intestinal tract comprises a large number of cells, which are referred to as the second gene pool of the human body and form a complex symbiotic relationship with the host. The knowledge of the complex interaction between the intestinal flora and various life activities of the host is a novel and rapidly expanding field. Recently, many studies are being conducted on the relationship between the intestinal flora and bone homeostasis and indicate that the intestinal flora can regulate bone homeostasis via the host immune, metabolic, and endocrine systems. What's more, based on several clinical and preclinical pieces of evidence, changing the composition and function of the host intestinal flora through the application of probiotics, prebiotics, and fecal microbiota transplantation is being considered to be a potential novel target for the regulation of bone homeostasis. Here, we searched relevant literature and reviewed the role of the intestinal flora in the regulation of bone homeostasis and its modulating interventions.

Keywords: bone formation; bone homeostasis; bone resorption; intestinal flora; prebiotics; probiotics.

Figure 1

Pathways of immune system affecting bone homeostasis. 1) Disturbance of intestinal flora increases the permeability of intestinal mucosal barrier, letting more LPS and pathogens into the circulation system, which can lead to systemic inflammation. 2) Th17 cells produce IL-17, resulting in the increase of inflammatory cytokines such as TNF-α and IL-1, thus enhancing the expression of RANKL. 3) Treg cells inhibit the activation of T cells through CTLA-4-mediated pathway, thus inhibiting the differentiation of osteoclasts. 4) NOD1 and NOD2 bind peptidoglycans on the surface of bacteria and activate the NF-κB pathway through RIP2, resulting in gene expression of chemokines and cytokines. 5) TLR5 binds with the flagellin of bacteria and inhibit the inflammation. 6) Disturbance of intestinal flora increases intestinal pH and decreases calcium absorption.

Figure 2

Pathways of SCFA affecting bone homeostasis. 1) SCFA reduces intestinal pH and increases calcium absorption. 2) SCFA inhibits the differentiation of osteoclasts by increasing the occurrence of intracellular glycolysis. 3) SCFA inhibits the activity of HDAC, thus increasing the differentiation of Treg cells. 4) SCFA can induce the increase of IGF-I.

Figure 3

Pathways of bile acids affecting bone homeostasis. 1) Intestinal flora can convert primary bile acids into secondary bile acids. 2) Some types of secondary bile acids can up-regulate the expression of Runx2 and enhance ERK and β-catenin signaling via FXR. 3) Some types of secondary bile acids increase GLP-1 production via TFR5, causing thyroid cells to secrete calcitonin through paracrine.

Figure 4

Pathways of IGF-1 affecting bone homeostasis. 1) IGF-1 acts directly on osteoblasts. 2) IGF-1 released by bone matrix activates mTOR signaling through PI3K–Akt pathway and induces the differentiation of osteoblasts.

Figure 5

Pathways of 5-HT and leptin affecting bone homeostasis. 1) Intestinal-derived 5-HT activates Htr1b on osteoblast progenitor cells and regulates its proliferation via Htr1b/PKA/CREB/cyclins signaling pathway. 2) Brain 5-HT promotes bone formation by acting on Htr2c to reduce the sympathetic activity. 3) Leptin has a direct anabolic effect on osteoblast lines. 4) Leptin decreases the production of brain 5-HT. 5) Leptin increases the levels of estrogen, cortisol, IGF-1 and PTH, thus promoting bone formation.

Figure 6

The role of intestinal flora in the regulation of bone homeostasis.