"Osteomicrobiology": The Nexus Between Bone and Bugs

Abstract

A growing body of scientific evidence supports the notion that gut microbiota plays a key role in the regulation of various physiological and pathological processes related to human health. Recent findings have now established that gut microbiota also contributes to the regulation of bone homeostasis. Studies on animal models have unraveled various underlying mechanisms responsible for gut microbiota-mediated bone regulation. Normal gut microbiota is thus required for the maintenance of bone homeostasis. However, dysbiosis of gut microbiota communities is reported to be associated with several bone-related ailments such as osteoporosis, rheumatoid arthritis, osteoarthritis, and periodontitis. Dietary interventions in the form of probiotics, prebiotics, synbiotics, and postbiotics have been reported in restoring the dysbiotic gut microbiota composition and thus could provide various health benefits to the host including bone health. These dietary interventions prevent bone loss through several mechanisms and thus could act as potential therapies for the treatment of bone pathologies. In the present review, we summarize the current knowledge of how gut microbiota and its derived microbial compounds are associated with bone metabolism and their roles in ameliorating bone health. In addition to this, we also highlight the role of various dietary supplements like probiotics, prebiotics, synbiotics, and postbiotics as promising microbiota targeted interventions with the clinical application for leveraging treatment modalities in various inflammatory bone pathologies.

Keywords: bone health; gut microbiota; osteomicrobiology; prebiotics; probiotics.

FIGURE 1

Schematic representation of microbial diversity throughout the human gastrointestinal tract. The stomach has the least microbial diversity whereas the colon and cecum are the most diverse (Ahmed et al., 2007). These microbes produce various essential secondary metabolites from the diet like short-chain fatty acids (SCFAs) and aryl hydrocarbon receptor (AhR) ligands. SCFAs are present in higher levels in the colon while AhR ligands are more concentrated in the small intestine (Mowat and Agace, 2014).

FIGURE 2

Bone remodeling cycle. Bone remodeling occurs in four phases: (1) Activation phase: In this phase, M-CSF and RANKL promote the differentiation of osteoclast precursors into osteoclasts. (2) Resorption phase: During this phase mature osteoclasts with unique ruffled borders induce resorption of bone by secreting cathepsin K, and H⁺ in the sealing zone. After resorption osteoclasts detach from the surface of the bone and undergo apoptosis. (3) Reversal phase: In the reversal phase osteoblasts’ precursors get differentiated into mature osteoblasts and are recruited to the resorption site. (4) Formation phase: In this phase osteoblasts get occupied in the resorbed lacuna and start depositing the bone matrix. After the formation phase, osteoid gets mineralized and bone surface returns to resting phase with bone lining cells.

FIGURE 3

Gut membrane integrity: Role of Gut Microbiota (GM) and immune system. GM has a crucial role in regulating gut permeability. GM maintains intestinal integrity via several mechanisms. In mice segmented filamentous bacteria (SFB) induce the secretion of serum amyloid A (SAA) from epithelial cells which further activates the dendritic cells to secrete IL-1β and IL-23. IL-1β and IL-23 promote the differentiation of Th17 cells which produce IL-17 and IL-22. These cytokines stimulate the epithelial cells to secrete antimicrobial peptides (AMPs). GM produces tryptophan metabolites like indole that enhance the expression of tight junction (TJ) proteins. Short-chain fatty acids (SCFAs) produced by GM promote the goblet cells to produce mucus. SCFAs such as butyrate also upregulate the expression of tight junction (TJ) proteins and induce the production of AMPs from epithelial cells. Parasites like Nippostrongylus brasiliensis promote the secretion of IL-25 from tuft cells. IL-25 stimulates the innate lymphoid cells (ILC)-2 to produce IL-4 and IL-13. These cytokines induce goblet cell hyperplasia and mucous secretion.

FIGURE 4

Gut-Immune-Bone axis. GM promotes the development of Treg, Th1 cells, Breg, and Th17 cells. Clostridium species, Bacteroidetes fragilis, and gram-negative bacteria promote differentiation of Tregs and Bregs via inducing tolerogenic DCs whereas segmented filamentous bacteria (SFB) through induction of inflammatory DCs stimulate differentiation of Th17 cells (role of SFB in inducing Th17 cells is observed in mice only). Tregs, Bregs, and Th1 cells prevent osteoclastogenesis via CTLA-4, IL-10, IL-4, TGF-β, and IFN-γ, respectively. Th17 cells on the other hand promote osteoclastogenesis by secreting IL-17, RANKL, and TNF-α. Tregs also induce differentiation of osteoblasts via TGF-β. Bregs also secrete TGF-β and thus like Tregs might also regulate osteoblastogenesis. By promoting the development of both anti-osteoclastogenic and osteoclastogenic cells, GM regulates the balance between bone formation and resorption and thus maintains bone homeostasis lines represent proposed mechanism of action.

FIGURE 5

Role of Gut Associated Metabolites (GAMs) in regulating Bone Health. (A) Gut microbiota (GM) produces short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate by the fermentation of dietary fibers. SCFAs then regulate bone health by inhibiting osteoclastogenesis and by promoting the differentiation of Tregs with the help of G-protein coupled receptor (GPR)-43. (B) Primary bile acids such as cholic acid and chenodeoxycholic acid are produced in the liver from cholesterol. These primary bile acids reach the intestine where GM converts them into secondary bile acids such as deoxycholic acids. Bile acids inhibit osteoclastogenesis whereas inducing osteoblasts and Tregs differentiation by interacting with Farnesoid X receptor (FXR). (C) L-arginine produced from the diet is metabolized by the GM into polyamines such as Spermine and Spermidine which have a role in suppressing osteoclastogenesis and promoting osteoblastogenesis.

FIGURE 6

Role of short-chain fatty acids (SCFAs) in regulating Bone Health. SCFAs are the energy source for the epithelial cells and regulate the activity of various hematopoietic and non-hematopoietic cells through the G protein-coupled receptors (GPCRs) such as GPR41, GPR43, GPR109a. SCFAs promote the differentiation of Tregs through inhibition of histone deacetylases (HDACs) and suppress the secretion of IL-17 from Th17 cells. SCFAs also stimulate the development of Tregs by inducing tolerogenic DCs. SCFAs inhibit the differentiation of osteoclasts by downregulating the expression of key osteoclastogenic markers TRAF6 and NFATc1.

FIGURE 7

GM modulation Strategies and Skeletal Health. During normal conditions, immune homeostasis is maintained. But in bone pathologies like osteoporosis, RA, and periodontitis due to dysbiosis, gut permeability increases resulting in an increase in the number of inflammatory Th17 cells. These Th17 cells outcompete the regulatory Tregs and Bregs which result in enhanced osteoclastogenesis and thus bone loss. Probiotics, prebiotics, synbiotics, postbiotics, FMT, Orthogonal niche engineering, autoimmune protocol diet (AIP), and Personalized GM modulation strategies prevent dysbiosis and restore the homeostatic balance of immune and bone cells.