OPEN Citation: Bone Research (2017) 5, 17046; :10.1038/boneres.2017.46 www.nature.com/boneres REVIEW ARTICLE Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis Xin Xu1,2, Xiaoyue Jia1,2, Longyi Mo1, Chengcheng Liu1,3, Liwei Zheng1,4, Quan Yuan1,5 and Xuedong Zhou1,2 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. Bone Research (2017) 5, 17046; doi:10.1038/boneres.2017.46; published online: 4 October 2017 INTRODUCTION bone loss and lower bone mineral density (BMD) in the jaw, Postmenopausal osteoporosis (PMO) is an estrogen especially in postmenopausal females with preexisting deficiency-induced metabolic bone disorder character- periodontitis who suffered from accelerated alveolar bone ized by reduced bone strength, which increases the risk of loss under routine treatment.5–7 In addition to bone loss and fracture in postmenopausal women.1 The onset of PMO is microstructural deterioration, PMO affects the osseous occult, without any obvious symptoms until a fracture formation processes. Delayed osseous maturation and occurs. The most prevalent complication is a fragility reduced bone regeneration during bone healing in fracture, which often occurs in the hip, femur, or spine ovariectomized (OVX) rats were reported.8–9 The high under non-traumatic or mildly traumatic conditions, result- morbidity and serious complications of PMO have ing in pain, malformation, dysfunction, and even death. attracted major research efforts on its prophylaxis and Studies showed that the mortality rate associated with a treatment for decades. Current medications for the hip fracture was 17% in the first year2 and ~ 12%–20% within treatment of PMO include bisphosphonates, raloxifene, the two following years.3 PMO is also a potential risk factor teriparatide and calcitonin, denosumab, estrogen and for oral bone loss and aggressive periodontitis in postme- menopausal hormone therapy, and so on. These medica- nopausal females. PMO animal models showed an tions can prevent bone loss and increase bone mineral equivalent bone loss in alveolar bone and femurs.4 density, with a decreased risk of fractures in the vertebra, Compared with healthy postmenopausal women, patients hip, or long bones.1,10 All of these pharmacological agents afflicted with PMO also exhibited an inclination to more can reduce bone resorption by inhibiting osteoclasts, 1State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 2Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 3Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 4Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China and 5Department of Dental Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China Correspondence: Xuedong Zhou ([email protected]) Received: 1 July 2017; Accepted: 24 July 2017 Intestinal microbiota and osteoporosis XXuet al 2 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. except teriparatide, which acts as an anabolic agent by They are generally classified into five categories, including activating or increasing osteoblast activity and prompting lactobacilli, bifidobacteria, streptococci, yeast, and bone formation.1,11 Recent studies have demonstrated a others.37 Lactobacilli and bifidobacteria are the most close relationship between the intestinal microbiota and commonly used probiotics. Probiotics can selectively bone metabolism,12–15 providing evidence that the intest- ferment prebiotics, which contain soluble dietary fibers inal microbiome may serve as a potential therapeutic such as oligosaccharides and inulin, facilitating the pro- target for the treatment of PMO. duction of beneficial products conducive to the growth of certain probiotics such as bifidobacteria.34,38–39 However, it is still disputed whether probiotics can alter the gut THE INTESTINAL MICROBIOTA AND ITS REGULATORS microbiota composition. Randomized controlled trials The intestinal microbiota is the collection of microorganisms (RCTs) in healthy adults indicated that probiotic interven- that colonize the gastrointestinal tract, which consists of tion or probiotics-fermented products resulted in changes – approximately 10 trillion bacteria.16 Obligate anaerobes in intestinal microbiota composition or diversity.40 43 such as Bacteroidetes and Firmicutes are the predominant Although probiotics promoted the significant increase of residents of the healthy gastrointestinal tract, outnumber- certain bacteria, Bacteroides was the dominant genus ing aerobes and facultative anaerobes.16–17 On the basis under probiotics administration, while other bacteria such – of their roles in maintaining human health, intestinal as Clostridiales were inhibited.40 41 In addition, the effect of microorganisms can be categorized into beneficial, harm- probiotics on Clostridiales genera may be associated ful and neutral bacteria. Both host and environmental with the initial status of the intestinal microbiome and factors can shape intestinal microbial composition and butyrate concentrations.41 RCTs in elder adults showed structure (Figure 1). Animal experiments18–21 and twin that the age-associated intestinal microbiota imbalance studies22–23 revealed that the host genetic background was restored by probiotic-based functional foods, with had a significant impact on the abundance of the increased resident probiotic-related bacteria and – intestinal microbiota and the predisposition to the coloni- decreased emergence of opportunistic pathogens.44 45 zation of pathogens (for example, Escherichia coli). Though Animal experimentation also showed that probiotic admin- still disputed, gender may be another host factor affecting istration improved the intestinal microbiota composition in intestinal microbiome species diversity.24–25 Environmental hyperlipidemic rats by recovering the abundance of factors, including diet, lifestyle, hygiene, antibiotic treat- Bacteroidetes and Verrucomicrobia and reducing ment, and probiotics, also contribute to the alteration of Firmicutes.46 However, another RCT in healthy adults the intestinal microbiota composition.26–31 Notably, the demonstrated that Lactobacillus rhamnosus GG (LGG) effects of diet and antibiotics on the intestinal microbiota supplement induced no alteration in gut microbiota also depend on the host genetic background.32–33 composition or diversity stability, except for a transient Probiotics are defined as dietary or medical supplements increased fecal excretion of probiotic-associated bacteria consisting of live bacteria that can benefit the host if during the intervention.47 In addition, one RCT in healthy provided in adequate quantities.34–36 Currently, ~ 20 types subjects and patients with irritable bowel syndrome (IBS) of beneficial bacteria are used in probiotic supplements. showed parallel, transient, and distinct increases in Bone Research (2017) 17046 Intestinal microbiota and osteoporosis XXuet al 3 probiotics but limited changes in other specific bacteria in through which gut microbiota may regulate bone meta- fecal samples of both healthy and IBS-afflicted subjects bolism have been proposed, including actions on the with Bifidobacterium infantis intervention.48 immune system, endocrine system, and calcium absorp- tion (Figure 1). THE INTESTINAL MICROBIOTA REGULATES BONE (a) The gut microbiota regulates bone metabolism METABOLISM through the immune system. Recent studies have Involvement of the intestinal microbiota in bone revealed a close interrelationship between the immune metabolism system and bone metabolism, leading to the develop- The dynamic homeostasis of the gut microbiome is critical to ment of “osteoimmunology,” which highlights the health. Accumulating evidence has demonstrated that the role of immune-related factors in modulating bone gut microbiota is associated with physiological bone remodeling.54–55 In immune-mediated bone metabolism, fl metabolism and a range of in ammatory or metabolic the RANKL (receptor activator NF kappa B ligand)-RANK-