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World J Orthop. Mar 18, 2019; 10(3): 123-127
Published online Mar 18, 2019. doi: 10.5312/wjo.v10.i3.123
Linkage of microbiota and osteoporosis: A mini literature review
David Yatsonsky II, Karen Pan, Vithal B Shendge, Jiayong Liu, Nabil A Ebraheim
David Yatsonsky II, Karen Pan, Vithal B Shendge, Jiayong Liu, Nabil A Ebraheim, Department of Orthopedic Surgery, University of Toledo Medical Center, Toledo, OH 43614, United States
ORCID number: David Yatsonsky II (0000-0002-4173-8322); Karen Pan (0000-0002-3001-8928); Vithal B Shendge (0000-0001-7697-2496); Jiayong Liu (0000-0002-5895-8276); Nabil A Ebraheim (0000-0002-0950-3689).
Author contributions: All authors contributed to this paper.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jiayong Liu, MD, Assistant Professor, Department of Orthopedic Surgery, University of Toledo Medical Center, 3065 Arlington Avenue, Toledo, OH 43614, United States. jiayong.liu@utoledo.edu
Telephone: +1-419-383536 Fax: +1-419-3833562
Received: November 16, 2018
Peer-review started: November 19, 2018
First decision: December 17, 2018
Revised: January 6, 2019
Accepted: January 28, 2019
Article in press: January 28, 2019
Published online: March 18, 2019

Abstract

The gut microbiota (GM) has become a recent topic of interest in the role of many disease states. Assessing patients with osteoporosis (OP), there is a strong correlation between gut microbe dysregulation and decreased bone density. Gut dysbiosis may lead to inflammation, dysregulation of nutrient and calcium transport across the intestine into circulation and systemic inflammation. Investigation of microbial profile relative to normal gut microbiomes, assessment of inflammatory markers such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha. Therapies to normalize GM in patients with OP or prevent occurrence of OP to be investigated include: High fiber prebiotic diets to promote growth of normal gut bacteria and short chain fatty acid production, Probiotics to encourage growth of normal gut microbes, and antibiotic treatment followed by fecal matter transplant.

Key Words: Osteoporosis, Microbiota, Linkage, Bone density, Gut microbiota

Core tip: Assessing patients with osteoporosis (OP), there is a strong correlation between gut microbe dysregulation and decreased bone density. Gut dysbiosis may lead to inflammation, dysregulation of nutrient and calcium transport across the intestine into circulation and systemic inflammation. Therapies to normalize gut microbiota in patients with OP or prevent occurrence of OP to be investigated include: High fiber prebiotic diets to promote growth of normal gut bacteria and short chain fatty acid production, Probiotics to encourage growth of normal gut microbes, and antibiotic treatment followed by fecal matter transplant.



GUT MICROBIOTA DYSREGULATION AND DECREASED BONE DENSITY

There exists a correlation between gut microbiota (GM) dysregulation and decreased bone density. Osteoporosis (OP) is a disease state: The loss of bone density and increased risk of bone fracture[1-3]. The most current United States data shows that 10.3% of adults in United States over 50 years of age had OP based on data collected from 2005-2010, affecting over 10 million adults with 43.9% of adults over 50 experiencing low bone mass[4]. There are two forms of OP: Primary, due to estrogen deficiency and natural aging and secondary, due to disease pathology[3,5-9]. Both forms of OP result from an imbalance of bone remodeling slated toward bone loss[1-3,5-9].

The flora of the human gastrointestinal tract has nearly one hundred trillion microbes[10,11]. For millions of years these organisms have symbiotically evolved to habituate the human gut: Converting much of what mankind consumes into nutrients that can cross the GI tract into circulation[11]. The contents of each person’s gut varies; however, there are four main classes that are consistent in most normal GM: Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria, with Bacteroidetes and Firmicutes comprising over 90% of the phylogenic categories[11-13]. The ratio of Firmicutes to Bacteroidetes GM is indicative of various dysregulation of biological processes[11-13].

Ratio of Firmicutes/Bacteriodetes negatively correlated with bone volume and levels of clostridia and lachnospiraceae. Abundance of actinobacteria phylum members: Bifidobacteriaceae were positively correlated with bone volume[11-13].

Osteomicrobiology: The role of microbiota in bone health may bridge the gap between bone physiology, gastroenterology, immunology, and microbiology. GM may lead to novel targets for OP and as biomarkers for future susceptibilities[7,10].

POSSIBLE MECHANISM OF GUT DYSBIOSIS LEADS TO OP
Microbiota: Normal function, dysbiosis and its role in calcium transport and inflammatory response

GM dysregulation is correlated with increased inflammatory response and bone resorption. Proposed mechanisms include impaired calcium transport, T cell response, systemic inflammation via cytokine activation: Osteoclast activation and bone resorption. Short-term colonization of germ-free mice with GM results in activation of CD4+ T cells, increased pro-inflammatory cytokines in bone and subsequent activation of Osteoclastic bone resorption[14]. Mice with normal GF demonstrated decreased frequency of CD4+ T cells and CD11b+/GR1 osteoclast precursors than those mice with dysbiosis[14]. GM is also involved in nutritional uptake and may thereby regulate overall body growth and bone sizes mediated by altered insulin-like growth factors-1 levels. Mechanism of bone degradation, in murine models, is inflammatory in nature and normalization of GM may lead to prevention or limitation of OP[14].

A diversity analysis of the GM in OP and osteopenia (ON) patients was conducted using 16s ribosomal RNA sequencing. There was an inverse correlation between diversity estimators and bone density. In OP, ON, and control groups the four dominant phyla included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria[11-13]. In OP samples Firmicutes were significantly increased and Bacteroidetes significantly decreased but were largest proportion in all groups. In the control group Bacteroides, Faecalibacterium, and Prevotella contributed more than half of the bacterial community, while in ON and OP groups five and 11 genera accounted for 50% of the bacterial community[15]. Blautia, Parabacteroides, and Ruminococcaceae genera differed significantly between OP and control group [15]. Lachnoclostridium and Klebsiella were more abundant in OP and ON than control[15]. The immune-inflammatory axis is hypothesized to be the mediator between GM and Bone metabolism.

Microbiota play an integral role in the transport and uptake of nutrients needed for bone growth and remodeling: Vitamin D[11,16,17]. Vitamin D stimulates intestinal calcium absorption, while 1,25-dihydroxyvitamin D3 can regulate calcium homeostasis including calcium channel: TRPV6 and calbindin-D9K, which mediates intracellular calcium diffusion[11,16]. Intestinal resistance of 1,25(OH)2D3 and decreased calcium absorption increase in old age and are strongly correlated to gut dysbiosis[11,16,17]. Subsequently, dysbiosis can impact absorption of calcium and vitamin D contributing to OP.

Colonization of Firmicutes and increased biodiversity is associated with increased inflammatory response in gut. Increased inflammation is correlated with osteoclast activation at the site of the bones. Osteoclasts originate from monocytic precursors in the bone marrow (CD4+/Gr1-)[18]. Osteoclasts carry out bone resorption and are regulated by several pathways including calcium and vitamin D, estrogen, and Inflammation[18]. Therefore gut-mediated inflammation, specifically markers: Tumor necrosis factor-α, interleukin-1 (IL-1), and IL-6 can play a role in osteoclast activation and if sustained OP[18].

How normalization of GM can decrease/prevent occurrence of OP and related disorders

Probiotics modify the microbiota composition, intestinal barrier function and immune system resulting in systemic benefits to the host: Bone health (growth, density, and structure) under conditions of dysbiosis, intestinal permeability, and inflammation[5,19,20]. Probiotics may be useful in postmenopausal OP[19]. Probiotic supplementation may prevent OP in healthy individuals and slow its progression in those with the disease based on testing in rodents[5]. In a rat study the probiotic (Bacillus subtilis) supplementation the number of osteoclasts decreased versus vehicle, while number of osteoblasts increased[21]. Additionally, Probiotic Lactobacillus reuteri supplementation mice studies, blocked type-1 diabetes-induced OP and post-menopausal OP: Mimicked by ovariectomized mice[22,23]. Lactobacillis reuteri supplementation suppressed increase in CD4+ T-Lymphocytes, and directly suppressed Osteoclastogenesis in vitro[23]. Probiotics supplemented with the isoflavone contributing red clover extract RCE, which has estrogen receptor affinity, have shown to decrease bone loss in postmenopausal osteopenic women supplemented with calcium, magnesium, and calcitriol[24]. This trial demonstrated potential benefit over hormone replacement therapy, which has increased risk of cancer[24]. Further benefits of Probiotics are related to intestinal permeability and inflammation, which mediates bone loss and OP)[18].

Prebiotics, non-digestible carbohydrate compounds, have also shown to increase calcium absorption in the lower gut of animals and humans and improve bone mineral density and strength in rodent models[24,25]. Non-digestible oligosaccharides have much potential to improve bone health and merit more investigation[25]. Most commonly accepted mechanism is microbial fermentation of prebiotics. This leads to increase in short-chain fatty acids and decrease in pH increasing bioavailability of calcium in the colon[24,26].

Antibiotics can vastly alter the composition of the GM. In a normal GM antibiotics used for other purposes may clear out normal flora and promote growth of resistant strains that may induce inflammation and associated symptoms[26]. Alternatively, antibiotic treatment and subsequent fecal microbiota transplants can be used to correct dysbiosis: Overgrowth of Clostridioides difficile and to promote growth of normal microbiota[27] (Table 1).

Table 1 Potential therapies of gut microbiota, proposed mechanisms of action, and subsequent immunological and metabolic effects.
Proposed therapyMechanism of actionEffect on GM
Antibiotics supplemented by fecal transplantBroad spectrum antibiotics clear out dysregulated GM Fecal transplant with Bacteroides and immunoprotective microbiota (i.e., Lactobacilli) suppresses inflammatory responseRemoval of inflammatory inducing bacteria species replaced with immunoprotective flora, normalizes GM and reduces inflammatory response
Prebiotic supplementationPromote growth of bacterial species that induce fermentation of nondigestible carbohydrates, increases SCFAs, and decreases pH of GM and increases calcium absorptionDecreased pH promotes growth of bacteria less likely to induce inflammatory response, while SCFAs promote anti-inflammatory effects systemically Decreased pH and increased calcium absorption correlated with increased bone density
Probiotic supplementationSupplementation by Lactobacilli reuteri, Bacilis subtilis and Bacteroidetes promote immunoprotective response in gut Reduced inflammatory response should reduce cytokine storm and active reduction in bone densitySupplementation of these bacteria to promote a normal GM, immunoprotective effects: IL-10

Short chain fatty acids such as acetate mediate anti-inflammatory conditions systemically[28,29]. These have demonstrated positive effects in preventing bone density loss and preventing OP progression in a rat model by directly feeding them to rats, which not only bolstered anti-inflammatory effects but also enabled normal GM to proliferate[25]. Exercise alters ratio of Firmicutes/Bacteriodetes and may be another venue of investigation into its effects on the GM and potentially as a preventative or therapeutic solution to OP[30,31].

In conclusion, the current literature shows that there may be a linkage between the GM and OP; subsequently, understanding the microbiota and how changes in diet and exercise can modify microbiota can prevent or improve OP disease pathology.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Orthopedics

Country of origin: United States

Peer-review report classification

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P- Reviewer: Sun TS, Wu DC S- Editor: Ji FF L- Editor: A E- Editor: Wu YXJ

References
1.  Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994;9:1137-1141.  [PubMed]  [DOI]
2.  Cummings SR, Kelsey JL, Nevitt MC, O'Dowd KJ. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev. 1985;7:178-208.  [PubMed]  [DOI]
3.  Mahakala A, Thoutreddy S, Kleerekoper M. Prevention and treatment of postmenopausal osteoporosis. Treat Endocrinol. 2003;2:331-345.  [PubMed]  [DOI]
4.  Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29:2520-2526.  [PubMed]  [DOI]
5.  Collins FL, Rios-Arce ND, Schepper JD, Parameswaran N, McCabe LR. The Potential of Probiotics as a Therapy for Osteoporosis. Microbiol Spectr. 2017;5.  [PubMed]  [DOI]
6.  Tella SH, Gallagher JC. Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol. 2014;142:155-170.  [PubMed]  [DOI]
7.  Chen YC, Greenbaum J, Shen H, Deng HW. Association Between Gut Microbiota and Bone Health: Potential Mechanisms and Prospective. J Clin Endocrinol Metab. 2017;102:3635-3646.  [PubMed]  [DOI]
8.  Gough A, Sambrook P, Devlin J, Huissoon A, Njeh C, Robbins S, Nguyen T, Emery P. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol. 1998;25:1282-1289.  [PubMed]  [DOI]
9.  Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. 2005;115:3318-3325.  [PubMed]  [DOI]
10.  Ohlsson C, Sjögren K. Osteomicrobiology: A New Cross-Disciplinary Research Field. Calcif Tissue Int. 2018;102:426-432.  [PubMed]  [DOI]
11.  McCabe LR, Parameswaran N, eds. Understanding the Gut-bone Signaling Axis: Mechanisms and Therapeutic Implications. Springer. 2013;1033 Available from: https://www.springer.com/series/5584.  [PubMed]  [DOI]
12.  Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J; MetaHIT Consortium, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59-65.  [PubMed]  [DOI]
13.  Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005;308:1635-1638.  [PubMed]  [DOI]
14.  Sjögren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, Bäckhed F, Ohlsson C. The gut microbiota regulates bone mass in mice. J Bone Miner Res. 2012;27:1357-1367.  [PubMed]  [DOI]
15.  Wang J, Wang Y, Gao W, Wang B, Zhao H, Zeng Y, Ji Y, Hao D. Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ. 2017;5:e3450.  [PubMed]  [DOI]
16.  DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66:S73-S87.  [PubMed]  [DOI]
17.  Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67:373-378.  [PubMed]  [DOI]
18.  Quach D, Britton RA. Gut Microbiota and Bone Health. Adv Exp Med Biol. 2017;1033:47-58.  [PubMed]  [DOI]
19.  Xu X, Jia X, Mo L, Liu C, Zheng L, Yuan Q, Zhou X. Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res. 2017;5:17046.  [PubMed]  [DOI]
20.  Ibáñez L, Rouleau M, Wakkach A, Blin-Wakkach C. Gut microbiome and bone. Joint Bone Spine. 2018;pii:S1297-319X(18)30061-7.  [PubMed]  [DOI]
21.  Pazzini CA, Pereira LJ, da Silva TA, Montalvany-Antonucci CC, Macari S, Marques LS, de Paiva SM. Probiotic consumption decreases the number of osteoclasts during orthodontic movement in mice. Arch Oral Biol. 2017;79:30-34.  [PubMed]  [DOI]
22.  Zhang J, Motyl KJ, Irwin R, MacDougald OA, Britton RA, McCabe LR. Loss of Bone and Wnt10b Expression in Male Type 1 Diabetic Mice Is Blocked by the Probiotic Lactobacillus reuteri. Endocrinology. 2015;156:3169-3182.  [PubMed]  [DOI]
23.  Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, Parameswaran N, McCabe LR. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol. 2014;229:1822-1830.  [PubMed]  [DOI]
24.  Weaver CM. Diet, gut microbiome, and bone health. Curr Osteoporos Rep. 2015;13:125-130.  [PubMed]  [DOI]
25.  Whisner CM, Castillo LF. Prebiotics, Bone and Mineral Metabolism. Calcif Tissue Int. 2018;102:443-479.  [PubMed]  [DOI]
26.  Francino MP. Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances. Front Microbiol. 2016;6:1543.  [PubMed]  [DOI]
27.  Brandt LJ. American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol. 2013;108:177-185.  [PubMed]  [DOI]
28.  Scott KP, Duncan SH, Flint HJ. Dietary fibre and the gut microbiota. Nutr Bull. 2008;33:201-211.  [PubMed]  [DOI]
29.  Pan MH, Lai CS, Ho CT. Anti-inflammatory activity of natural dietary flavonoids. Food Funct. 2010;1:15-31.  [PubMed]  [DOI]
30.  Pane M, Amoruso A, Deidda F, Graziano T, Allesina S, Mogna L. Gut Microbiota, Probiotics, and Sport: From Clinical Evidence to Agonistic Performance. J Clin Gastroenterol. 2018;52 Suppl 1:S46-S49.  [PubMed]  [DOI]
31.  Ohlsson C, Sjögren K. Effects of the gut microbiota on bone mass. Trends Endocrinol Metab. 2015;26:69-74.  [PubMed]  [DOI]