[Osteomicrobiology - Literature Review]. / Osteomikrobiologie ­ aktuelle Literaturübersicht.

Osteomicrobiology - Literature Review Abstract. Abtract: Several in vivo studies show interesting correlations between microbiota and bone remodeling. The microbiota model and stimulate the immune system, which exerts a direct effect on the bone. The first clinical studies confirm these results and open new perspectives for the prevention of osteoporosis.

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis.

An expanding body of research asserts that the gut microbiota has a role in bone metabolism and the pathogenesis of osteoporosis. This review considers the human gut microbiota composition and its role in osteoclastogenesis and the bone healing process, specifically in the case of osteoporosis. Although the natural physiologic processes of bone healing and the pathogenesis of osteoporosis and bone disease are now relatively well known, recent literature suggests that a healthy microbiome is tied to bone homeostasis. Nevertheless, the mechanism underlying this connection is still somewhat enigmatic. Based on the literature, a relationship between the microbiome, osteoblasts, osteoclasts, and receptor activator of nuclear factor-kappa-Β ligand (RANKL) is contemplated and explored in this review. Studies have proposed various mechanisms of gut microbiome interaction with osteoclastogenesis and bone health, including micro-RNA, insulin-like growth factor 1, and immune system mediation. However, alterations to the gut microbiome secondary to pharmaceutical and surgical interventions cannot be discounted and are discussed in the context of clinical therapeutic consideration. The literature on probiotics and their mechanisms of action is examined in the context of bone healing. The known and hypothesized interactions of common osteoporosis drugs and the human gut microbiome are examined. Since dysbiosis in the gut microbiota can function as a biomarker of bone metabolic activity, it may also be a pharmacological and nutraceutical (i.e., pre- and probiotics) therapeutic target to promote bone homeostasis.

The Association of Gut Microbiota With Osteoporosis Is Mediated by Amino Acid Metabolism: Multiomics in a Large Cohort.

CONTEXT: Several small studies have suggested that the gut microbiome might influence osteoporosis, but there is little evidence from human metabolomics studies to explain this association. OBJECTIVE: This study examined the association of gut microbiome dysbiosis with osteoporosis and explored the potential pathways through which this association occurs using fecal and serum metabolomics. METHODS: We analyzed the composition of the gut microbiota by 16S rRNA profiling and bone mineral density using dual-energy X-ray absorptiometry in 1776 community-based adults. Targeted metabolomics in feces (15 categories) and serum (12 categories) were further analyzed in 971 participants using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. RESULTS: This study showed that osteoporosis was related to the beta diversity, taxonomy, and functional composition of the gut microbiota. The relative abundance of Actinobacillus, Blautia, Oscillospira, Bacteroides, and Phascolarctobacterium was positively associated with osteoporosis. However, Veillonellaceae other, Collinsella, and Ruminococcaceae other were inversely associated with the presence of osteoporosis. The association between microbiota biomarkers and osteoporosis was related to levels of peptidases and transcription machinery in microbial function. Fecal and serum metabolomics analyses suggested that tyrosine and tryptophan metabolism and valine, leucine, and isoleucine degradation were significantly linked to the identified microbiota biomarkers and to osteoporosis, respectively. CONCLUSION: This large population-based study provided robust evidence connecting gut dysbiosis, fecal metabolomics, and serum metabolomics with osteoporosis. Our results suggest that gut dysbiosis and amino acid metabolism could be targets for intervention in osteoporosis.

Agastache rugosa ethanol extract suppresses bone loss via induction of osteoblast differentiation with alteration of gut microbiota.

PURPOSE: Osteoporosis is a metabolic skeletal disease characterized by bone loss and an increased risk of fractures. This study aimed to investigate the therapeutic effect of Agastache rugosa on postmenopausal osteoporosis and elucidate its mechanisms in modulating the bone status. METHODS AND RESULTS: In the osteoblast differentiation process with MC3T3-E1 pre-osteoblasts, ethanol extract of Agastache rugosa (EEAR) and its compounds increased the expression of the proteins and genes of the osteoblast differentiation-related markers such as Runt-related transcription factor 2 (RUNX2) and ß-catenin along with the elevation of calcium deposits. An ovariectomized mouse model was utilized to determine the impact of EEAR extract on postmenopausal osteoporosis. Twelve weeks of AR treatment suppressed the loss of bone strength, which was observed through micro-computed tomography. AR elevated osteogenic markers in the bone marrow cells, and collagen type 1 alpha 1 in the distal femoral bone. The results of the 16S rRNA gene sequencing analysis of cecal gut microbiomes demonstrated that AR reversed the ovariectomy-induced changes in the gut microbiomes. CONCLUSION: Ethanol extract of Agastache rugosa has a therapeutic effect on postmenopausal osteoporosis via bone morphogenic protein, transforming growth factor ß, and Wnt signaling pathway. It also increases the diversity of gut microbiota. Therefore, these data suggest that EEAR could be a potential candidate to treat postmenopausal osteoporosis.

Anthocyanins, Microbiome and Health Benefits in Aging.

The percentage of individuals over the age of 60 is projected to reach 22% by 2050; chronic diseases associated with aging can present challenges for these individuals. Anthocyanins and the gut microbiome have each been studied as independent influencers of health. Both these factors have shown to have a positive effect on cardiovascular and bone health in individuals, as well as on the prevention or treatment of certain forms of cancers. Anthocyanins have shown to modulate the composition of the gut microbiome and may have overlapping mechanisms in the prevention and treatment of cardiovascular disease, cancer, neurodegenerative disorders and aging-associated bone loss. These health outcomes are responsible for the hospitalization and deaths of millions of Americans every year and they cost the United States billions of dollars each year to maintain, prevent and treat. Alternative methods of treatment and prevention are desired since conventional methods (surgical and pharmacological methods, physical therapy, etc.) can be costly and have significant side effects; evidence suggests that anthocyanins and the gut microbiome may be potential avenues for this. This review evaluates the findings of existing literature on the role of anthocyanins and the gut microbiome on health and their potential as a natural therapeutic agent or a target organ to provide an alternative to the conventional methods of disease prevention and treatment.

Arecanut (Areca catechu L.) Seed Polyphenol-Ameliorated Osteoporosis by Altering Gut Microbiome via LYZ and the Immune System in Estrogen-Deficient Rats.

Polyphenol can improve osteoporosis and is closely associated with gut microbiota, while the mechanism and the relationship among polyphenol, osteoporosis, and gut microbiota colonization remain unclear. Here, an osteoporosis rat model established by ovariectomy was employed to investigate the improving mechanism of arecanut (Areca catechu L.) seed polyphenol (ACP) on osteoporosis by regulating gut microbiota. We analyzed the bone microstructure, Paneth cells, regulating microbial protein (lysozyme (LYZ)), proinflammatory cytokines, macrophage infiltration levels, and gut microbial communities in a rat. ACP improved the trabecular microstructure compared to OVX, including the increased trabecular number (Tb.N) (P < 0.01) and trabecular thickness (Tb.Th) (P < 0.001) and decreased trabecular separation (Tb.Sp) (P < 0.01). At the phylum level, Bacteroidetes was increased after ovariectomy (P < 0.001) and Firmicutes and Proteobacteria were increased in ACP (P < 0.001). Antiosteoporosis groups with lower LYZ and Paneth cells (P < 0.001) showed that the microbiota Alistipes, which have a negative effect on bone metabolism were decreased in ACP (P < 0.001). Altogether, these studies showed that the estrogen deficiency could induce the shedding of Paneth cells, which leads to the decrease of LYZ, while ACP could increase the LYZ expression by maintaining the population of Paneth cells in an estrogen-deficient host, which were implicated in gut microbiota regulation and improved osteoporosis by controlling the inflammatory reaction.

The Osteoporosis/Microbiota Linkage: The Role of miRNA.

Hundreds of trillions of bacteria are present in the human body in a mutually beneficial symbiotic relationship with the host. A stable dynamic equilibrium exists in healthy individuals between the microbiota, host organism, and environment. Imbalances of the intestinal microbiota contribute to the determinism of various diseases. Recent research suggests that the microbiota is also involved in the regulation of the bone metabolism, and its alteration may induce osteoporosis. Due to modern molecular biotechnology, various mechanisms regulating the relationship between bone and microbiota are emerging. Understanding the role of microbiota imbalances in the development of osteoporosis is essential for the development of potential osteoporosis prevention and treatment strategies through microbiota targeting. A relevant complementary mechanism could be also constituted by the permanent relationships occurring between microbiota and microRNAs (miRNAs). miRNAs are a set of small non-coding RNAs able to regulate gene expression. In this review, we recapitulate the physiological and pathological meanings of the microbiota on osteoporosis onset by governing miRNA production. An improved comprehension of the relations between microbiota and miRNAs could furnish novel markers for the identification and monitoring of osteoporosis, and this appears to be an encouraging method for antagomir-guided tactics as therapeutic agents.

Associations of Changes in Serum Inflammatory Factors, MMP-3, 25(OH)D and Intestinal Flora with Osteoporosis and Disease Activity in Rheumatoid Arthritis Patients.

BACKGROUND: To explore the associations of changes in serum inflammatory factors, matrix metalloproteinase-3 (MMP-3), 25-hydroxy vitamin D [25(OH)D], and intestinal flora with osteoporosis and disease activity in rheumatoid arthritis (RA) patients, so as to provide references for clinical diagnosis and treatment. METHODS: A total of 98 RA patients were selected as the objects of study (RA group), and divided into active-stage group (n = 56) and remission-stage group (n = 42) according to the disease activity score (DAS28). Another 50 healthy people receiving physical examination in our hospital during the same period were selected as the control group. The changes in serum inflammatory factors, MMP-3, 25(OH)D, and intestinal flora were compared among the three groups, and the osteoporosis of the subjects was analyzed in each group. Moreover, the associations of changes in serum inflammatory factors, MMP-3, 25(OH)D, and intestinal flora with osteoporosis and disease activity in RA patients were analyzed using the Pearson's method. RESULTS: Compared with those in the control group, the levels of serum MMP-3, interleukin-6 (IL-6), IL-10, and C-reactive protein (CRP). The Escherichia coli count were significantly increased, while the level of serum 25(OH)D, bone mineral density (BMD), and Lactobacillus and Bifidobacterium counts were significantly decreased in the active-stage group and remission-stage group, more obviously in active-stage group (p < 0.05). The osteoporosis and disease activity in RA patients were positively correlated with serum IL-6, IL-10, CRP, MMP-3, Escherichia coli and BMD, but negatively correlated with 25(OH)D, Lactobacillus and Bifidobacterium (p < 0.05), and not correlated with the sharp score (p > 0.05). CONCLUSIONS: There are certain associations of changes in serum inflammatory factors, MMP-3, 25(OH)D, and in-testinal flora with osteoporosis and disease activity in RA patients, showing certain value in clinical application.

The role of Bacillus acidophilus in osteoporosis and its roles in proliferation and differentiation.

BACKGROUND: Osteoporosis is one of the most closely related diseases associated with the elderly. In recent years, the studies found that gut microbiota can cause osteoporosis. We evaluated the role of Bacillus acidophilus in osteoporosis and its roles in proliferation and differentiation. METHODS: We selected 5 healthy people and 10 osteoporosis patients and analyzed their level of 25-hydroxyvitamin D and procollagen type I N-terminal peptide (PINP), the characteristic of gut microbiota. The effect of lactobacillus acidophilus and Lactobacillus rhamnosus supernatant and butanoic acids on proliferation, differentiation, and maturity of osteoblasts MC3T3-E1 and osteoclasts RAW 264.7 cells and the activity of alkaline phosphatase, concentration of osteocalcin, and the expression of RUNX2, RANK, NFATc1, cathepsin K, DC-STAMP, OSCAR, WNT2, and CTNNB1 were measured in the above cell lines. RESULTS: The diversity of gut microbiota in osteoporosis patients is decreased and imbalanced with lower abundance of lactobacillus and butyric acid bacteria; meanwhile, 25-hydroxyvitamin D and PINP of osteoporosis patient were significantly lower than the normal group. The proliferation, differentiation, and maturity of MC3T3-E1 cells were stimulated; the activity of alkaline phosphatase, concentration of osteocalcin, and the expression of RUNX2, NFATc1, cathepsin K, DC-STAMP, OSCAR, WNT2, and CTNNB1 were improved by supernatant of lactobacillus acidophilus, Lactobacillus rhamnosus and butanoic acids; however, the proliferation, differentiation, maturity, and the expression of RANK, NFATc1, cathepsin K, DC-STAMP, OSCAR, WNT2, and CTNNB1 in RAW 264.7 cells were suppressed. CONCLUSIONS: The lactobacillus acidophilus and Lactobacillus rhamnosus supernatant could stimulate the proliferation, differentiation, and maturation of osteoblasts; the production of butyric acid may be the potential mechanism.

Effect of Periodontal Pathogens on Total Bone Volume Fraction: A Phenotypic Study.

Studies have shown that periodontal pathogens can enter the bloodstream, causing a series of reactions that can lead to a variety of systemic diseases. Epidemiological investigations also found a tight correlation between periodontitis (PD) and osteoporosis. This study aimed to further explore the effect of periodontal pathogens on bone volume fraction like bone tissue and mass, and explain the relationship between PD and osteoporosis. Sprague Dawley rats (female, 16 weeks old) were divided into the wild-type (WT) control group (n=9) and PD group (n=9). After eight weeks, periodontal tissues and ligatures, the fourth lumbar vertebra, the femur, the tibia, and blood were extracted and analyzed by micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, tartrate-resistant acid phosphatase (TRAP) staining, polymerase chain reaction (PCR), and enzyme-linked immunoassay (ELISA), respectively. We found that the bone mass of the lumbar vertebra, femur, and tibia was decreased in the PD group. The number of osteoclasts was higher in bone tissue in the PD group than in the WT group (P<0.05). The levels of inflammatory mediators and type I collagen C-terminal peptide (CTX-1) were higher in the PD group than in the WT group (P<0.05), although no significant difference in bone glutamic acid protein (BGP) levels was observed (P>0.05). In addition, we detected several periodontal pathogens, such as Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, and Fusobacterium nucleatum, in blood samples from rats in the PD group. These findings suggest that periodontal pathogens can enter the blood circulation from periodontal tissue, promote a systemic inflammation response, and subsequently reduce systemic bone density.

The relationship between intestinal flora changes and osteoporosis in rats with inflammatory bowel disease and the improvement effect of probiotics.

OBJECTIVE: The aim of this study was to investigate the relationship between the changes in intestinal flora and the occurrence of osteoporosis in rats with inflammatory bowel disease and the improvement effect of probiotics. MATERIALS AND METHODS: A total of 100 Sprague Dawley (SD) model rats with colitis were selected as research objects. All rats were randomly divided into two groups, including: bowel disease group and osteoporosis group, with 50 rats in each group. Stool samples were collected from all rats, and Lactobacillus, Escherichia coli and Bifidobacteria were cultured and counted. The relationship between the occurrence of related osteoporosis and intestinal flora was analyzed as well. Thereafter, the rats in osteoporosis group were randomly divided into two subgroups, namely, control group (n=25) and observation group (n=25). Observation group was treated with probiotics by gastrogavage, while the control group was treated with the same volume of physiological saline. Next, the changes in serum osteoprotegerin (OPG), osteoprotegerin ligand [receptor activator of nuclear factor-kappa B ligand (RANKL)], procollagen type I carboxy-terminal propeptide (PICP), bone mineral density (BMD), bone alkaline phosphatase (BALP), tartrate-resistant acid phosphatase (TRACP), calcium concentration (Ca), and inflammatory cytokine levels were compared between the two groups after intervention. RESULTS: Osteoporosis group had significantly more Escherichia coli and notably fewer Lactobacillus and Bifidobacteria than bowel disease group (p<0.05). Pearson correlation analysis revealed that the occurrence of osteoporosis in rats with inflammatory bowel disease was negatively correlated with the count of Escherichia coli, whereas was positively related to the counts of Lactobacillus and Bifidobacteria (p<0.05). Moreover, the levels of serum OPG, PICP, TRACP, and Ca in observation group were remarkably higher than those in the control group (p<0.05). However, the levels of serum RANKL, BALP, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) were markedly lower than those in the control group (p<0.05). CONCLUSIONS: Osteoporosis in rats with inflammatory bowel disease has a negative association with the count of Escherichia coli, and a positive correlation with the counts of Lactobacillus and Bifidobacteria. In addition, treatment with probiotics can effectively alleviate osteoporosis symptoms in rats with inflammatory bowel disease by influencing the level of corresponding cytokines.

Association of gut microbiota composition and function with an aged rat model of senile osteoporosis using 16S rRNA and metagenomic sequencing analysis.

Recently, more interest has been paid to the association between bone mass and gut microecological dysbiosis. The results of clinical studies comparing gut microbiota (GM) in osteoporosis patients have been inconsistent due to different inclusion and exclusion criteria. To date, the association between the GM and senile osteoporosis remains poorly understood. Here, we utilized an aged rat model (22 months old) of senile osteoporosis to study the association of the composition and function of the GM with osteoporosis by 16S rRNA and metagenomic sequencing. The results showed that there was a significant reduction in alpha diversity and the F/B (Firmicutes/Bacteroidetes) ratio in aged rats. At the genus level, the enrichment of Helicobacter was potentially related to osteoporosis as a risk factor. Metagenomics results based on two databases indicated that shifts in the GM contribute to senile osteoporosis through metabolic pathways and subsequent immune disorders. In conclusion, our study reveals the association of gut microbiota composition and function with senile osteoporosis in an aged rat model in a brand new way, and variations in the GM might contribute to senile osteoporosis through metabolic pathways.

Are Probiotics the New Calcium and Vitamin D for Bone Health?

PURPOSE OF REVIEW: Calcium and vitamin D supplementation is recommended for patients at high risk of fracture and/or for those receiving pharmacological osteoporosis treatments. Probiotics are micro-organisms conferring a health benefit on the host when administered in adequate amounts, likely by influencing gut microbiota (GM) composition and/or function. GM has been shown to influence various determinants of bone health. RECENT FINDINGS: In animal models, probiotics prevent bone loss associated with estrogen deficiency, diabetes, or glucocorticoid treatments, by modulating both bone resorption by osteoclasts and bone formation by osteoblast. In humans, they interfere with 25-hydroxyvitamin D levels, and calcium intake and absorption, and slightly decrease bone loss in elderly postmenopausal women, in a quite similar magnitude as observed with calcium ± vitamin D supplements. A dietary source of probiotics is fermented dairy products which can improve calcium balance, prevent secondary hyperparathyroidism, and attenuate age-related increase of bone resorption and bone loss. Additional studies are required to determine whether probiotics or any other interventions targeting GM and its metabolites may be adjuvant treatment to calcium and vitamin D or anti-osteoporotic drugs in the general management of patients with bone fragility.

The Interplay between Immune System and Microbiota in Osteoporosis.

Osteoporosis is a disease characterized by low bone mass and alterations of bone microarchitecture, with an increased risk of fractures. It is a multifactorial disorder that is more frequent in postmenopausal women but can be associated to other diseases (inflammatory and metabolic diseases). At present, several options are available to treat osteoporosis trying to block bone reabsorption and reduce the risk of fracture. Anyway, these drugs have safety and tolerance problems in long-term treatment. Recently, gut microbiota has been highlighted to have strong influence on bone metabolism, becoming a potential new target to modify bone mineral density. Such evidences are mainly based on mouse models, showing an involvement in modulating the interaction between the immune system and bone cells. Germ-free mice represent a basic model to understand the interaction between microbiota, immune system, and bone cells, even though data are controversial. Anyway, such models have unequivocally demonstrated a connection between such systems, even if the mechanism is unclear. Gut microbiota is a complex system that influences calcium and vitamin D absorption and modulates gut permeability, hormonal secretion, and immune response. A key role is played by the T helper 17 lymphocytes, TNF, interleukin 17, and RANK ligand system. Other important pathways include NOD1, NOD2, and Toll-like receptor 5. Prebiotics and probiotics are a wide range of substances and germs that can influence and modify microbiota. Several studies demonstrated actions by different prebiotics and probiotics in different animals, differing according to sex, age, and hormonal status. Data on the effects on humans are poor and controversial. Gut microbiota manipulation appears a possible strategy to prevent and treat osteopenia and/or osteoporosis as well as other possible bone alterations, even though further clinical studies are necessary to identify correct procedures in humans.

PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells.

Bone loss is a frequent but not universal complication of hyperparathyroidism. Using antibiotic-treated or germ-free mice, we show that parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched by the Th17 cell-inducing taxa segmented filamentous bacteria (SFB). SFB+ microbiota enabled PTH to expand intestinal TNF+ T and Th17 cells and increase their S1P-receptor-1 mediated egress from the intestine and recruitment to the bone marrow (BM) that causes bone loss. CXCR3-mediated TNF+ T cell homing to the BM upregulated the Th17 chemoattractant CCL20, which recruited Th17 cells to the BM. This study reveals mechanisms for microbiota-mediated gut-bone crosstalk in mice models of hyperparathyroidism that may help predict its clinical course. Targeting the gut microbiota or T cell migration may represent therapeutic strategies for hyperparathyroidism.

Gut microbiota and osteoarthritis management: An expert consensus of the European society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO).

The prevalence of osteoarthritis (OA) increases not only because of longer life expectancy but also because of the modern lifestyle, in particular physical inactivity and diets low in fiber and rich in sugar and saturated fats, which promote chronic low-grade inflammation and obesity. Adverse alterations of the gut microbiota (GMB) composition, called microbial dysbiosis, may favor metabolic syndrome and inflammaging, two important components of OA onset and evolution. Considering the burden of OA and the need to define preventive and therapeutic interventions targeting the modifiable components of OA, an expert working group was convened by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) to review the potential contribution of GMB to OA. Such a contribution is supported by observational or dietary intervention studies in animal models of OA and in humans. In addition, several well-recognized risk factors of OA interact with GMB. Lastly, GMB is a critical determinant of drug metabolism and bioavailability and may influence the response to OA medications. Further research targeting GMB or its metabolites is needed to move the field of OA from symptomatic management to individualized interventions targeting its pathogenesis.

Gut microbiota alterations associated with reduced bone mineral density in older adults.

OBJECTIVE: To investigate compositional differences in the gut microbiota associated with bone homeostasis and fractures in a cohort of older adults. METHODS: Faecal microbiota profiles were determined from 181 individuals with osteopenia (n = 61) or osteoporosis (n = 60), and an age- and gender-matched group with normal BMD (n = 60). Analysis of the 16S (V3-V4 region) amplicon dataset classified to the genus level was used to identify significantly differentially abundant taxa. Adjustments were made for potential confounding variables identified from the literature using several statistical models. RESULTS: We identified six genera that were significantly altered in abundance in the osteoporosis or osteopenic groups compared with age- and gender-matched controls. A detailed study of microbiota associations with meta-data variables that included BMI, health status, diet and medication revealed that these meta-data explained 15-17% of the variance within the microbiota dataset. BMD measurements were significantly associated with alterations in the microbiota. After controlling for known biological confounders, five of the six taxa remained significant. Overall microbiota alpha diversity did not correlate to BMD in this study. CONCLUSION: Reduced BMD in osteopenia and osteoporosis is associated with an altered microbiota. These alterations may be useful as biomarkers or therapeutic targets in individuals at high risk of reductions in BMD. These observations will lead to a better understanding of the relationship between the microbiota and bone homeostasis.

Depletion of Intestinal Microbiome Partially Rescues Bone Loss in Sickle Cell Disease Male Mice.

Osteoporosis or osteopenia are common clinical manifestations of sickle cell disease (SCD) with unclear mechanisms. Since senescence of circulating neutrophil can be modulated by signals derived from intestinal microbiome and neutrophils are abundant in bone marrow and can regulate osteoblasts and osteoclasts, we examined whether gut microbiome contributes to bone loss in SCD mice. SCD and their littermates control mice were treated with antibiotics to deplete gut microbiome. At the end of 7 weeks treatment, serum was collected for biochemistry marker measurements. Bone mass and remodeling were evaluated by dual beam X-ray absorptiometry, micro-computed tomography, and histomorphometry. Bone-related genes in tibia and barrier marker genes in the small intestine were analyzed by quantitative PCR. Antibiotic treatment rescued increased intestinal inflammatory cytokine marker genes (Tnfα, IL17, Ifnγ) expression, rescued decreased intestinal barrier marker genes (claudin 3 and claudin 15) expression, and rescued increased serum cytokines (IFNγ, IL27, IL10) in SCD mice. Antibiotic significantly improved decreased bone mass in SCD mice mainly through enhanced osteoblast function and increased osteoblast-related genes (Runx2 and Igf1) expression in SCD mice. Our findings support that increased bacteria load augments antigenic load traversing the impaired intestinal barrier through inflammation, leading to increased inflammatory cytokines, impaired osteoblast function, and bone loss in SCD mice.

[Intestinal microbiota: relationship to age-associated diseases (review of literature).]

In connection with the increase in life expectancy, the number of people of older age groups is increasing, and with it the age of associated diseases, which are of tremendous medical and social importance. Such diseases include Alzheimer's disease, osteoporosis, sarcopenia, atherosclerosis and other cardiovascular pathology. The role of the gut microbiota in the pathogenesis of these nosologies is widely discussed in the literature. In addition, a number of studies have shown the effectiveness of the use of probiotics and prebiotics in the treatment of these diseases. The review of the literature summarizes the current understanding of the role of the intestinal microbiota in the development, prevention, and treatment of major age-related diseases.