Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (p Akk) could prevent ovx-induced bone loss. Mice were treated with vehicle or p Akk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with p Akk reduced fat mass accumulation confirming earlier findings. However, treatment with p Akk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with p Akk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with p Akk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and p Akk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with p Akk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with p Akk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.
Interleukin (IL)-17A is a well-described mediator of bone resorption in inflammatory diseases, and postmenopausal osteoporosis is associated with increased serum levels of IL-17A. Ovariectomy (OVX) can be used as a model to study bone loss induced by estrogen deficiency and the role of IL-17A in osteoporosis development has previously been investigated using various methods to inhibit IL-17A signaling in this model. However, the studies show opposing results. While some publications reported IL-17A as a mediator of OVX-induced osteoporosis, others found a bone-protective role for IL-17 receptor signaling. In this study, we provide an explanation for the discrepancies in previous literature and show for the first time that loss of IL-17A has differential effects on OVX-induced osteoporosis; with IL-17A being important for cortical but not trabecular bone loss. Interestingly, the decrease in trabecular bone after OVX in IL-17A knockout mice, was accompanied by increased adipogenesis depicted by elevated leptin levels. Additionally, the bone marrow adipose tissue expanded, and the bone-turnover decreased in ovariectomized mice lacking IL-17A compared to ovariectomized WT mice. Our results increase the understanding of how IL-17A signaling influences bone remodeling in the different bone compartments, which is of importance for the development of new treatments of postmenopausal osteoporosis. Bone homeostasis is an orchestrated process involving both osteoblasts (OBL), which produce new bone, and osteoclasts (OCL) that break it down. While OBL are mono-nucleated cells originating from mesenchymal stem cells (MSC), OCL are multinucleated cells arising from the hematopoietic lineage by fusion of OCL precursor cells (pOCL) 1,2. This fine-tuned equilibrium of bone formation and resorption can easily be set off-balance in response to hormonal changes, inflammation, and growth. Reduced levels of endogenously produced estrogens are the major cause of osteoporosis in post-menopausal women and hormone replacement therapy is known to prevent fractures 3,4. However, long-term treatment with estradiol (E2) can result in severe side effects including certain malignancies and is therefore not recommended anymore 5. E2 plays a critical role in the regulation of bone mass homeostasis by controlling bone-forming OBL and bone-resorbing OCL. In post-menopausal women, the balance between bone formation and resorption is skewed towards resorption, resulting in a reduction of bone mineral density (BMD). E2 protects bone directly through two main mechanisms. First, it induces osteoprotegrin (OPG) expression in OBL. OPG serves as a decoy receptor for the cytokine receptor activator of NFκB ligand (RANKL), the primary differentiation factor for OCL 6. Second, E2 protects bone through induction of OCL apoptosis via autocrine Fas-ligand signaling 7. Furthermore, E2 affects the bone marrow (BM) composition and leads to a decrease in B lymphocyte numbers, a cell type known to be a major producer of RANKL 8. Thus, in addition to its direct effect...
The gut microbiome has the capacity to regulate bone mass. The aim of this study was to develop a synbiotic dietary assemblage at an optimal dose to maintain bone mass in ovariectomized (Ovx) mice. We performed genomic analyses and in vitro experiments in a large collection of bacterial and fungal strains (>4000) derived from fresh fruit and vegetables to identify candidates with the synergistic capacity to produce bone-protective short-chain fatty acids (SCFA) and vitamin K2. The candidate SBD111, composed of Lactiplantibacillus plantarum, Levilactobacillus brevis, Leuconostoc mesenteroides, Pseudomonas fluorescens, and Pichia kudriavzevii together with prebiotic dietary fibers, produced high levels of SCFA in vitro and protected against Ovx-induced trabecular bone loss in a dose-dependent manner in mice. Metagenomic sequencing revealed that SBD111-treatment changed the taxonomic composition and enriched specific pathways for synthesis of bone protective SCFA, vitamin K2, and branched chain amino acids in the gut microbiome.
Studies in humans and rodents show that probiotic bacteria can protect from bone loss caused by sex-steroid deficiency. We showed earlier that a mixture of three probiotic bacteria, Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) protects mice from ovariectomy (ovx)-induced bone loss when treatment was started two weeks before sham and ovx surgery. In addition, the same probiotic treatment protected against lumbar spine bone loss in early postmenopausal women. In the present study we wanted to evaluate the therapeutic potential of L. Mix by starting treatment 1.5 weeks after ovx when most of the rapid bone loss as a result of estrogen deficiency, has already occurred. Treatment with L. Mix for 5.5 weeks increased the trabecular thickness but not the trabecular number in the proximal metaphyseal region of tibia compared to vehicle treatment. Cortical thickness and cortical area of the mid-diaphyseal part of tibia were decreased in the vehicle-treated ovx mice but not in L. Mix-treated ovx mice compared to sham mice. The bone protective effects of L. Mix in ovx mice were associated with a protection against ovx-induced reduction of the frequency of regulatory T-cells and of the expression of Tgfβ in the bone marrow. In conclusion, the probiotic L. Mix exerted a moderate stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 weeks after ovariectomy in mice. This effect was associated with effects on bone protecting regulatory T-cells. The results suggest that L. Mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.
Studies in postmenopausal women and ovariectomized mice show that the probiotic mix Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) can protect from bone loss caused by sex steroid deficiency. Whether probiotic bacteria can protect bone also in sex steroid deficient males is less studied. We used the orchiectomized mouse as a model for age dependent bone loss caused by decreasing sex hormone levels in males. We treated ten-week-old male mice with either vehicle (veh) or L. Mix for 6 weeks, starting 2 weeks before orchiectomy (orx) or sham surgery. Importantly, mice treated with L. Mix had a general increase in total body bone mineral density (BMD) and lean mass (p < 0.05) compared with veh treated mice. Detailed computer tomography analysis of dissected bones showed increased trabecular BMD of the distal metaphyseal region of the femur in L. Mix compared to veh treated orx mice (+8.0%, p < 0.05). In the vertebra, L. Mix treatment increased trabecular bone volume fraction BV/TV (+11.5%, p < 0.05) compared to veh in orx mice. Also, L.Mix increased the levels of short-chain fatty acids (SCFAs), propionate and acetate and important intermediates in SCFA synthesis, succinate and lactate in the cecal content of male mice. In conclusion, L. Mix treatment resulted in a general increase in BMD in adult male mice and prevented trabecular bone loss in femur and vertebra of orx mice. These bone protective effects of L. Mix were associated with increased levels of SCFAs in the cecal content of male mice.
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