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- Blacher, E., et al.
(författare)
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Potential roles of gut microbiome and metabolites in modulating ALS in mice
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 572:7770
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.
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| 2. |
- Terpos, Evangelos, et al.
(författare)
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High Serum Sclerostin Correlates with Advanced Stage, Increased Bone Resorption, Reduced Osteoblast Function, and Poor Survival in Newly-Diagnosed Patients with Multiple Myeloma.
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 114:22, s. 425-425
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is characterized by the presence of lytic bone disease due to increased osteoclast activity which is accompanied by reduced osteoblast function. To-date dickkopf-1 (Dkk-1) is considered as the main osteoblast inhibitor which is overproduced by myeloma cells and inhibits Wnt signaling leading to osteoblast exhaustion. Sclerostin is another canonical Wnt antagonist through its binding to low-density lipoprotein-receptor-related protein 5/6. Sclerostin is specifically expressed by osteocytes and inhibits bone morphogenic protein-induced osteoblast differentiation and ectopic bone formation. Osteonectin (SPARC) is a multi-faceted protein that belongs to a family of matricellular proteins. It is secreted by osteoblasts during bone formation, initiating mineralization and promoting mineral crystal formation. SPARC shows affinity for collagen in addition to bone mineral calcium. The aim of this study contacted by the Greek Myeloma Study Group in collaboration with Biomarker Design Forschungs GmbH (BDF), Vienna, Austria was to evaluate, for the first time in the literature, the serum levels of sclerostin in patients with MM and explore possible correlations with clinical and laboratory data, including SPARC levels, ISS stage and survival. One hundred and fifty-seven patients (87M/70F, median age 68 years) with MM at diagnosis before the administration of any type of therapy, including bisphosphonates, were evaluated. Serum sclerostin and SPARC were measured using an ELISA methodology developed by BDF for Biomedica Medizinprodukte GmbH & Co KG (Vienna, Austria). Both assays are sandwich type ELISA using biotinylated antibodies/HRP-streptavidine for the detection of sclerostin and SPARC in the serum. The detection limit of the sclerostin ELISA was 0.18 ng/ml and the coefficient of variation (CV) 6%. The standard range was set from 0.3-3 ng/ml. For the SPARC ELISA we found a detection limit of 1.95 ng/ml and CVs of 8% using a standard range from 5-130 ng/ml. Serum sclerostin and SPARC were determined in MM patients, 21 patients with MGUS and 21 healthy controls, of similar gender and age. Bone remodeling was also studied by the measurement of a series of serum indices within one week from diagnosis: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) Dkk-1, iii) bone resorption markers [C-terminal cross-linking telopeptide of collagen type-I (CTX) and 5b-isoenzyme of tartrate resistant acid phosphatase (TRACP-5b)], and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Patients with MM had increased levels of serum sclerostin compared with MGUS patients (mean value±SD: 0.48±0.46 vs. 0.26±0.29 ng/ml; p=0.004) and healthy controls (0.31±0.20 ng/ml, p=0.01). In contrast, both patients with MM and MGUS had reduced levels of serum SPARC (26.3±16.2 and 27.2±18.0 ng/ml, respectively) compared to controls (52.8±50.2 ng/ml; p<0.001). Sclerostin values strongly correlated with beta2-microglobulin (r=0.354, p<0.0001), cystatin-C (r=0.389, p<0.0001), serum creatinine (r=0.380, p<0.0001), and bALP (r=-0.541, p<0.0001). No correlations were observed between sclerostin with sRANKL, OPG, Dkk-1 or SPARC. Patients with advanced bone disease assessed by conventional radiography (>3 lytic lesions and/or a pathological fracture) had a borderline increase of sclerostin compared to all others (median value: 0.51 vs. 0.41 ng/ml, p=0.09). Patients with ISS-3 disease had increased levels of sclerostin compared to patients with ISS-1 and ISS-2 MM (ANOVA p=0.001). Median survival of MM patients was 48 months and median follow-up period was 20 months. Patients who had a serum sclerostin of ≥0.62 ng/ml (upper quartile, n=40 patients) had a median survival of 27 months, while median survival of all other patients was 98 months (p=0.031). In conclusion, our study provided evidence that sclerostin is increased in the serum of patients with MM and correlates with advanced ISS stage, increased bone resorption, reduced osteoblast function and poor survival. SPARC is reduced in MM possibly confirming the reduced osteoblast function observed in these patients. Sclerostin seems to participate in the biology of MM and thus it may be a possible target for the development of novel therapies that can both increase osteoblast function and target myeloma cells.
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