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PURPOSE: To assess the current scientific literature on the microbiome's relation with knee osteoarthritis (OA), with specific focuses on the gut microbiome-joint axis and joint microbiome-joint axis. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines; the PubMed, Embase, and Cochrane databases were searched for relevant English-language clinical studies on the gut and/or joint microbiomes' association with knee OA in humans. Bias was evaluated using the Methodological Index for Non-randomized Studies score. RESULTS: Thirty-five thousand bacterial species comprise the gut microbiome; approximately 90% are members of the phyla Bacteroides and Firmicutes. Symbiosis between the gut microbiome and host under normal physiological conditions positively affects host growth, development, immunity, and longevity. Gut microbiome imbalance can negatively influence various physiological processes, including immune response, inflammation, metabolism, and joint health including the development of knee OA. In addition, next-generation gene sequencing suggests the presence of microorganisms in the synovial fluid of OA knees, and distinct microbiome profiles detected are presumed to play a role in the development of OA. Regarding the gut microbiome, consistent alterations in microbial composition between OA patients and controls are noted, in addition to several associations between certain gut bacteria and OA-related knee pain, patient-reported outcome measure performance, imaging findings, and changes in metabolic and inflammatory pathways. Regarding the joint microbiome, studies have revealed that increased levels of lipopolysaccharide and lipopolysaccharide-binding protein in synovial fluid are associated with activated macrophages-and are correlated with worsened osteophyte severity, joint space narrowing, and pain scores in knee OA patients. In addition, studies have shown various microbial composition differences in OA patients compared with controls, with certain joint microbes directly associated with OA pathogenesis, inflammation, and metabolic dysregulation. CONCLUSIONS: The gut microbiome-joint axis and joint microbiome show alterations in microbial composition between patients with OA and controls. These alterations are associated with perturbations of metabolic and inflammatory pathways, imaging findings, OA-related pain, and patient-reported outcome measure performance. LEVEL OF EVIDENCE: Level III, systematic review of Level II and III studies.
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SCOPE: A dose-ranging study is performed using young estrogen-depleted rats to determine whether dietary isoliquiritigenin (ILQ) alters bone metabolism and if the effects are associated with estrogen receptor signaling. METHODS AND RESULTS: Six-week-old rats (ovariectomized at 4 weeks of age) are fed diets containing 0, 100, 250, or 750 ppm ILQ (n = 5/treatment) for 7 days. Gene expression in femur and uterus, blood markers of bone turnover, body composition, and uterine weight and epithelial cell height are determined. Because ILQ lowers bone resorption, the effect of ILQ on in vitro differentiation of osteoclasts from bone marrow of mice is assessed. Treatment resulted in a dose-dependent increases in serum ILQ but no changes in serum osteocalcin, a marker of global bone formation. Contrastingly, ILQ administration results in reduced serum CTX-1, a marker of global bone resorption, and reduces tartrate resistant acid phosphatase expression in osteoclast culture. ILQ treatment and endogenous estrogen production had limited overlap on gene expression in femur and uterus. However, uterine epithelial cell hyperplasia is observed in two of five animals treated with 750 ppm. CONCLUSIONS: In conclusion, dietary ILQ reduces bone resorption in vivo and osteoclast differentiation in vitro, by mechanisms likely differing from actions of ovarian hormones.
