Gut Microbiome Dysbiosis Alleviate the Progress of Osteoarthritis in Mice

Objective: To evaluate the contribution of gut microbiota dysbiosis on the development of osteoarthritis (OA) in different gender mice. Design: We used a mouse OA model (8 weeks) of the destabilization of the medial meniscus(DMM) and gut microbiome dysbiosis induced by antibiotic treatment (ABT) with ampicillin and neomycin for 8 weeks. The severity of OA was evaluated by micro-CT scanning, X-rays and the Osteoarthritis Research Society International (OARSI) histology score. Microbiome analysis via PCR of 16S DNA was performed on fecal samples, and the serum LPS, IL-6, TNF-α, osteocalcin, estrogen, calcium and magnesium ion levels were measured by enzyme-linked immunosorbent assay (ELISA). Finding: Compared to those in normal mice, the bone volume over total volume (BV/TV) (P<0.01) and the OARSI score (P<0.01) in subchondral bone decreased significantly in the female and male ABT treatment groups. ABT decreased the osteophyte score in female mice in the standard normal group (P<0.05) and decreased the osteophyte maturity score in both female (P<0.01) and male (P<0.05) mice. The levels of IL-6 (P<0.01), TNF-α (P<0.01 for both subgroups), calcium (P<0.01) and expression of MMP-13 were decreased significantly in the ABT group compared with those in the control group, while magnesium and estrogen were increased significantly in the ABT-female group compared with those in the control-female group (P<0.01). For DMM surgery treatment, BV/TV (P<0.01) and serum level of IL-6 (P<0.01) were decreased significantly but the ratio of serum level of Ca2+ and Mg2+ increased significantly in male mice compare than female mice. the bone volume over total volume (BV/TV) of subchondral bone sclerosis has been increased significant in female mice after joint injury than male mice. However, trabecular thickness (Tb.Th) and osteophyte score have been increased significantly in antibiotic-induced male mice than female mice. We further used network correlations analysis to verify the effect of gut microbiota dysbiosis on OA. Interpretation: Our data showed the factors to the gut microbiome dysbiosis alleviating the progression of OA. Funding Statement: This work was partly supported by the National Natural Science Foundation of China (Grants no. 81874010, 81672133). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The experiments and protocol were approved by The Peking University Third Hospital Committee on Ethics in the Care and Use of Laboratory Animals (No. LA2019209).