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Lactobacillus Rhamnosus GG Attenuates Tenofovir Disoproxil Fumarate-induced Bone Loss in Male Mice via Gut Microbiota-dependent Anti-inflammation

Hao Liu  Ranli Gu  Wei Li  Wen Zhou  Zhe Cong  Jing Xue  Yunsong Liu  Qiang Wei  Yongsheng Zhou  
【摘要】:Background:Although anti-retroviral agent widely triggered bone loss in HIV patients,tenofovir disoproxil fumarate(TDF) indeed induces severer bone damage like osteoporosis.However,the mechanisms is obscure.However,probiotic supplements may be effective against osteoporosis.Methods:C57 BL6/J mice were administered Lactobacillus rhamnosus GG(LGG)+TDF,TDF,and zoledronate+TDF,respectively.Next,bone morphometry and biomechanics was evaluated by micro-CT,bone slicing,and flexural tests.The lymphocyte,proinflammatory cytokines,and intestinal permeability were detected by ELISA,qPCR,and flow cytometry.The gut microbiota composition and metabolomics were analyzed by 16 S r DNA pyrosequencing and UPLC-Q-TOF/MS.Results:LGG administered orally marked increases in trabecular bone microarchitecture,cortical bone volume,and biomechanical properties in LGG+TDF group compared with that in the TDF only group.Moreover,LGG treatment increased intestinal barrier integrity,expanded regulatory T cells,decreased Th17 cells,and downregulated osteoclastogenesis-related cytokines in the bone marrow,spleen,and gut.Furthermore,LGG reconstructed the gut microbiota and changed the metabolites composition,especially lysophosphatidycholines levels.However,the amount of N-Acetyl-leukotriene E4 was the highest in the TDF only group.Conclusion:LGG reconstructed the community structure of the gut microbiota,promoted the expression of lysophosphatidycholines and improved intestinal integrity to suppress TDF-induced inflammatory response,which resulted in attenuation of TDF-induced bone loss in mice.It may be safe and effective strategy of using probiotics to prevent and/or treat TDF-induced osteoporosis.

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