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

doi:10.1177/2040622319860653

Lactobacillus rhamnosus GG attenuates tenofovir disoproxil fumarate-induced bone loss in male mice via gut-microbiota-dependent anti-inflammation

Ther Adv Chronic Dis. 2019 Jul 3:10:2040622319860653. doi: 10.1177/2040622319860653. eCollection 2019.

Authors

Hao Liu¹, Ranli Gu², Wei Li³, Wen Zhou¹, Zhe Cong⁴, Jing Xue⁴, Yunsong Liu⁵, Qiang Wei⁶, Yongsheng Zhou⁵

Affiliations

¹ The Central Laboratory, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China.
² Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China.
³ Department of Oral Pathology, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China.
⁴ Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.
⁵ Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, People's Republic of China.
⁶ Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, No.5, Panjiayuan, Nanli, Chaoyang District, Beijing 100021, People's Republic of China.

Abstract

Background: Although antiretroviral agents trigger bone loss in human immunodeficiency virus patients, tenofovir disoproxil fumarate (TDF) induces more severe bone damage, such as osteoporosis. While, the mechanisms are unclear, probiotic supplements may be effective against osteoporosis.

Methods: C57BL6/J mice were administered with Lactobacillus rhamnosus GG (LGG)+TDF, TDF, and zoledronic acid+TDF, respectively. Bone morphometry and biomechanics were evaluated using microcomputed tomography, bone slicing, and flexural tests. The lymphocyte, proinflammatory cytokines, and intestinal permeability levels were detected using enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, and flow cytometry. The gut microbiota composition and metabolomics were analyzed using 16S recombinant deoxyribonucleic acid pyrosequencing and ultra-performance liquid-chromatography-quadrupole time-of-flight mass spectrometry.

Results: LGG administered orally induced marked increases in trabecular bone microarchitecture, cortical bone volume, and biomechanical properties in the 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 metabolite composition, especially lysophosphatidylcholine 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 lysophosphatidylcholines, and improved intestinal integrity to suppress the TDF-induced inflammatory response, which resulted in attenuation of TDF-induced bone loss in mice. LGG probiotics may be a safe and effective strategy to prevent and treat TDF-induced osteoporosis.

Keywords: Lactobacillus rhamnosus GG; inflammatory response; microbial metabolomics; osteoporosis; tenofovir disoproxil fumarate.