Chinese Journal of Tissue Engineering Research ›› 2024, Vol. 28 ›› Issue (27): 4325-4331.doi: 10.12307/2024.559

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Gut microbiota and drug-associated osteonecrosis: a two‑sample Mendelian randomization study

Chai Jinlian1, Li Shudong2, Li Wei3, Du Haitao4, Dong Limin1, Liang Xuezhen2, Wang Ping1, 4   

  1. 1College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China; 2First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China; 3College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China; 4Shandong Provincial Research Institute of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
  • Received:2023-10-16 Accepted:2023-11-20 Online:2024-09-28 Published:2024-01-27
  • Contact: Wang Ping, MD, Researcher, Master’s supervisor, College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China; Shandong Provincial Research Institute of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China Liang Xuezhen, MD, Associate professor, Master’s supervisor, First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
  • About author:Chai Jinlian, Master candidate, College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
  • Supported by:
    the National Natural Science Foundation of China, No. 82205154 (to LXZ); Shandong Province Centralized Guided Local Science and Technology Development Fund Project, No. YDZX20203700002055 (to WP); Shandong Province Natural Science Foundation (General Project), No. ZR2020MH386 (to WP); Shandong Province Natural Science Foundation (Youth Project), No. ZR2021QH004 (to LXZ); Shandong Province Medicine and Health Science and Technology Development Program, No. 2019WS577 (to LXZ); Shandong Province Traditional Chinese Medicine Science and Technology Project, No. 2020Q009 (to LXZ); Jinan Clinical Medicine Science and Technology Innovation Program, No. 202019056 (to LXZ)

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Abstract: BACKGROUND: Osteonecrosis due to drugs is a serious adverse reaction occurring after the application of such drugs. Increasing evidence suggests that the gut microbiota composition is associated with osteonecrosis due to drugs. However, the causal relationship of the gut microbiota to osteonecrosis due to drugs is still unclear.
OBJECTIVE: To evaluate the potential causal relationship between the gut microbiota and the risk of osteonecrosis due to drugs using the Mendelian randomization method.
METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n=13 266) conducted by the MiBioGen consortium as well as the summary statistics of osteonecrosis due to drugs obtained from the FinnGen consortium R9 release data (264 cases and 377 013 controls). Inverse variance weighted, MR-Egger, weighted median, weighted model and simple model were used to examine the causal association between gut microbiota and osteonecrosis due to drugs. Sensitivity analysis was used to test whether the results of the Mendelian randomization analysis were reliable. Reverse Mendelian randomization analysis was performed on all the bacteria as an outcome for effect analysis and sensitivity analysis.
RESULTS AND CONCLUSION: Inverse variance weighted estimates suggested that Lentisphaerae (phylum), Lentisphaeria (class), Melainabacteria (class), Gastranaerophilales (order), Rhodospirillales (order), Victivallales (order) and Bifidobacterium (genus) had protective causal effects on osteonecrosis due to drugs. Methanobacteria (class), Bacillales (order), Methanobacteriaceae (family), Lachnospiraceae (family), Methanobacteriales (order), Holdemania (genus), Holdemania (UCG010 group) (genus), Odoribacter (genus) and Tyzzerella3 (genus) had negative causal effects on osteonecrosis due to drugs. According to the results of reverse Mendelian randomization analysis, Clostridiaceae1 (family), Peptostreptococcaceae (family), Streptococcaceae (family), Clostridiumsensustricto1 (genus) and Streptococcus (genus) showed negative causal effects on osteonecrosis due to drugs. However, Eisenbergiella (genus) showed protective causal effects on osteonecrosis due to drugs. None of the bidirectional sensitivity analysis revealed heterogeneity or horizontal pleiotropy. When gut microbiota were used as exposure and osteonecrosis due to drugs as the outcome, Mendelian randomization analysis found that seven bacterial traits were positively correlated to osteonecrosis due to drugs, nine bacterial traits were negatively related to osteonecrosis due to drugs. When osteonecrosis due to drugs were used as exposure and gut microbiota as the outcome, reverse Mendelian randomization analysis found a negative correlated relationship with five bacterial traits and a positive causal relationship with one bacterial trait. By changing the diversity and composition of gut microbiota, it is expected to improve the incidence and prognosis of osteonecrosis due to drugs, providing new ideas for the study of orthopedic diseases.

Key words: osteonecrosis due to drugs, gut microbiota, Mendelian randomization, single-nucleotide polymorphism, Genome-Wide Association Study, causality, inverse variance weighted, heterogeneity, horizontal pleiotropy, sensitivity analysis

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