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<p>Low back pain is a leading cause of global disability, with intervertebral disc degeneration (IVDD) as a primary contributor. Emerging evidence suggests a link between gut microbiota and disc health, yet the underlying mechanisms remain unclear. Through Mendelian randomization and a clinical cohort analysis, we identified a causal inverse relationship between <i>Akkermansia muciniphila</i> (<i>Akk</i>) abundance and IVDD risk, with reduced fecal <i>Akk</i> levels correlating with increased IVDD severity. <i>Akk</i> protected against IVDD in microbiota-depleted mice, and this protection was abolished by pharmacologic inhibition of extracellular vesicle (EV) secretion. Consistently, <i>Akk</i>-derived EVs (<i>Akk</i>-EVs) recapitulated the benefits of <i>Akk</i> across natural aging, tail needle puncture, and bipedal standing mouse models, while control bacterium (<i>Escherichia coli</i>) and its EVs did not. Proteomics and functional validation identified B2UKX5 as a key <i>Akk</i>-EV-enriched effector protein. Furthermore, recombinant B2UKX5 attenuated IVDD in vivo and regulated critical pathways for disc homeostasis, including collagen synthesis, extracellular matrix remodeling, and chromatin silencing, as revealed by transcriptomic profiling of microdissected nucleus pulposus and annulus fibrosus tissues. Analysis of clinical samples further confirmed that <i>Akk</i>-EVs and B2UKX5 levels in circulation and intervertebral disc tissues were negatively correlated with IVDD severity. These findings establish a novel gut-disc axis, highlighting <i>Akk</i>, <i>Akk</i>-EVs, and B2UKX5 as promising therapeutic candidates for IVDD prevention and treatment.</p>

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Akkermansia muciniphila attenuates intervertebral disc degeneration via extracellular vesicle-mediated delivery of the effector protein B2UKX5

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Zhe Guan,
  • Xiaoxue Li,
  • Yixiao Chen,
  • Sheng Zhu,
  • Jie Wen,
  • Hongliang Zhou,
  • Chunyuan Chen,
  • Jianghua Liu,
  • Guoqiang Zhu,
  • Zhilin Pang,
  • Yiwei Liu,
  • Ling Jin,
  • Shiyu Zeng,
  • Yi Luo,
  • Xiaoxiao Gong,
  • Yu Yang,
  • Ya Chen,
  • Yang Wu,
  • Meidan Wan,
  • Hao Yin,
  • Yong Zhou,
  • Zhenxing Wang,
  • Hui Xie

摘要

Low back pain is a leading cause of global disability, with intervertebral disc degeneration (IVDD) as a primary contributor. Emerging evidence suggests a link between gut microbiota and disc health, yet the underlying mechanisms remain unclear. Through Mendelian randomization and a clinical cohort analysis, we identified a causal inverse relationship between Akkermansia muciniphila (Akk) abundance and IVDD risk, with reduced fecal Akk levels correlating with increased IVDD severity. Akk protected against IVDD in microbiota-depleted mice, and this protection was abolished by pharmacologic inhibition of extracellular vesicle (EV) secretion. Consistently, Akk-derived EVs (Akk-EVs) recapitulated the benefits of Akk across natural aging, tail needle puncture, and bipedal standing mouse models, while control bacterium (Escherichia coli) and its EVs did not. Proteomics and functional validation identified B2UKX5 as a key Akk-EV-enriched effector protein. Furthermore, recombinant B2UKX5 attenuated IVDD in vivo and regulated critical pathways for disc homeostasis, including collagen synthesis, extracellular matrix remodeling, and chromatin silencing, as revealed by transcriptomic profiling of microdissected nucleus pulposus and annulus fibrosus tissues. Analysis of clinical samples further confirmed that Akk-EVs and B2UKX5 levels in circulation and intervertebral disc tissues were negatively correlated with IVDD severity. These findings establish a novel gut-disc axis, highlighting Akk, Akk-EVs, and B2UKX5 as promising therapeutic candidates for IVDD prevention and treatment.