Xiao Peng, Chen Zhehang, Cai Xuechun, Xia Wenhao, Liu Xia, Song Zhangfa, Wang Huijuan, Zhao Yuening, Huang Youling, Zhang Yu, Guo Ke, Chen Haotian, Liu Rongbei, Meng Changcheng, Fang Yanfei, Lu Yunkun, Cao Qian
Department of Gastroenterology and.
Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, and.
JCI Insight. 2025 Jan 9;10(1):e180425. doi: 10.1172/jci.insight.180425.
Although biologics have been revolutionizing the treatment of inflammatory bowel diseases (IBD) over the past decade, a significant number of patients still fail to benefit from these drugs. Overcoming the nonresponse to biologics is one of the top challenges in IBD treatment. In this study, we revealed that hyaluronan (HA), an extracellular matrix (ECM) component in the gut, is associated with nonresponsiveness to infliximab and vedolizumab therapy in patients with IBD. In murine colitis models, inhibition of HA synthase 2-mediated (HAS2-mediated) HA synthesis sensitized the therapeutic response to infliximab. Mechanistically, HA induced the expression of MMP3 in colonic fibroblasts by activating STAT3 signaling, thereby mediating the proteolytic cleavage of multiple IgG1 biologics. Finally, we found that macrophage-derived factors upregulated HAS2 expression in fibroblasts, thereby contributing to infliximab nonresponse. In summary, we identified a pathogenic connection between abnormal ECM remodeling and biologics nonresponse and provided insights for the precise therapy for IBD.
尽管在过去十年中生物制剂彻底改变了炎症性肠病（IBD）的治疗方式，但仍有相当数量的患者未能从这些药物中获益。克服对生物制剂的无反应性是IBD治疗的最大挑战之一。在本研究中，我们揭示了透明质酸（HA），一种肠道中的细胞外基质（ECM）成分，与IBD患者对英夫利昔单抗和维多珠单抗治疗的无反应性相关。在小鼠结肠炎模型中，抑制透明质酸合酶2介导的（HAS2介导的）HA合成可使对英夫利昔单抗的治疗反应敏感化。从机制上讲，HA通过激活STAT3信号通路诱导结肠成纤维细胞中MMP3的表达，从而介导多种IgG1生物制剂的蛋白水解切割。最后，我们发现巨噬细胞衍生因子上调了成纤维细胞中HAS2的表达，从而导致对英夫利昔单抗无反应。总之，我们确定了异常ECM重塑与生物制剂无反应之间的致病联系，并为IBD的精准治疗提供了见解。
