Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
J Immunol. 2018 Mar 1;200(5):1889-1900. doi: 10.4049/jimmunol.1700547. Epub 2018 Jan 19.
Dysregulation of the immune barrier function of the intestinal epithelium can often result in dysbiosis. In this study we report a novel role of intestinal epithelial cell (IEC)-derived liver kinase B1 (LKB1) in suppressing colitogenic microbiota. IEC-specific deletion of LKB1 (LKB1) resulted in an increased susceptibility to dextran sodium sulfate (DSS)-induced colitis and a definitive shift in the composition of the microbial population in the mouse intestine. Importantly, transfer of the microbiota from LKB1 mice was sufficient to confer increased susceptibility to DSS-induced colitis in wild-type recipient mice. Collectively, the data indicate that LKB1 deficiency in intestinal epithelial cells nurtures the outgrowth of colitogenic bacteria in the commensal community. In addition, LKB1 deficiency in the intestinal epithelium reduced the production of IL-18 and antimicrobial peptides in the colon. Administration of exogenous IL-18 restored the expression of antimicrobial peptides, corrected the outgrowth of several bacterial genera, and rescued the LKB1 mice from increased sensitivity to DSS challenge. Taken together, our study reveals an important function of LKB1 in IECs for suppressing colitogenic microbiota by IL-18 expression.
肠道上皮免疫屏障功能失调通常会导致微生态失调。在这项研究中，我们报告了肠上皮细胞（IEC）衍生的肝激酶 B1（LKB1）在抑制致结肠炎菌群方面的新作用。IEC 特异性缺失 LKB1（LKB1）会导致对葡聚糖硫酸钠（DSS）诱导的结肠炎的易感性增加，并导致小鼠肠道中微生物种群的组成发生明确改变。重要的是，从 LKB1 小鼠中转移的微生物足以使野生型受体小鼠对 DSS 诱导的结肠炎易感性增加。总的来说，这些数据表明，肠上皮细胞中的 LKB1 缺乏会促进共生群落中致结肠炎细菌的过度生长。此外，肠上皮细胞中的 LKB1 缺乏会减少结肠中 IL-18 和抗菌肽的产生。外源性 IL-18 的给药恢复了抗菌肽的表达，纠正了几种细菌属的过度生长，并使 LKB1 小鼠免于对 DSS 挑战的敏感性增加。总之，我们的研究揭示了 LKB1 在 IEC 中通过表达 IL-18 抑制致结肠炎菌群的重要功能。
