Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Gut Microbes. 2021 Jan-Dec;13(1):1968257. doi: 10.1080/19490976.2021.1968257.
Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate on IBD neutrophils and elucidate the therapeutic potential in regulating mucosal inflammation. Peripheral neutrophils were isolated from IBD patients and healthy donors, and profiles of proinflammatory cytokines and chemokines were determined by qRT-PCR and ELISA, respectively. The migration and release of neutrophil extracellular traps (NETs) were studied by a Transwell model and immunofluorescence, respectively. The role of butyrate in regulating IBD neutrophils was evaluated in a DSS-induced colitis model in mice. We found that butyrate significantly inhibited IBD neutrophils to produce proinflammatory cytokines, chemokines, and calprotectins. Blockade of GPCR signaling with pertussis toxin (PTX) did not interfere the effects whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked the role of butyrate. Furthermore, studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients. RNA sequencing analysis revealed that the immunomodulatory effects of butyrate on IBD neutrophils were involved in leukocyte activation, regulation of innate immune response and response to oxidative stress. Consistently, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced murine colitis through inhibition of neutrophil-associated immune responses such as proinflammatory mediators and NET formation. Our data thus reveal that butyrate constrains neutrophil functions and may serve as a novel therapeutic potential in the treatment of IBD.
宿主-微生物的相互作用在维持肠道内稳态中起着至关重要的作用。然而，微生物衍生的代谢物（如丁酸盐）如何调节中性粒细胞在炎症性肠病（IBD）发病机制中的功能仍然难以捉摸。我们试图研究丁酸盐对 IBD 中性粒细胞的影响，并阐明其在调节黏膜炎症方面的治疗潜力。从 IBD 患者和健康供体中分离外周血中性粒细胞，并通过 qRT-PCR 和 ELISA 分别测定促炎细胞因子和趋化因子的谱。通过 Transwell 模型和免疫荧光分别研究中性粒细胞细胞外陷阱（NETs）的迁移和释放。在小鼠 DSS 诱导的结肠炎模型中评估丁酸盐在调节 IBD 中性粒细胞中的作用。我们发现丁酸盐可显著抑制 IBD 中性粒细胞产生促炎细胞因子、趋化因子和钙卫蛋白。用百日咳毒素（PTX）阻断 G 蛋白偶联受体信号不会干扰其作用，而泛组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素 A（TSA）则可有效模拟丁酸盐的作用。此外，研究证实丁酸盐可抑制来自 CD 和 UC 患者的中性粒细胞迁移和 NET 的形成。RNA 测序分析表明，丁酸盐对 IBD 中性粒细胞的免疫调节作用涉及白细胞激活、固有免疫反应调节和氧化应激反应。一致地，丁酸盐的口服给药通过抑制中性粒细胞相关免疫反应，如促炎介质和 NET 形成，显著改善 DSS 诱导的小鼠结肠炎中的黏膜炎症。我们的数据表明，丁酸盐限制中性粒细胞的功能，可能成为治疗 IBD 的一种新的治疗潜力。
