丁酸盐通过组织特异性机制改善鹅膏蕈碱诱导的急性胰腺炎及其相关的肠道损伤。
Butyrate ameliorates caerulein-induced acute pancreatitis and associated intestinal injury by tissue-specific mechanisms.
机构信息
State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China.
School of Food Science and Technology, Jiangnan University, Wuxi, China.
出版信息
Br J Pharmacol. 2019 Dec;176(23):4446-4461. doi: 10.1111/bph.14806. Epub 2019 Dec 8.
BACKGROUND AND PURPOSE
Acute pancreatitis (AP) is a common acute abdominal condition, frequently associated with intestinal barrier dysfunction, which aggravates AP retroactively. Butyrate exhibits anti-inflammatory effects in a variety of inflammatory diseases. However, its potential beneficial effect on AP and the underlying mechanisms have not been investigated.
EXPERIMENTAL APPROACH
Experimental AP was induced by caerulein hyperstimulation in wild-type and GPR109A mice. Sodium butyrate was administered intragastrically for 7 days prior to caerulein hyperstimulation. Anti-inflammatory mechanisms of butyrate were further investigated in peritoneal macrophages.
KEY RESULTS
Butyrate prophylaxis attenuated AP as shown by reduced serum amylase and lipase levels, pancreatic oedema, myeloperoxidase activity, and improved pancreatic morphology. Amelioration of pancreatic damage by butyrate was associated with reduced levels of TNF-α, IL-6, and CCL2 and suppressed activation of the NLRP3 inflammasome in both pancreas and colon. Further, butyrate ameliorated pancreatic inflammation by suppressing interactions between histone deacetylase 1 (HDAC1) and AP1 and STAT1 with increased histone acetylation at H3K9, H3K14, H3K18, and H3K27 loci, resulting in suppression of NLRP3 inflammasome activation and modulation of immune cell infiltration in pancreas. Additionally, butyrate mediated STAT1/AP1-NLRP3 inflammasome suppression via HDAC1 inhibition was demonstrated in peritoneal macrophage. In colon, butyrate inhibited NLRP3 inflammasome activation via GPR109A. Accordingly, the modulatory effects of butyrate on AP, AP-associated gut dysfunction, and NLRP3 inflammasome activation were diminished in GPR109A mice.
CONCLUSION AND IMPLICATIONS
Our study dissected tissue-specific anti-inflammatory mechanisms of butyrate during AP, suggesting that increased colonic levels of butyrate may be a strategy to protect against AP.
背景与目的
急性胰腺炎（AP）是一种常见的急性腹部疾病，常伴有肠道屏障功能障碍，从而使 AP 病情加重。丁酸盐在多种炎症性疾病中具有抗炎作用。然而，其对 AP 的潜在有益作用及其潜在机制尚未得到研究。
实验方法
采用胆囊收缩素（caerulein）过度刺激诱导野生型和 GPR109A 小鼠的实验性 AP。在 caerulein 过度刺激前，通过胃内给予丁酸钠进行 7 天的预防治疗。进一步在腹膜巨噬细胞中研究了丁酸钠的抗炎机制。
主要结果
丁酸钠预防治疗可减轻 AP，表现为血清淀粉酶和脂肪酶水平降低、胰腺水肿减轻、髓过氧化物酶活性降低以及胰腺形态改善。丁酸钠减轻胰腺损伤与 TNF-α、IL-6 和 CCL2 水平降低以及胰腺和结肠中 NLRP3 炎性小体激活抑制有关。此外，丁酸钠通过抑制组蛋白去乙酰化酶 1（HDAC1）和 AP1 与 STAT1 的相互作用，增加 H3K9、H3K14、H3K18 和 H3K27 位点的组蛋白乙酰化，从而抑制 NLRP3 炎性小体的激活，并调节胰腺中的免疫细胞浸润，从而改善胰腺炎症。此外，在腹膜巨噬细胞中，丁酸钠通过抑制 HDAC1 介导 STAT1/AP1-NLRP3 炎性小体抑制。在结肠中，丁酸钠通过 GPR109A 抑制 NLRP3 炎性小体的激活。因此，在 GPR109A 小鼠中，丁酸盐对 AP、AP 相关的肠道功能障碍和 NLRP3 炎性小体激活的调节作用减弱。
结论和意义
本研究剖析了丁酸盐在 AP 过程中的组织特异性抗炎机制，提示结肠中丁酸盐水平的增加可能是预防 AP 的一种策略。
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