丁酸及产丁酸菌在维持肠道稳态及重症急性胰腺炎中的作用研究

Severe acute pancreatitis (SAP) is the most severe type of this acute abdominal disease with complicated pathogenesis and high mortality. Accumulating evidence supports that dysregulated gut homeostasis plays a pivotal role in the development of SAP and hence is a key target to intervene the disease. .Our preliminary data have shown that butyrate and its producing bacteria, importantly Clostridium butyrica strains maintain gut homeostasis and have positive effects on SAP. However, their modulatory effects and underlying mechanisms have not been elucidated. The current study hypothesizes that butyrate and butyrate-producing bacteria maintain gut homeostasis, thereby hindering the development of SAP. To this end, (1) gut microbiota composition, particularly on butyrate-producing bacteria, and levels of butyrate will be analyzed and compared using samples from patients or experimental mice with SAP and their healthy controls; (2) modulatory effects of butyrate on dysregulated gut homeostasis and SAP will be investigated; (3) by using G protein-coupled receptor (GPR)41-deficient (GPR41-/-), GPR43-/- and cathelicidin deficient (Cnlp-/-) mice, the underlying mechanisms by which butyrate and butyrate-producing bacteria modulate gut homeostasis and SAP will be elucidated; (4) Butyrate-producing bacteria significantly different in SAP will be selected and their effects to intervene SAP will be evaluated and confirmed..The current study emphasizes maintenance of gut homeostasis by using butyrate and its producing probiotics in protecting the development of SAP.

重症急性胰腺炎（SAP）是一种发病机制复杂、死亡率高的急腹症。肠道稳态失衡是SAP病程加剧的重要诱因。申请人前期研究提示丁酸和产丁酸菌在维持肠道稳态和SAP发病中发挥积极作用，但其具体作用及机制尚未被揭示。本项目拟开展以下研究：1）分析临床/实验性SAP肠道产丁酸菌和丁酸的变化，确定丁酸/产丁酸菌与SAP发病的相关性；2）明确丁酸维持肠道稳态在SAP发病中的调控作用；3）结合使用丁酸受体G蛋白偶联受体41敲除（GPR41-/-）、GPR109A敲除（GPR109A-/-）小鼠、其下游抗菌肽cathelicidin敲除（Cnlp-/-）小鼠，及慢病毒GPR43过表达/沉默技术，揭示丁酸维持肠道稳态和延缓SAP发病的分子机制；4）筛选出有显著差异的产丁酸菌并探讨其调控肠道稳态对SAP的防治作用。本项目将为丁酸及产丁酸菌在SAP防治中的应用提供重要实验依据。

急性胰腺炎是一种发病机制复杂、死亡率高的急腹症，肠道稳态失衡是急性胰腺炎发生发展的关键。申请人前期研究表明丁酸和产丁酸菌在维持肠道稳态和急性胰腺炎发病中发挥积极作用；通过本项目实施，明确了肠道丁酸和产丁酸菌通过维持肠道稳态从而抑制肠道菌群易位到胰腺，发挥减轻急性胰腺炎发病进程的作用；阐明了肠道丁酸通过GPR109a发挥调控NLRP3炎症小体激活减轻肠道炎症反应、保护肠道屏障功能发挥维持肠道稳态作用，同时丁酸可通过抑制胰腺组织HDAC1活性，抑制急性胰腺炎过程中胰腺炎症反应，对胰腺炎发挥双重保护作用的分子机制；筛选发现产丁酸菌丁酸梭菌CB0313.1能够调控肠道丁酸水平，调节肠道菌群稳态并维持肠道屏障功能，减轻肠道菌群易位发挥对急性胰腺炎的保护作用；本项目实验阐明了维持肠道功能稳态（菌群、屏障功能）在防治胰腺炎发病过程中发挥至关重要的作用，而产丁酸菌和肠道丁酸可通过维持菌群稳态、保护肠屏障防治胰腺炎发病，将为急性胰腺炎的防治提供新策略。