肠内营养调节特异性促炎症消退介质生成促克罗恩病腹腔脓肿愈合的机制研究

Transmural inflammation such as intra-abdominal abscess caused by Crohn’s disease often brings dilemma in introducing immune-modulators and biologic therapy. Nutritional therapy especially enteral nutrition were proved to be effective in termination or resolution of luminal inflammation. However little is known as to its effectiveness in curbing intraabdominal inflammation. By using cecal ligation-and-perforation model we compared enteral nutrition and parenteral nutrition during intraabdominal inflammation resolution. Enteral nutrition significantly accelerated intraabdominal abscess healing most probably by increasing local specialized pro-resolving mediators’ concentration. Widely recognized as braking signal in inflammation, specialized pro-resolving mediators (SPMs) were found to be produced by innate lymphoid cells (ILC). In this study we set to elucidate whether enteral nutrition could augment SPMs production by acetylcholine responsive ILC3 via increased vagal tone that followed oral feeding. Our investigation would help justify the usage of enteral nutrition in transmural inflammation treatment from a brand new perspective.

克罗恩病是一种以透壁性炎症为特征的消化道慢性炎症性疾病，常出现穿透性并发症，并给免疫抑制剂及生物制剂的应用带来难题。营养治疗是克罗恩病综合治疗中极为重要的一环。大量研究发现肠内营养在限制肠道炎症方面有独到的优势，但肠内营养是否可促进克罗恩病的穿透型并发症的愈合尚罕见于报道。在前期工作中我们发现肠内营养可有效促进小鼠腹腔内脓肿消退，限制腹腔内炎症过度发展，其机制可能与促进腹腔内3型先天淋巴细胞（ILC3）合成特异性促炎症消退介质有关。这种脂质衍生介质被喻为炎症刹车信号，已在多种模型中证实具备免疫调节功能。本项目拟深入研究并明确肠内营养对ILC3细胞的脂质代谢功能的调控模式，尝试回答肠内营养治疗是否通过提高腹腔内迷走神经张力调节胆碱能反应性的ILC3细胞功能，以期为肠内营养在IBD穿透型并发症综合治疗中的应用奠定理论基础。

肠黏膜中先天淋巴样细胞（Innate lymphoid cells, ILC）产生的IL-22对维持肠道免疫稳态至关重要，既往研究表明肠道菌群是调节IL-22产生的关键，但具体调节机制尚不明确。本项目中，我们完整揭示了肠道菌群来源的短链脂肪酸（short-chain fatty acids, SCFA）通过激活芳烃受体（aryl hydrocarbon receptor, AhR）调控ILC细胞生成IL-22的产生，AhR下游的缺氧诱导因子1α（hypoxia-inducible factor 1α, HIF1α）可直接与IL-22启动子结合，而SCFA通过组蛋白修饰增加HIF1α与IL-启动子的结合。炎症性肠病（inflammatory bowel disease, IBD）患者行菌群移植（fecal microbiota transplant, FMT）后，粪便代谢产物中SCFA及IL-22的水平升高，产SCFA菌属增多，与黏膜炎症及粪钙卫水平变化呈负相关。本项目为肠道菌群调节肠黏膜炎症提供重要理论依据。

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