Department of Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Peptides. 2018 Mar;101:1-9. doi: 10.1016/j.peptides.2017.12.023. Epub 2017 Dec 27.
The octapeptide NAP has been shown to exert neuroprotective properties and reduce neuro-inflammatory responses. The aim of the present study was to investigate if NAP provides anti-inflammatory effects in acute murine colitis. To address this, C57BL/6 j mice were challenged with 3.5% dextran sulfate sodium from day 0 until day 6 to induce colitis, either treated intraperitoneally with NAP or placebo (NaCl 0.9%) from day 1 until day 6 post-induction (p.i.) and subjected to in depth macroscopic, microscopic and immunological evaluations. Whereas NAP application did not alleviate macroscopic (i.e. clinical) sequelae of colitis, lower numbers of apoptotic, but higher counts of proliferating/regenerating colonic epithelial cells could be observed in NAP as compared to placebo treated mice at day 7 p.i. Furthermore, lower numbers of adaptive immune cells such as T lymphocytes and regulatory T cells were abundant in the colonic mucosa and lamina propria upon NAP versus placebo treatment that were accompanied by less colonic secretion of pro-inflammatory mediators including IFN-γ and nitric oxide at day 7 p.i. In mesenteric lymph nodes, pro-inflammatory IFN-γ, TNF and IL-6 concentrations were increased in placebo, but not NAP treated mice at day 7 p.i., whereas interestingly, elevated anti-inflammatory IL-10 levels could be observed in NAP treated mice only. The assessed anti-inflammatory properties of NAP were not restricted to the intestinal tract, given that in extra-intestinal compartments such as the kidneys, IFN-γ levels increased in placebo, but not NAP treated mice upon colitis induction. NAP induced effects were accompanied by distinct changes in intestinal microbiota composition, given that colonic luminal loads of bifidobacteria, regarded as anti-inflammatory, "health-promoting" commensal species, were two orders of magnitude higher in NAP as compared to placebo treated mice and even naive controls. In conclusion, NAP alleviates intestinal and extra-intestinal pro-inflammatory sequelae of acute experimental colitis and may provide novel treatment options of intestinal inflammatory diseases in humans.
八肽 NAP 已被证明具有神经保护作用，并能减轻神经炎症反应。本研究旨在探讨 NAP 是否对急性小鼠结肠炎具有抗炎作用。为此，将 C57BL/6j 小鼠从第 0 天到第 6 天用 3.5%葡聚糖硫酸钠处理以诱导结肠炎，从诱导后第 1 天到第 6 天分别用 NAP 或安慰剂（NaCl 0.9%）经腹腔内给药，并进行深入的宏观、微观和免疫学评估。尽管 NAP 的应用并没有缓解结肠炎的宏观（即临床）后遗症，但与安慰剂治疗的小鼠相比，在诱导后第 7 天，NAP 治疗的小鼠中凋亡细胞数量减少，但增殖/再生的结肠上皮细胞数量增加。此外，与安慰剂治疗相比，在 NAP 治疗的小鼠中，适应性免疫细胞（如 T 淋巴细胞和调节性 T 细胞）在结肠黏膜和固有层中更为丰富，并且伴随着在诱导后第 7 天结肠分泌的促炎介质（包括 IFN-γ 和一氧化氮）减少。在肠系膜淋巴结中，在诱导后第 7 天，安慰剂组而非 NAP 组的促炎 IFN-γ、TNF 和 IL-6 浓度增加，而有趣的是，仅在 NAP 治疗的小鼠中观察到升高的抗炎 IL-10 水平。NAP 表现出的抗炎特性不仅局限于肠道，因为在肠道外的器官如肾脏中，在诱导结肠炎后，安慰剂组而非 NAP 组的 IFN-γ 水平增加。NAP 诱导的作用伴随着肠道微生物群组成的明显变化，因为在 NAP 治疗的小鼠的结肠腔内容物中双歧杆菌的负荷增加了两个数量级，双歧杆菌被认为是抗炎的“促进健康”共生物种，甚至在 NAP 治疗的小鼠和对照的未处理小鼠中也是如此。总之，NAP 减轻了急性实验性结肠炎的肠道和肠道外促炎后遗症，并可能为人类肠道炎症性疾病提供新的治疗选择。
