Obesity is a definitive factor of severity and mortality of acute pancreatitis (AP), and gut microbiota dysbiosis is involved in its pathogenesis. However, the effect of gut microbiota modulation by dietary components on high fat diet (HFD)-induced severe AP remains unclear. Here, we found that the inulin, a soluble dietary fiber, mitigated pancreatic injury and systematic inflammation in mice fed HFD, which was dependent on gut microbiota as this protective effect was attenuated in germ-free mice. Inulin treatment suppressed the overgrowth of pathogenic bacteria Escherichia Shigella, Enterococcus, Klebsiella, while increased the abundance of probiotics Akkermansia. Fecal microbiota transplantation from inulin-treated mice to recipient mice reduced pancreatic damage and remodeled intestinal homeostasis. Additionally, inulin increased fecal short chain fatty acids (SCFAs), strengthened gut barrier and restored Paneth cells. The beneficial effect of inulin on improving pancreatic damage and leaky gut was diminished after the suppression of SCFAs. Notably, SCFAs administration, especially butyrate, to HFD mice blocked pancreatic and intestinal injury with the inhibition of histone deacetylase 3 (HDAC3), and pharmacological HDAC3 inhibition mimicked the ameliorative effect of SCFAs. Mechanically, butyrate modulated macrophage M1/M2 polarization balance by suppressing HDAC3 and subsequent acetylation of histone H3K27. Collectively, our data offer new insights into the gut microbiota-pancreas axis that may be leveraged to augment the potential supplementation of prebiotic inulin in the management of obesity associated severe AP.

中文翻译：

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膳食菊粉通过肠胰轴改善肥胖引起的严重急性胰腺炎。


肥胖是急性胰腺炎 （AP） 严重程度和死亡率的决定性因素，肠道菌群失调参与其发病机制。然而，膳食成分对肠道微生物群调节对高脂饮食 （HFD） 诱导的严重 AP 的影响仍不清楚。在这里，我们发现菊粉是一种可溶性膳食纤维，可以减轻喂食 HFD 的小鼠的胰腺损伤和全身炎症，HFD 依赖于肠道微生物群，因为这种保护作用在无菌小鼠中减弱。菊粉处理抑制了病原菌志贺氏菌、肠球菌、克雷伯菌的过度生长，同时增加了益生菌阿克曼氏菌的丰度。将菊粉处理的小鼠的粪便微生物群移植到受体小鼠中，减少了胰腺损伤并重塑了肠道稳态。此外，菊粉增加了粪便短链脂肪酸 （SCFA），增强了肠道屏障并恢复了潘氏细胞。抑制 SCFAs 后，菊粉对改善胰腺损伤和肠漏的有益作用减弱。值得注意的是，对 HFD 小鼠施用 SCFAs，尤其是丁酸盐，通过抑制组蛋白脱乙酰酶 3 （HDAC3） 阻断胰腺和肠道损伤，药理学 HDAC3 抑制模拟了 SCFA 的改善作用。在机械上，丁酸盐通过抑制 HDAC3 和随后的组蛋白 H3K27 乙酰化来调节巨噬细胞 M1/M2 极化平衡。总的来说，我们的数据为肠道微生物群-胰腺轴提供了新的见解，可用于增加益生元菊粉补充剂在管理与肥胖相关的严重 AP 中的潜在补充。