Inflammatory bowel disease (IBD) refers to a pair of prevalent conditions (Crohn’s disease and ulcerative colitis) distinguished by persistent inflammation of the large intestine. Procyanidin C1 (PCC1) is a naturally occurring substance derived from grape seeds that has demonstrated notable anti-inflammatory properties. This study examines the potential utility of PCC1 as a treatment for IBD and subsequently examines the host-cell- and microbiome-related mechanisms underlying the detected therapeutic benefits. Working with a classic dextran sodium sulfate (DSS)-induced mouse IBD model, we show that PCC1 protects the mucosal barrier and thereby confers strong protective effects against IBD. PCC1 pretreatment resulted in anti-inflammatory effects and protection against multiple pathological phenotypes in the IBD model mice, including reduced weight loss, lower Disease Activity Index (DAI) totals, and enhanced colon size, as well as obviously beneficial effects on the mucosal barrier (e.g., barrier thickness and activity of mucus-degrading enzymes). We also analyzed the autophagy marker LC3 and found that the level of LC3 was significantly elevated in the intestinal epithelial cell samples of the PCC1-pretreatment group as compared with the non-model mice samples. PCC1 altered the fecal microbiome composition, which included elevating the abundance of and . Fecal microbiome transplant (FMT) experiments showed that delivering a microbiome from PCC1-treated animals into PCC1-naïve animals conferred protection. Metabolic profiling revealed that both the PCC1-pretreatment and PCC1 FMT groups had elevated levels of the microbiota-derived metabolite valeric acid, and supplementation with this short-chain fatty acid (SCFA) also conferred strong protection against IBD. Finally, inhibitor experiments confirmed that the beneficial effects of valeric acid on the mucus layer are mediated by FOXO1 signaling in the goblet cells of the intestinal epithelium. Beyond showing that PCC1 confers anti-inflammatory effects and protection against IBD by altering the microbiome, our study demonstrates proof of principle for multiple straightforward interventions (PCC1, FMT, and valeric acid supplementation) for ameliorating mucosal barrier damage to treat IBD.

中文翻译：

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原花青素 C1 调节微生物组以增加 FOXO1 信号传导和戊酸水平，以保护炎症性肠病的粘膜屏障

炎症性肠病（IBD）是指两种常见疾病（克罗恩病和溃疡性结肠炎），其特征是大肠持续炎症。原花青素 C1 (PCC1) 是一种从葡萄籽中提取的天然物质，具有显着的抗炎特性。这项研究探讨了 PCC1 作为 IBD 治疗方法的潜在效用，并随后研究了所检测到的治疗益处背后的宿主细胞和微生物组相关机制。通过使用经典的右旋糖酐硫酸钠 (DSS) 诱导的小鼠 IBD 模型，我们发现 PCC1 可以保护粘膜屏障，从而对 IBD 具有强大的保护作用。PCC1 预处理对 IBD 模型小鼠产生抗炎作用并针对多种病理表型提供保护，包括减轻体重、降低疾病活动指数 (DAI) 总量和增大结肠大小，并对粘膜屏障产生明显的有益作用。例如，屏障厚度和粘液降解酶的活性）。我们还分析了自噬标记物LC3，发现PCC1预处理组的肠上皮细胞样本中LC3的水平与非模型小鼠样本相比显着升高。PCC1 改变了粪便微生物组的组成，其中包括提高了 和 的丰度。粪便微生物组移植 (FMT) 实验表明，将经过 PCC1 处理的动物的微生物组转移到未经 PCC1 处理的动物体内可提供保护。代谢分析显示，PCC1 预处理组和 PCC1 FMT 组的微生物群衍生代谢物戊酸水平升高，补充这种短链脂肪酸 (SCFA) 也能提供针对 IBD 的强大保护作用。最后，抑制剂实验证实，戊酸对粘液层的有益作用是由肠上皮杯状细胞中的 FOXO1 信号传导介导的。除了表明 PCC1 通过改变微生物组具有抗炎作用和预防 IBD 的作用外，我们的研究还证明了多种直接干预措施（PCC1、FMT 和戊酸补充剂）可改善粘膜屏障损伤以治疗 IBD 的原理证据。