Ketone body β-hydroxybutyrate ameliorates colitis by promoting M2 macrophage polarization through the STAT6-dependent signaling pathway.
Ketone body β-hydroxybutyrate ameliorates colitis by promoting M2 macrophage polarization through the STAT6-dependent signaling pathway.
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酮体β-羟基丁酸通过依赖信号转导及转录激活因子6（STAT6）的信号通路促进M2型巨噬细胞极化，从而改善结肠炎。
DOI：
10.1186/s12916-022-02352-x
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发表时间：
2022-04-15
期刊：
影响因子：
9.3
通讯作者：
Zhi, Fachao
中科院分区：
文献类型：
--
作者：
Huang, Chongyang;Wang, Jun;Liu, Hongbin;Huang, Ruo;Yan, Xinwen;Song, Mengyao;Tan, Gao;Zhi, Fachao
酮体β-羟基丁酸酯（BHB）因其在临床和医学领域具有许多有益的、维持生命的作用而受到越来越多的关注。然而，BHB在肠道炎症中的作用尚未研究。收集炎症性肠病（IBD）患者和健康对照者的结肠粘膜，用于评估BHB水平。此外，通过体重变化、结肠长度、疾病活动指数和组织病理学切片来评估外源性BHB在急性葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型中的治疗效果。通过RT-qPCR、免疫荧光和体内微生物分析来分析BHB的调节效应物。此外，BHB的分子机制在骨髓源性巨噬细胞（BMDM）中得到进一步证实。在这项研究中，在IBD患者的结肠粘膜中发现BHB水平显著降低，并与IBD活动指数相关。此外，我们证明了外源性BHB的施用减轻了急性实验性结肠炎的严重程度，其特征在于体重减轻、疾病活动指数、结肠缩短和组织学评分减少，以及隐窝损失和上皮损伤减少。此外，BHB导致DSS暴露后M2巨噬细胞相关基因（包括IL-4 Ra、IL-10、精氨酸酶1（Arg-1）和几丁质酶样蛋白3）的结肠表达显著增加，表明体内M2巨噬细胞偏斜增加。此外，体外实验表明，BHB的加入直接促进IL-4刺激的巨噬细胞中STAT 6磷酸化和M2巨噬细胞特异性基因表达。此外，我们发现BHB通过促进肠上皮细胞增殖，明显增强M2巨噬细胞诱导的粘膜修复。然而，BHB对M2巨噬细胞诱导的粘膜修复和抗炎的增强作用被STAT 6抑制剂AS 1517499完全抑制。总之，我们发现BHB通过STAT 6依赖性信号通路促进M2巨噬细胞极化，这有助于肠道炎症的解决和受损肠组织的修复。我们的研究结果表明，外源性BHB补充剂可能是一种有用的治疗IBD的治疗方法。在线版本包含补充材料，可通过10.1186/s12916-022-02352-x获得。
Ketone body β-hydroxybutyrate (BHB) has received more and more attentions, because it possesses a lot of beneficial, life-preserving effects in the fields of clinical science and medicine. However, the role of BHB in intestinal inflammation has not yet been investigated. Colonic mucosa of inflammatory bowel disease (IBD) patients and healthy controls were collected for evaluation of BHB level. Besides, the therapeutic effect of exogenous BHB in a murine model of acute dextran sulfate sodium (DSS)-induced colitis were assessed by body weight change, colon length, disease activity index, and histopathological sections. The regulatory effectors of BHB were analyzed by RT-qPCR, immunofluorescence, and microbe analysis in vivo. Moreover, the molecular mechanism of BHB was further verified in bone marrow-derived macrophages (BMDMs). In this study, significantly reduced BHB levels were found in the colonic mucosa from IBD patients and correlated with IBD activity index. In addition, we demonstrated that the administration of exogenous BHB alleviated the severity of acute experimental colitis, which was characterized by less weight loss, disease activity index, colon shortening, and histology scores, as well as decreased crypt loss and epithelium damage. Furthermore, BHB resulted in significantly increased colonic expression of M2 macrophage-associated genes, including IL-4Ra, IL-10, arginase 1 (Arg-1), and chitinase-like protein 3, following DSS exposure, suggesting an increased M2 macrophage skewing in vivo. Moreover, an in vitro experiment revealed that the addition of BHB directly promoted STAT6 phosphorylation and M2 macrophage-specific gene expression in IL-4-stimulated macrophages. Besides, we found that BHB obviously increased M2 macrophage-induced mucosal repair through promoting intestinal epithelial proliferation. However, the enhancement effect of BHB on M2 macrophage-induced mucosal repair and anti-inflammation was completely inhibited by the STAT6 inhibitor AS1517499. In summary, we show that BHB promotes M2 macrophage polarization through the STAT6-dependent signaling pathway, which contributes to the resolution of intestinal inflammation and the repair of damaged intestinal tissues. Our finding suggests that exogenous BHB supplement may be a useful therapeutic approach for IBD treatment. The online version contains supplementary material available at 10.1186/s12916-022-02352-x.
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影响因子：
4.9
作者：
Lissner D;Schumann M;Batra A;Kredel LI;Kühl AA;Erben U;May C;Schulzke JD;Siegmund B
通讯作者：
Siegmund B
DOI：
10.1038/s41575-020-00360-x
发表时间：
2021-01
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Kaplan GG;Windsor JW
通讯作者：
Windsor JW
Synbindin 抑制结肠炎期间微生物群和粘膜炎症的促炎巨噬细胞活化
影响因子：
24.5
作者：
Ai, Luoyan;Ren, Yimeng;Xu, Antao
通讯作者：
Xu, Antao
影响因子：
64.5
作者：
Ang, Qi Yan;Alexander, Margaret;Turnbaugh, Peter J.
通讯作者：
Turnbaugh, Peter J.
影响因子：
3.7
作者：
Bhattacharya, Kaustuv;Matar, Walid;Tchan, Michel
通讯作者：
Tchan, Michel