Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai, China.
Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University , Shanghai, China.
Gut Microbes. 2020 Nov 9;12(1):1-20. doi: 10.1080/19490976.2020.1819155.
High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus , and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus . Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.
高脂肪饮食（HFD）导致全身低度炎症，这与多种代谢和炎症性疾病的发病机制有关。由于促炎巨噬细胞的浸润，结肠被认为是在 HFD 条件下首先受到炎症影响的器官，然而，关于诱导结肠巨噬细胞产生促炎表型的机制尚不清楚。在这项研究中，我们发现 HFD 增加了革兰氏阳性菌的比例，特别是属，并且导致粪便脱氧胆酸（DCA）的显著增加，DCA 是一种主要由属细菌产生的肠道微生物代谢物。值得注意的是，用万古霉素减少革兰氏阳性菌可以减少粪便 DCA，并显著减轻结肠中促炎巨噬细胞的浸润，而用 DCA 补充饲料给万古霉素处理的小鼠会引起明显的促炎巨噬细胞浸润和结肠炎症。同时，腹腔内给予 DCA 也会引起大量具有促炎表型的巨噬细胞募集。在机制上，DCA 至少部分通过 M2 毒蕈碱乙酰胆碱受体（M2-mAchR）/Src 途径转激活的 Toll 样受体 2（TLR2），以剂量依赖的方式促进 M1 巨噬细胞极化和促炎细胞因子的产生。此外，M2-mAchR 介导的 TLR2 转录增加主要通过靶向 AP-1 转录因子来实现。此外，TLR2 下游的 NF-κB/ERK/JNK 信号通路参与了 DCA 诱导的巨噬细胞极化。总之，我们的研究结果表明，HFD 引起的高水平 DCA 可能作为一种启动子激活巨噬细胞并驱动结肠炎症，从而为调节肠道微生物群或干预特定胆汁酸受体信号可能是治疗与 HFD 相关的炎症性疾病的潜在治疗方法提供了机制基础。
