Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway
Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway
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DOI：
10.1016/j.phrs.2019.104603
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发表时间：
2020-02-01
影响因子：
9.3
通讯作者：
Su, Ziren
中科院分区：
文献类型：
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作者：
Li, Cailan;Ai, Gaoxiang;Su, Ziren
小檗碱（BBR）是一种天然存在的异喹啉生物碱，从几种中草药中分离出来，已被广泛用于治疗痢疾和结肠炎。但其血药浓度低于1%，肠道菌群介导的代谢产物被认为是BBR生物活性的重要物质基础。在这里，我们研究了氧化小檗碱（OBB）的抗结肠炎活性和潜在的机制，一种新的肠道微生物群代谢物的BBR，在DSS诱导的结肠炎小鼠。用含3%DSS的饮用水处理以诱导急性结肠炎的Balb/C小鼠口服施用OBB，每天一次，持续8天。分析临床症状，并收集生物样品用于显微镜、免疫炎症、肠屏障功能和肠道微生物群分析。结果表明，OBB能显著减轻DSS诱导的小鼠结肠炎的临床表现、结肠缩短和组织学损伤，其疗效与硫唑嘌呤（AZA）相似，但优于BBR，且具有上级作用。此外，ORB还能显著改善结肠炎性反应和肠上皮屏障功能障碍。OBB通过下调TLR 4和MyD 88的蛋白表达，抑制I kappa B α的磷酸化和NF-κ B B p65从细胞质向细胞核的转位，明显抑制TLR 4-MyD 88-NF-κ B B信号通路。此外，OBB明显调节DSS引起的肠道菌群失调，使其恢复到正常水平。综上所述，结果首次揭示ORB有效地改善DSS诱导的实验性结肠炎，至少部分地通过维持结肠完整性、抑制炎症反应和调节肠道菌群分布。
Berberine (BBR), a naturally-occurring isoquinoline alkaloid isolated from several Chinese herbal medicines, has been widely used for the treatment of dysentery and colitis. However, its blood concentration was less than 1%, and intestinal microflora-mediated metabolites of BBR were considered to be the important material basis for the bioactivities of BBR. Here, we investigated the anti-colitis activity and potential mechanism of oxyberberine (OBB), a novel gut microbiota metabolite of BBR, in DSS-induced colitis mice. Balb/C mice treated with 3 % DSS in drinking water to induce acute colitis were orally administrated with OBB once daily for 8 days. Clinical symptoms were analyzed, and biological samples were collected for microscopic, immune-inflammation, intestinal barrier function, and gut microbiota analysis. Results showed that OBB significantly attenuated DSS-induced clinical manifestations, colon shortening and histological injury in the mice with colitis which achieved similar therapeutic effect to azathioprine (AZA) and was superior to BBR. Furthermore, ORB remarkably ameliorated colonic inflammatory response and intestinal epithelial barrier dysfunction. OBB appreciably inhibited TLR4-MyD88-NF-kappa B signaling pathway through down-regulating the protein expressions of TLR4 and MyD88, inhibiting the phosphorylation of I kappa B alpha, and the translocation of NF-kappa B p65 from cytoplasm to nucleus. Moreover, OBB markedly modulated the gut dysbiosis induced by DSS and restored the dysbacteria to normal level. Taken together, the result for the first time revealed that ORB effectively improved DSS-induced experimental colitis, at least partly through maintaining the colonic integrity, inhibiting inflammation response, and modulating gut microflora profile.