5-Aminosalicylic Acid Ameliorates Colitis and Checks Dysbiotic Escherichia coli Expansion by Activating PPAR-γ Signaling in the Intestinal Epithelium.
5-Aminosalicylic Acid Ameliorates Colitis and Checks Dysbiotic Escherichia coli Expansion by Activating PPAR-γ Signaling in the Intestinal Epithelium.
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DOI：
10.1128/mbio.03227-20
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发表时间：
2021-01-19
期刊：
影响因子：
6.4
通讯作者：
Bäumler AJ
中科院分区：
文献类型：
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作者：
Cevallos SA;Lee JY;Velazquez EM;Foegeding NJ;Shelton CD;Tiffany CR;Parry BH;Stull-Lane AR;Olsan EE;Savage HP;Nguyen H;Ghanaat SS;Byndloss AJ;Agu IO;Tsolis RM;Byndloss MX;Bäumler AJ
粪便微生物群中肠道菌群的扩张是与许多非传染性疾病（包括溃疡性结肠炎）相关的生态失调的微生物特征。在这里，我们使用大肠杆菌，肠球菌目的代表，以表明其在结肠炎期间的微生态扩张可以通过调节宿主上皮代谢来补救。5-氨基水杨酸（5-阿萨）是一种过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂，是治疗溃疡性结肠炎的一线药物，但其抗炎机制尚未完全阐明。在这里，我们发现5-阿萨通过激活肠上皮细胞中的PPAR-γ信号来改善葡聚糖硫酸钠（DSS）治疗小鼠的结肠炎。DSS诱导的结肠炎与上皮缺氧的丧失和大肠杆菌的呼吸依赖性管腔扩张相关，这可以通过5-阿萨治疗来改善。然而，5-阿萨不再能够减轻炎症，恢复上皮缺氧，或钝E。大肠杆菌中的DSS处理的小鼠，缺乏Pparg表达，特别是在肠上皮细胞。这些数据表明，5-阿萨的抗炎活性需要激活上皮细胞的PPAR-γ信号传导，因此指出肠上皮细胞是溃疡性结肠炎治疗干预的潜在靶点。
An expansion of Enterobacterales in the fecal microbiota is a microbial signature of dysbiosis that is linked to many noncommunicable diseases, including ulcerative colitis. Here, we used Escherichia coli, a representative of the Enterobacterales, to show that its dysbiotic expansion during colitis can be remediated by modulating host epithelial metabolism. 5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfate sodium (DSS)-treated mice by activating PPAR-γ signaling in the intestinal epithelium. DSS-induced colitis was associated with a loss of epithelial hypoxia and a respiration-dependent luminal expansion of Escherichia coli, which could be ameliorated by treatment with 5-ASA. However, 5-ASA was no longer able to reduce inflammation, restore epithelial hypoxia, or blunt an expansion of E. coli in DSS-treated mice that lacked Pparg expression specifically in the intestinal epithelium. These data suggest that the anti-inflammatory activity of 5-ASA requires activation of epithelial PPAR-γ signaling, thus pointing to the intestinal epithelium as a potential target for therapeutic intervention in ulcerative colitis.