Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil.
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-900, Brazil.
Cell Rep. 2019 Apr 16;27(3):750-761.e7. doi: 10.1016/j.celrep.2019.03.054.
Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.
抗生素诱导的菌群失调是导致艰难梭菌肠道感染的一个关键因素。在这里，我们表明，恢复肠道丁酸盐水平的干预措施可以减轻艰难梭菌诱导的结肠炎的临床和病理特征。丁酸盐对艰难梭菌的定植或毒素产生没有影响。然而，它可以减轻感染小鼠的肠道炎症并改善肠道屏障功能，这表现为肠道上皮通透性降低和细菌易位，这些作用与肠道上皮细胞紧密连接成分的表达增加有关。转录因子 HIF-1 在肠道上皮细胞中的激活在艰难梭菌诱导的结肠炎中发挥保护作用，并且是丁酸盐作用所必需的。我们得出结论，丁酸盐通过稳定 HIF-1 来保护肠道上皮细胞免受艰难梭菌毒素的损伤，从而减轻感染的局部炎症反应和全身后果。
