Sokol Harry, Pigneur Bénédicte, Watterlot Laurie, Lakhdari Omar, Bermúdez-Humarán Luis G, Gratadoux Jean-Jacques, Blugeon Sébastien, Bridonneau Chantal, Furet Jean-Pierre, Corthier Gérard, Grangette Corinne, Vasquez Nadia, Pochart Philippe, Trugnan Germain, Thomas Ginette, Blottière Hervé M, Doré Joël, Marteau Philippe, Seksik Philippe, Langella Philippe
Unité Ecologie et Physiologie du Système Digestif, Institut National de la Recherche Agronomique U910, Domaine de Vilvert, 78350 Jouy-en-Josas, France.
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16731-6. doi: 10.1073/pnas.0804812105. Epub 2008 Oct 20.
A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients. In this study, we determined the composition of the mucosa-associated microbiota of CD patients at the time of surgical resection and 6 months later using FISH analysis. We found that a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. To evaluate the immunomodulatory properties of F. prausnitzii we analyzed the anti-inflammatory effects of F. prausnitzii in both in vitro (cellular models) and in vivo [2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced] colitis in mice. In Caco-2 cells transfected with a reporter gene for NF-kappaB activity, F. prausnitzii had no effect on IL-1beta-induced NF-kappaB activity, whereas the supernatant abolished it. In vitro peripheral blood mononuclear cell stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-gamma production levels and higher secretion of IL-10. Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis, as demonstrated by real-time quantitative PCR (qPCR) analysis. F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-kappaB activation and IL-8 production. These results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment.
在克罗恩病(CD)患者中,已反复观察到占主导地位的厚壁菌门肠道细菌的丰度和生物多样性下降。在本研究中,我们使用荧光原位杂交(FISH)分析确定了CD患者手术切除时及6个月后的黏膜相关微生物群组成。我们发现,厚壁菌门的一个主要成员——普拉梭菌的减少与回肠CD术后复发风险较高有关。切除的回肠克罗恩黏膜上普拉梭菌比例较低也与6个月时的内镜复发有关。为了评估普拉梭菌的免疫调节特性,我们分析了普拉梭菌在体外(细胞模型)和体内[2,4,6-三硝基苯磺酸(TNBS)诱导]小鼠结肠炎中的抗炎作用。在用NF-κB活性报告基因转染的Caco-2细胞中,普拉梭菌对IL-1β诱导的NF-κB活性没有影响,而其培养上清液可消除该活性。普拉梭菌体外刺激外周血单个核细胞导致IL-12和IFN-γ产生水平显著降低,IL-10分泌增加。口服活的普拉梭菌或其培养上清液可显著降低TNBS结肠炎的严重程度,并倾向于纠正与TNBS结肠炎相关的生态失调,实时定量PCR(qPCR)分析证明了这一点。普拉梭菌在细胞和TNBS结肠炎模型中均表现出抗炎作用,部分原因是其分泌的代谢产物能够阻断NF-κB激活和IL-8产生。这些结果表明,使用普拉梭菌作为益生菌来平衡生态失调在CD治疗中是一种有前景的策略。