F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Department of Bioengineering, University of California San Diego, La Jolla, California 92093, USA.
Cell. 2020 Oct 29;183(3):666-683.e17. doi: 10.1016/j.cell.2020.09.009. Epub 2020 Sep 28.
A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.
克罗恩病（CD）的一个显著特征是“ creeping fat”（CrF）的肠外表现，定义为围绕发炎和纤维化的肠道的肠系膜脂肪组织扩张。在本研究中，我们探讨了 CD 中的微生物易位是否作为 CrF 发展的核心线索。我们发现了一组黏膜相关肠道细菌，它们在 CD 回肠手术切除中的 CrF 中持续易位并保持存活，并鉴定出无害梭菌是该菌群的一个特征，黏膜和脂肪分离株之间存在菌株变异，表明其对富含脂质的环境有偏好。单细胞 RNA 测序将 CrF 鉴定为既具有促纤维化又具有促脂肪生成的特征，其中富含对微生物刺激做出反应的活化免疫细胞，我们在定植了无害梭菌的无菌小鼠中得到了证实。对表达模式的体外验证表明，无害梭菌通过 M2 巨噬细胞刺激组织重塑，导致脂肪组织屏障，从而防止细菌向全身扩散。
