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Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2018-07-09 , DOI: 10.1038/s41385-018-0055-y
Noam Jacob 1, 2 , Jonathan P Jacobs 2 , Kotaro Kumagai 1 , Connie W Y Ha 1 , Yoshitake Kanazawa 1 , Venu Lagishetty 2 , Katherine Altmayer 1 , Ariel M Hamill 1 , Aimee Von Arx 1 , R Balfour Sartor 3 , Suzanne Devkota 1 , Jonathan Braun 4 , Kathrin S Michelsen 1 , Stephan R Targan 1 , David Q Shih 1
Affiliation  

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice lead to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been investigated. We demonstrate that the pro-fibrotic and inflammatory phenotype resulting from Tl1a-overexpression is abrogated in the absence of resident microbiota. To evaluate if this is due to the absence of a unique bacterial population, as opposed to any bacteria per se, we gavaged germ-free (GF) wild-type and Tl1a-transgenic (Tl1a-Tg) mice with stool from specific pathogen free (SPF) mice and a healthy human donor (Hu). Reconstitution with SPF, but not Hu microbiota, resulted in increased intestinal collagen deposition and fibroblast activation in Tl1a-Tg mice. Notably, there was reduced fibroblast migration and activation under GF conditions compared to native conditions. We then identified several candidate organisms that correlated directly with increased fibrosis in reconstituted mice and showed that these organisms directly impact fibroblast function in vitro. Thus, Tl1a-mediated intestinal fibrosis and fibroblast activation are dependent on specific microbial populations.

中文翻译:

非炎症依赖性 TL1A 介导的肠道纤维化依赖于肠道微生物组。

肿瘤坏死因子样细胞因子 1A(TL1A、TNFSF15)与炎症性肠病 (IBD) 相关,可调节肠道炎症和纤维化的位置和严重程度。TL1A 表达在发炎的肠粘膜中增加并且与纤维狭窄性克罗恩病有关。小鼠 Tl1a 过度表达导致自发性回肠炎,并加剧诱发的近端结肠炎和纤维化。IBD 与肠道微生物组的变化有关,但尚未研究不同微生物种群及其与 TL1A 的相互作用对纤维化的影响。我们证明,在没有常驻微生物群的情况下,由 Tl1a 过表达引起的促纤维化和炎症表型被消除。为了评估这是否是由于缺乏独特的细菌种群,而不是任何细菌本身,我们用无特定病原体 (SPF) 小鼠和健康人类供体 (Hu) 的粪便灌胃无菌 (GF) 野生型和 Tl1a 转基因 (Tl1a-Tg) 小鼠。用 SPF 而非 Hu 微生物群重建导致 Tl1a-Tg 小鼠肠道胶原蛋白沉积增加和成纤维细胞活化。值得注意的是,与自然条件相比,在 GF 条件下成纤维细胞迁移和活化减少。然后,我们确定了几种与重组小鼠纤维化增加直接相关的候选生物,并表明这些生物直接影响体外成纤维细胞功能。因此,Tl1a 介导的肠道纤维化和成纤维细胞活化取决于特定的微生物种群。用 SPF 而非 Hu 微生物群重建导致 Tl1a-Tg 小鼠肠道胶原蛋白沉积增加和成纤维细胞活化。值得注意的是,与自然条件相比,在 GF 条件下成纤维细胞迁移和活化减少。然后,我们确定了几种与重组小鼠纤维化增加直接相关的候选生物,并表明这些生物直接影响体外成纤维细胞功能。因此,Tl1a 介导的肠道纤维化和成纤维细胞活化取决于特定的微生物种群。用 SPF 而非 Hu 微生物群重建导致 Tl1a-Tg 小鼠肠道胶原蛋白沉积增加和成纤维细胞活化。值得注意的是,与自然条件相比,在 GF 条件下成纤维细胞迁移和活化减少。然后,我们确定了几种与重组小鼠纤维化增加直接相关的候选生物,并表明这些生物直接影响体外成纤维细胞功能。因此,Tl1a 介导的肠道纤维化和成纤维细胞活化取决于特定的微生物种群。然后,我们确定了几种与重组小鼠纤维化增加直接相关的候选生物,并表明这些生物直接影响体外成纤维细胞功能。因此,Tl1a 介导的肠道纤维化和成纤维细胞活化取决于特定的微生物种群。然后,我们确定了几种与重组小鼠纤维化增加直接相关的候选生物,并表明这些生物直接影响体外成纤维细胞功能。因此,Tl1a 介导的肠道纤维化和成纤维细胞活化取决于特定的微生物种群。
更新日期:2018-07-10
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