Intestinal Metabolites Are Profoundly Altered in the Context of HLA-B27 Expression and Functionally Modulate Disease in a Rat Model of Spondyloarthritis.
Intestinal Metabolites Are Profoundly Altered in the Context of HLA-B27 Expression and Functionally Modulate Disease in a Rat Model of Spondyloarthritis.
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DOI：
10.1002/art.40183
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Rosenbaum JT
中科院分区：
文献类型：
--
作者：
Asquith M;Davin S;Stauffer P;Michell C;Janowitz C;Lin P;Ensign-Lewis J;Kinchen JM;Koop DR;Rosenbaum JT
HLA-B27相关的脊柱关节病与肠道微生物群改变和肠道炎症有关。因此，我们试图确定HLA-B27/β2m大鼠宿主和微生物代谢物中b27依赖性的变化，以及微生物衍生代谢物是否会影响这种主要脊椎关节病模型的疾病。收集6周（病变前）和16周（病变）Fischer 344 HLA-B27/β2m转基因大鼠和WT对照的盲肠内容物。代谢组学分析采用高通量气相色谱和液相色谱质谱法进行。将HLA-B27/β2m大鼠用微生物代谢物丙酸盐或丁酸盐在饮用水中治疗10周，随后评估疾病活动性。我们的筛选鉴定了582种代谢物，其中一半以上在16周时被B27的表达显著改变。微生物和宿主代谢产物均发生改变，氨基酸、碳水化合物、外源代谢和中链脂肪酸代谢等多种途径受到影响。HLA-B27/β2m大鼠的组氨酸、酪氨酸、亚精胺、n -乙酰氨基甲酸酯和甘油水平在6周时也出现上调。短链脂肪酸丙酸可显著减轻b27相关炎症性疾病，但与FoxP3+ T细胞诱导增加或细胞因子IL-10、IL-33或紧密连接蛋白ZO-1表达改变无关。HLA-B27的表达还与宿主微生物代谢物受体基因FFAR2、FFAR3和NIACR1的表达改变有关。HLA-B27的表达深刻影响肠道代谢组，即使在6周龄的大鼠中也有明显的变化。关键的是，我们证明了一种微生物代谢物，丙酸酯可以减轻b27相关炎症性疾病的发展。这些和其他微生物衍生的生物活性介质可能为b27相关的脊椎病提供新的治疗方式。
HLA-B27 associated spondyloarthropathies are associated with an altered intestinal microbiota and bowel inflammation. Therefore, we sought to identify B27-dependent changes in both host and microbial metabolites in the HLA-B27/β2m rat and whether microbiota-derived metabolites could impact disease in this major model of spondyloarthropathy. Cecal contents were collected from 6wk (pre-diseased) and 16wk (diseased) Fischer 344 HLA-B27/β2m transgenic rats and WT controls. Metabolomic profiling was performed by high-throughput gas- and liquid-chromatography-based mass spectrometry. HLA-B27/β2m rats were treated with microbial metabolites propionate or butyrate in drinking water for 10wks and disease activity subsequently assessed. Our screen identified 582 metabolites, of which over half were significantly altered by B27 expression at 16wks. Both microbial and host metabolites were altered, with multiple pathways including amino acid, carbohydrate, xenobiotic and medium chain fatty acid metabolism affected. Differences were even observed at 6wks, with upregulation of histidine, tyrosine, spermidine, N-acetylmuramate and glycerate in HLA-B27/β2m rats. Administration of the short chain fatty acid propionate significantly attenuated B27-associated inflammatory disease, albeit was not associated with increased FoxP3+ T cell induction, or altered expression of cytokines IL-10, IL-33 or tight junction protein ZO-1. HLA-B27 expression was also associated with altered host expression of microbial metabolite receptor genes FFAR2, FFAR3 and NIACR1. HLA-B27 expression profoundly impacts the intestinal metabolome, with changes evident in rats even at 6wks of age. Critically, we demonstrate a microbial metabolite, propionate attenuates development of B27-associated inflammatory disease. These and other microbiota-derived bioactive mediators may provide novel treatment modalities in B27-associated spondyloathropathies.
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DOI：
10.1016/j.berh.2014.10.018
发表时间：
2014-10
期刊：
Best practice & research. Clinical rheumatology
影响因子：
--
作者：
Asquith M;Elewaut D;Lin P;Rosenbaum JT
通讯作者：
Rosenbaum JT
影响因子：
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DOI：
10.1152/ajpgi.00407.2004
发表时间：
2005-06-01
影响因子：
4.5
作者：
Guo, X;Rao, JN;Wang, JY
通讯作者：
Wang, JY
影响因子：
4.9
作者：
Hoentjen, F;Welling, GW;Dieleman, LA
通讯作者：
Dieleman, LA
DOI：
10.1002/art.39681
发表时间：
2016-09
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Asquith MJ;Stauffer P;Davin S;Mitchell C;Lin P;Rosenbaum JT
通讯作者：
Rosenbaum JT