Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases
Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases
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DOI：
10.1053/j.gastro.2017.08.028
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发表时间：
2017-12-01
期刊：
影响因子：
29.4
通讯作者：
Schreiber, Stefan
中科院分区：
文献类型：
--
作者：
Nikolaus, Susanna;Schulte, Berenice;Schreiber, Stefan
背景与目的：给予色氨酸及其部分代谢物可降低小鼠结肠炎的严重程度，而从饮食中去除色氨酸会增加对结肠炎的易感性。肠道微生物群的转移将产生结肠菌的表型从色氨酸饥饿的动物转移到正常营养的小鼠。本研究旨在系统评价炎症性肠病(IBD)患者血清色氨酸及其代谢物水平，并探讨其与临床及血清学特征的关系。方法：我们研究了从2013年8月至2014年4月在德国登记的连续IBD患者(211例溃疡性结肠炎[UC]，234例克罗恩病[CD]；236名男性)，并随访至2016年7月。血清样本来自患者和291名没有IBD的匹配个体(对照组)；色氨酸水平用高效液相色谱法测定。用质谱法测定了148例患者和100例正常对照血清中色氨酸的代谢产物。采用双抗体夹心酶联免疫吸附试验检测28例患者血清白细胞介素22水平。从活动期UC(n=10)或CD(n=8)患者中收集配对粪便和血清样本，通过16S核糖体DNA扩增序列分析，研究血清色氨酸水平与粪便微生物群组成之间的关系。我们使用实时聚合酶链式反应检测了60名UC患者、50名CD患者和30名对照组的结肠活检组织中信使RNA的水平。在招募和随访期间，我们收集了患者的疾病活动评分、药物、实验室评估和临床检查的信息。结果：IBD患者血清色氨酸水平显著低于对照组(P=5.3×10(-6))，CD组较UC组下降更明显(vs对照组，P=1.1×10(-10))。我们发现血清色氨酸水平与疾病活动性或C反应蛋白水平呈负相关。IBD患者结肠组织中编码色氨酸2，3-双加氧酶-2和溶质载体家族6成员19(又称B0AT1)的信使RNA水平显著低于对照组，而编码吲哚胺2，3-双加氧酶-1的信使RNA水平显著高于对照组。粪便微生物区系的组成与血清色氨酸水平有关。对色氨酸代谢产物的分析显示，与对照组相比，IBD患者体内高水平的喹啉酸激活了犬尿氨酸途径。血清白介素22水平与IBD患者疾病活动性相关；白介素22水平与血清色氨酸水平呈负相关。结论：在对500多名IBD患者血清样本的分析中，我们观察到血清色氨酸水平与疾病活动性呈负相关。色氨酸代谢物水平升高--尤其是喹啉酸--表明活动期IBD患者的色氨酸降解活性很高。色氨酸缺乏可能导致IBD的发生或加重疾病活动性。需要进行干预性临床研究来确定肠道色氨酸通路的改变是否影响IBD的严重程度。
BACKGROUND & AIMS: Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their association with clinical and serologic features. METHODS: We studied 535 consecutive patients with IBD (211 with ulcerative colitis [UC], 234 with Crohn's disease [CD]; 236 male), enrolled in Germany from August 2013 through April 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liquid chromatography. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by enzyme-linked immunosorbent assay. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate associations between serum levels of tryptophan and composition of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of messenger RNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients' disease activity scores, medications, laboratory assessments, and clinical examinations during recruitment and follow-up visits. RESULTS: Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 x 10(-6)) with a stronger reduction in patients with CD (vs control; P = 1.1 x 10(-10)) than UC (vs control; P = 2.8 x 10(-3)). We found a negative correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of messenger RNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of messenger RNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The composition of the fecal microbiota associated with serum levels of tryptophan. Analysis of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan. CONCLUSIONS: In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites-especially of quinolinic acid-indicated a high activity of tryptophan degradation in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clinical studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD.