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 × 10⁻⁶) with a stronger reduction in patients with CD (vs control; P = 1.1 × 10⁻¹⁰) than UC (vs control; P = 2.8 × 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.

中文翻译：

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色氨酸代谢增加与炎症性肠病的活动有关

背景与目标

给予色氨酸及其某些代谢产物可降低小鼠结肠炎的严重程度，而从饮食中去除色氨酸则会增加对结肠炎的易感性。肠道微生物组的转移会将大肠菌素表型从色氨酸饥饿的动物转移到正常营养的小鼠。我们旨在系统评估炎症性肠病（IBD）患者的血清色氨酸及其代谢产物的水平，并研究其与临床和血清学特征的关系。

方法

我们研究了2013年8月至2014年4月在德国入组的535例IBD患者（211例溃疡性结肠炎[UC]，234例克罗恩病[CD]，236例男性），随后随访至2016年7月。 291名没有IBD的匹配个体（对照）；使用高效液相色谱法测定色氨酸的水平。通过质谱法测定了148位患者和100位对照的血清中色氨酸的代谢产物。我们通过酶联免疫吸附测定法测量了28例患者血清中白介素22的水平。通过16S核糖体DNA扩增子测序分析从活跃的UC（n = 10）或CD（n = 8）患者的子集中收集配对的粪便和血清样品，以研究血清色氨酸水平与粪便微生物群组成之间的关联。我们使用实时聚合酶链反应测量了60例UC患者，50例CD患者和30例对照的结肠活检组织中信使RNA的水平。在募集和随访期间，我们收集了有关患者疾病活动评分，药物，实验室评估和临床检查的信息。

结果

IBD患者的血清色氨酸水平显着低于对照组（P  = 5.3×10 ^-6），而CD患者（vs对照；P  = 1.1×10 ^-10）的降低程度比UC（vs对照；P  = 2.8×10 ^-3）。我们发现血清色氨酸水平与疾病活动或C反应蛋白水平之间呈负相关。与对照组相比，IBD患者结肠活检中编码色氨酸2,3-双加氧酶-2和溶质载体家族6成员19（也称为B0AT1）的信使RNA水平显着降低，而编码吲哚胺2,3-的信使RNA水平双加氧酶-1明显增加。粪便微生物群的组成与血清色氨酸水平有关。色氨酸代谢产物的分析显示，与对照组相比，IBD患者的喹啉酸水平高，可激活犬尿氨酸途径。IBD患者的血清白细胞介素22浓度与疾病活动相关；

结论

在对来自500多名IBD患者的血清样本进行的分析中，我们观察到血清中色氨酸水平与疾病活动之间呈负相关。色氨酸代谢物（尤其是喹啉酸）水平升高表明，患有活动性IBD的患者色氨酸降解活性较高。色氨酸缺乏可能会促进IBD的发展或加剧疾病的活动。需要进行干预性临床研究来确定肠色氨酸途径的改变是否会影响IBD的严重性。