3 years ago

Increased Tryptophan Metabolism is Associated With Activity of Inflammatory Bowel Diseases

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 can increase susceptibility of mice to colitis. 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 100 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 (IL22) in serum from 28 patients by ELISA. 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 rDNA amplicon sequencing. We used real-time PCR to measure levels of mRNAs 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, clinical examinations during recruitment and follow-up visits. Results Serum levels of tryptophan were significantly lower in patients with IBD than controls (P=5.3x10–6) with a stronger reduction in patients with CD (vs control, P=1.1x10–10) than UC (vs control P=2.8x10–3). We found a negative correlation between serum levels of tryptophan and disease activity or level of c-reactive protein. Levels of mRNAs encoding tryptophan 2,3- dioxygenase-2 (TDO2) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1) were significantly decreased in liver biopsies from patients with IBD compared with controls, whereas level of mRNA encoding indoleamine 2,3-dioxygenase-1 (IDO1) 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 IL22 associated with disease activity in patients with IBD; there was an inverse association between level of IL22 and serum level of tryptophan. Conclusions In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum level 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. Studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD.

Publisher URL: www.sciencedirect.com/science

DOI: S0016508517360614

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