Tryptophan Levels May Reflect IBD Activity

By Marilynn Larkin

September 06, 2017

NEW YORK (Reuters Health) -- Tryptophan concentrations may contribute to the development of inflammatory bowel disease (IBD) and serve as a potential biomarker of IBD disease activity, researchers in Germany suggest.

Experiments in mice have shown that administration of tryptophan reduces colitis severity, whereas eliminating dietary tryptophan increases susceptibility to colitis, according to Dr. Stefan Schreiber of University Hospital Schleswig-Holstein, in Kiel, and colleagues.

Therefore, the team assessed serum levels of tryptophan and its metabolites in people with IBD to study the amino acid's association with clinical and serological features of the condition.

In all, 535 consecutive IBD patients were enrolled in 2013 and 2014; they were followed until mid-2016. The cohort included 211 patients with ulcerative colitis (UC; 48% males; mean age, 40), 324 with Crohn's disease (CD; 42% males; mean age, 42), and 100 matched controls without IBD.

Serum tryptophan levels were measured in all patients and controls. Tryptophan metabolites were measured in 148 patients and all controls, and interleukin 22 (IL22) levels were measured in 28 patients.

Paired stool and serum samples were collected from a subset of 10 patients with active UC and eight with active CD to assess associations between tryptophan serum levels and the composition of the fecal microbiota.

Levels of mRNAs encoding tryptophan and its metabolites were measured in colonic biopsies from 110 IBD patients and 30 controls.

As reported online August 14 in Gastroenterology, serum levels of tryptophan were significantly lower in patients with IBD, especially those with CD, than in controls. Serum levels of tryptophan also were negatively correlated with disease activity and with C-reactive protein levels.

Levels of mRNAs encoding tryptophan 2,3- dioxygenase-2 and solute carrier family 6 member 19 were significantly lower in liver biopsies from patients with IBD (vs. controls), whereas levels of mRNA encoding indoleamine 2,3-dioxygenase-1 were significantly higher.

The team also found that fecal microbiota composition was associated with serum levels of tryptophan.

Analysis of tryptophan metabolites showed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls, according to the authors. Serum concentrations of IL22 were associated with disease activity in patients with IBD, and an inverse association was seen between levels of IL22 and serum levels of tryptophan.

In an email to Reuters Health, Dr. Schreiber identified three take-home messages from the study.

"First, tryptophan levels appear to be a biomarker for chronic active disease," he said. "This is very important in order to optimize all kinds of therapies in IBD. Cutting down tryptophan is an ancient defense mechanism by the body, which is counterintuitive in IBD - the same way as cutting iron in chronic inflammation."

Second, he noted that "low tryptophan is not caused by malnutrition. More tryptophan in food does not help because it is all absorbed in the upper-GI tract."

Third, he explained, "Extensive animal experimentation shows that tryptophan metabolites released in high concentration at the mucosa of the lower GI tract are strongly anti-inflammatory. Key is modification of the microbiome. We are working on such a medication releasing nicotinamid targeted to the ileum and colon.""

"Whether used as biomarker or therapy," Dr. Schreiber concluded, "the story shows that molecular nutrition finally has come to life."

Dr. Louis Cohen of The Mount Sinai Hospital in New York City told Reuters Health, "The major strength of the study is the large number of patients through which to establish strong correlations between serum tryptophan levels, a diagnosis of IBD, and disease activity in patients with IBD."

"At a minimum," he said by email, "the study identifies a potential serum biomarker that may offer physicians another parameter through which to non-invasively assess disease activity in IBD."

"This study creates an important foundation on which future research into the mechanistic association between tryptophan metabolism and IBD pathogenesis can be performed," he observed. "However, at this time it is very premature to make a causative association between IBD pathogenesis and tryptophan metabolism or suggest tryptophan metabolism as a therapeutic target in IBD."

"Even without a causative association," Dr. Cohen concluded, "the potential addition of tryptophan as a serum biomarker of IBD disease activity may in itself provide an important method through which physicians can monitor patients’ disease activity and assess therapeutic response."


Gastroenterol 2017.