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Low tryptophan levels linked to IBD

 

Key clinical point: Patients with inflammatory bowel disease had significantly lower serum tryptophan levels than healthy controls.

Major finding: Serum tryptophan levels also correlated inversely with disease activity and C-reactive protein levels in patients with IBD.

Data source: An analysis of serum samples from 535 consecutive patients with IBD and 100 matched controls.

Disclosures: The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop therapies with inflammatory indications. The other investigators had no conflicts of interest.

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Is tryptophan deficiency an effect of active disease?

In this interesting study, Nikolaus et al. found an association of decreased serum tryptophan in patients with inflammatory bowel disease (IBD), compared with control subjects. The authors also found an inverse correlation of serum tryptophan levels in patients with C-reactive protein in both ulcerative colitis and Crohn's disease and with active disease as defined by clinical disease activity scores in Crohn's disease. A validated food-frequency questionnaire found no difference in tryptophan consumption based on disease activity in a subset of patients, decreasing the likelihood that this association is secondary to altered dietary intake only and may be related to other mechanisms.

Dr. Sarah Horst
An association of decreased serum tryptophan levels in IBD is very interesting and opens many avenues of research. It will be important to validate this relationship in the future with larger populations of IBD patients. Many of the exploratory analyses to further understand the mechanism behind this association, such as the relationship of serum tryptophan and microbiota diversity were done on a small number of patients and will need to be explored further. The effects of low tryptophan and ongoing inflammation may need to be characterized based on future endpoints such as endoscopic and/or histologic disease activity rather than just disease activity scores and/or CRP. Whether tryptophan deficiency is an effect of active disease or a contributor to the complex mechanism of mucosal inflammation is an important distinction to further understanding this pathway and its potential role as a biomarker or therapeutic target.

Sara Horst, MD, MPH, is an assistant professor, division of gastroenterology, hepatology & nutrition, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, Tenn. She had no relevant conflicts of interest.


 

FROM GASTROENTEROLOGY

Patients with inflammatory bowel disease (IBD) had significantly lower serum levels of the essential amino acid tryptophan than healthy controls in a large study reported in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.08.028).

Serum tryptophan levels also correlated inversely with both disease activity and C-reactive protein levels in patients with IBD, reported Susanna Nikolaus, MD, of University Hospital Schleswig-Holstein, Kiel, Germany, with her associates. “Tryptophan deficiency could contribute to development of IBD. Studies are needed to determine whether modification of intestinal tryptophan pathways affects [its] severity,” they wrote.

Several small case series have reported low levels of tryptophan in IBD and other autoimmune disorders, the investigators noted. Removing tryptophan from the diet has been found to increase susceptibility to colitis in mice, and supplementing with tryptophan or some of its metabolites has the opposite effect. For this study, the researchers used high-performance liquid chromatography to quantify tryptophan levels in serum samples from 535 consecutive patients with IBD and 100 matched controls. They used mass spectrometry to measure metabolites of tryptophan, enzyme-linked immunosorbent assay to measure interleukin-22 (IL-22) levels, and 16S rDNA amplicon sequencing to correlate tryptophan levels with fecal microbiota species. Finally, they used real-time polymerase chain reaction to measure levels of mRNA encoding tryptophan metabolites in colonic biopsy specimens.

Serum tryptophan levels were significantly lower in patients with IBD than controls (P = 5.3 x 10–6). The difference was starker in patients with Crohn’s disease (P = 1.1 x 10–10 vs. controls) compared with those with ulcerative colitis (P = 2.8 x 10–3 vs. controls), the investigators noted. Serum tryptophan levels also correlated inversely with disease activity in patients with Crohn’s disease (P = .01), while patients with ulcerative colitis showed a similar but nonsignificant trend (P = .07). Low tryptophan levels were associated with marked, statistically significant increases in C-reactive protein levels in both Crohn’s disease and ulcerative colitis. Tryptophan level also correlated inversely with leukocyte count, although the trend was less pronounced (P = .04).IBD was associated with several aberrations in the tryptophan kynurenine pathway, which is the primary means of catabolizing the amino acid. For example, compared with controls, patients with active IBD had significantly lower levels of mRNA encoding tryptophan 2,3-dioxygenase-2 (TDO2, a key enzyme in the kynurenine pathway) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1, a neutral amino acid transporter). Patients with IBD also had significantly higher levels of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial, rate-limiting oxidation of tryptophan to kynurenine. Accordingly, patients with IBD had a significantly higher ratio of kynurenine to tryptophan than did controls, and this abnormality was associated with disease activity, especially in Crohn’s disease (P = .03).

Patients with IBD who had relatively higher tryptophan levels also tended to have more diverse gut microbiota than did patients with lower serum tryptophan levels, although differences among groups were not statistically significant, the investigators said. Serum concentration of IL-22 also correlated with disease activity in patients with IBD, and infliximab responders had a “significant and sustained increase” of tryptophan levels over time, compared with nonresponders.

Potsdam dietary questionnaires found no link between disease activity and dietary consumption of tryptophan, the researchers said. Additionally, they found no links between serum tryptophan levels and age, smoking status, or disease complications, such as fistulae or abscess formation.The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop drugs with inflammatory indications. The other investigators had no conflicts of interest.