Fatigue in Inflammatory Bowel Disease: A Common Complaint With Few Answers

See “Effect of 5-hydroxytryptophan on fatigue in quiescent inflammatory bowel disease: a randomized controlled trial,” by Truyens ML, Lobatón T, Ferrante M, et al, on page 1294. See “Effect of 5-hydroxytryptophan on fatigue in quiescent inflammatory bowel disease: a randomized controlled trial,” by Truyens ML, Lobatón T, Ferrante M, et al, on page 1294. Approximately half of patients with inflammatory bowel disease (IBD) complain of fatigue, which is associated with psychosocial distress and poor quality of life.1Huppertz-Hauss G. Hoivik M.L. Jelsness-Jorgensen L.P. et al.Fatigue in a population-based cohort of patients with inflammatory bowel disease 20 years after diagnosis: the IBSEN study.Scand J Gastroenterol. 2017; 52: 351-358Crossref PubMed Scopus (40) Google Scholar, 2Artom M. Czuber-Dochan W. Sturt J. et al.Targets for health interventions for inflammatory bowel disease-fatigue.J Crohns Colitis. 2016; 10: 860-869Crossref PubMed Scopus (39) Google Scholar, 3Graff L.A. Clara I. Walker J.R. et al.Changes in fatigue over 2 years are associated with activity of inflammatory bowel disease and psychological factors.Clin Gastroenterol Hepatol. 2013; 11: 1140-1146Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 4D’Silva A. Fox D.E. Nasser Y. et al.Prevalence and risk factors for fatigue in adults with inflammatory bowel disease: a systematic review with meta-analysis.Clin Gastroenterol Hepatol. 2022; 20: 995-1009.e7Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 5Hashash J.G. Ramos-Rivers C. Youk A. et al.Quality of sleep and coexistent psychopathology have significant impact on fatigue burden in patients with inflammatory bowel disease.J Clin Gastroenterol. 2018; 52: 423-430Crossref PubMed Scopus (26) Google Scholar Although complaints of fatigue are more commonly associated with active disease, previous studies also report a high rate in patients with quiescent disease who do not have clinical symptoms.4D’Silva A. Fox D.E. Nasser Y. et al.Prevalence and risk factors for fatigue in adults with inflammatory bowel disease: a systematic review with meta-analysis.Clin Gastroenterol Hepatol. 2022; 20: 995-1009.e7Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar,6Zimmerman J. Extraintestinal symptoms in irritable bowel syndrome and inflammatory bowel diseases: nature, severity, and relationship to gastrointestinal symptoms.Dig Dis Sci. 2003; 48: 743-749Crossref PubMed Scopus (70) Google Scholar This suggests that biologic mediators independent of symptoms may result in fatigue. Most of the studies examining fatigue in IBD, however, are cross-sectional and have not investigated causation or treatment. Metabolism of tryptophan is a possible mechanistic link between mucosal inflammation, fatigue, sleep, and depression in patients with IBD. Tryptophan is an amino acid that is needed for the formation of the neurotransmitters melatonin and serotonin. More than 90% of dietary tryptophan, however, is metabolized down the kynurenine pathway in host immune and epithelial cells. Indoleamine 2,3-dioxygenase 1 (IDO1), which increases in the guts of patients with IBD with active inflammation, is the first and rate-limiting enzyme in tryptophan metabolism along the kynurenine pathway (Figure 1). This increase in IDO1 activity results in low tryptophan levels and changes in several kynurenine pathway metabolites in the peripheral blood in patients with Crohn’s disease and ulcerative colitis.7Gupta N.K. Thaker A.I. Kanuri N. et al.Serum analysis of tryptophan catabolism pathway: correlation with Crohn’s disease activity.Inflamm Bowel Dis. 2012; 18: 1214-1220Crossref PubMed Scopus (102) Google Scholar, 8Sofia M.A. Ciorba M.A. Meckel K. et al.Tryptophan metabolism through the kynurenine pathway is associated with increasing mucosal inflammation in ulcerative colitis.Inflamm Bowel Dis. 2018; 24: 1471-1480Crossref PubMed Scopus (63) Google Scholar, 9Nikolaus S. Schulte B. Al-Massad N. et al.Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases.Gastroenterology. 2017; 153: 1504-1516.e2Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Importantly, multiple kynurenine pathway metabolites are neuroactive, and an association between these metabolites and cognition, mood, fatigue, and sleep has been observed in other disease states.10Heitkemper M.M. Han C.J. Jarrett M.E. et al.Serum tryptophan metabolite levels during sleep in patients with and without irritable bowel syndrome (IBS).Biol Res Nurs. 2016; 18: 193-198Crossref PubMed Scopus (30) Google Scholar, 11Silber B.Y. Schmitt J.A. Effects of tryptophan loading on human cognition, mood, and sleep.Neurosci Biobehav Rev. 2010; 34: 387-407Crossref PubMed Scopus (174) Google Scholar, 12Cho H.J. Savitz J. Dantzer R. et al.Sleep disturbance and kynurenine metabolism in depression.J Psychosom Res. 2017; 99: 1-7Crossref PubMed Scopus (39) Google Scholar, 13Malhotra R. Persic V. Zhang W. et al.Tryptophan and kynurenine levels and its association with sleep, nonphysical fatigue, and depression in chronic hemodialysis patients.J Ren Nutr. 2017; 27: 260-266Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Thus, there is strong rationale to investigate whether tryptophan—or one of its metabolites that changes in the setting of mucosal inflammation—can be used as a treatment for these common symptoms in patients with IBD. 5-Hydroxytrytophan (5-HTP), an intermediary metabolite between tryptophan and serotonin, crosses the blood-brain barrier and has been explored as a treatment for depression and fatigue in various disease states. Truyens et al14Truyens M.L. Lobatón T. Ferrante M. et al.Effect of 5-hydroxytryptophan on fatigue in quiescent inflammatory bowel disease: a randomized controlled trial.Gastroenterology. 2022; 163: 1294-1305Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar investigated whether supplementation with 5-HTP is effective for the treatment of fatigue in patients with IBD in a multicenter randomized placebo-controlled crossover trial. In the study, 166 patients with Crohn’s disease or ulcerative colitis without active IBD, who had fatigue defined by a visual analog scale, were randomized to 100 mg of 5-HTP twice daily or placebo for 8 weeks, followed by a crossover period of 8 weeks. During treatment, there was a significant increase in serum 5-HTP levels. The primary end point, a ≥20% reduction in fatigue by the visual analog scale, however, was not different between treatment groups. Likewise, no differences were observed in patient-reported anxiety, depression, or stress in patients treated with 5-HTP. Although this study was rigorously performed and did not demonstrate benefit of 5-HTP on fatigue, there are several limitations to consider when pursuing future investigations of tryptophan metabolites or treatments of fatigue in patients with IBD. The investigators included a heterogenous group of patients and limited enrollment to patients without active disease. In contrast, the stronger mechanistic rationale based on low blood tryptophan levels and increased gut tryptophan metabolism during disease activity is to treat patients who have mucosal inflammation with 5-HTP or other tryptophan metabolites. Although the dose of 5-HTP used in the study was based on similar dosing used in trials for depression, it is possible the dosing was not optimal for this population given limited previous data exploring the impact of 5-HTP on fatigue and a reported rapid half-life of the medication.15Turner E.H. Loftis J.M. Blackwell A.D. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan.Pharmacol Ther. 2006; 109: 325-338Crossref PubMed Scopus (193) Google Scholar Furthermore, fatigue is difficult to measure and more objective measurements, including using innovative biomarkers or activity monitoring, would potentially be useful for assessing treatment outcomes. It is also possible that treatment with other neuroactive tryptophan pathway metabolites or targeting enzymes involved in tryptophan metabolism may be more effective alternatives for improving fatigue in patients with IBD. Despite the high prevalence of fatigue in patients with IBD and lack of known effective treatments, very few clinical trials have examined the effect of therapies on fatigue in this population. Fatigue and other centrally mediated symptoms, including depression and sleep disturbances, have a major negative impact on quality of life. These comorbidities can lead to poor performance and missed days at work or school, strain on interpersonal relationships, and exacerbations of symptoms associated with IBD. Thus, additional studies focused on identification of mechanisms and discovery of therapies treating these chronic symptoms should be a priority for the field. Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled TrialGastroenterologyVol. 163Issue 5PreviewThis multicentered study shows that oral intake of 5-hydroxytryptophan is not better than placebo in the treatment of fatigue in patients with inflammatory bowel diseases. Full-Text PDF