[en] BACKGROUND & AIMS: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD. METHODS: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling. RESULTS: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores. CONCLUSIONS: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.).
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Truyens, Marie; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium,
Lobatón, Triana; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium,
Ferrante, Marc; Department of Chronic Diseases & Metabolism (CHROMETA), Translational Research
Bossuyt, Peter; Imelda Gastrointestinal (GI) Clinical Research Center, Imelda General Hospital,
Vermeire, Séverine; Department of Chronic Diseases & Metabolism (CHROMETA), Translational Research
Pouillon, Lieven; Imelda Gastrointestinal (GI) Clinical Research Center, Imelda General Hospital,
Dewint, Pieter; Department of Gastroenterology, Algemeen Ziekenhuis (AZ) Maria Middelares, Ghent,
Cremer, Anneline; Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium.
Peeters, Harald; Department of Gastroenterology, Algemeen Ziekenhuis (AZ) St-Lucas, Ghent,
Lambrecht, Guy; Department of Gastroenterology, Algemeen Ziekenhuis (AZ) Damiaan, Ostend,
Louis, Edouard ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
Rahier, Jean-François; Department of Gastroenterology, Centre Hospitalier Universitaire (CHU) Université
FWO - Fonds Wetenschappelijk Onderzoek Vlaanderen [BE] BIRD - Belgian Inflammatory Bowel Disease Research and Development Group [BE]
Funding number :
T000617N
Funding text :
Grant support was received from The Research Foundation–Flanders (FWO) with a fund for applied biomedical research with a primary social finality, No. T000617N, and the Belgian IBD Research and Development
(BIRD) grant.
Romberg-Camps, M.J., Bol, Y., Dagnelie, P.C., et al. Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort. Inflamm Bowel Dis 16 (2010), 2137–2147.
D'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 20 (2022), 995–1009.e7.
Borren, N.Z., van der Woude, C.J., Ananthakrishnan, A.N., Fatigue in IBD: epidemiology, pathophysiology and management. Nat Rev Gastroenterol Hepatol 16 (2019), 247–259.
Radford, S.J., McGing, J., Czuber-Dochan, W., et al. Systematic review: the impact of inflammatory bowel disease-related fatigue on health-related quality of life. Frontline Gastroenterol 12 (2021), 11–21.
Hindryckx, P., Laukens, D., D'Amico, F., et al. Unmet needs in IBD: the case of fatigue. Clin Rev Allergy Immunol 55 (2018), 368–378.
Geldof, J., LeBlanc, J.-F., Lucaciu, L., et al. Are we addressing the top 10 research priorities in IBD?. Frontline Gastroenterol 12 (2020), 564–569.
McGing, J.J., Radford, S.J., Francis, S.T., et al. Review article: The aetiology of fatigue in inflammatory bowel disease and potential therapeutic management strategies. Aliment Pharmacol Ther 54 (2021), 368–387.
Bager, P., Hvas, C.L., Rud, C.L., et al. Randomised clinical trial: high-dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease. Aliment Pharmacol Ther 53 (2021), 79–86.
McNelly, A.S., Nathan, I., Monti, M., et al. The effect of increasing physical activity and/or omega-3 supplementation on fatigue in inflammatory bowel disease. Gastrointest Nurs 14 (2016), 39–50.
Banovic, I., Gilibert, D., Jebrane, A., et al. Personality and fatigue perception in a sample of IBD outpatients in remission: a preliminary study. J Crohns Colitis 6 (2012), 571–577.
Fuller-Thomson, E., Sulman, J., Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflamm Bowel Dis 12 (2006), 697–707.
Williet, N., Sarter, H., Gower-Rousseau, C., et al. Patient-reported outcomes in a French nationwide survey of inflammatory bowel disease patients. J Crohns Colitis 11 (2017), 165–174.
Lieberman, H.R., Agarwal, S., Fulgoni, V.L. 3rd, Tryptophan intake in the US adult population is not related to liver or kidney function but is associated with depression and sleep outcomes. J Nutr 146 (2016), 2609s–2615s.
Lavelle, A., Sokol, H., Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 17 (2020), 223–237.
Chen, L.-M., Bao, C.-H., Wu, Y., et al. Tryptophan-kynurenine metabolism: a link between the gut and brain for depression in inflammatory bowel disease. J Neuroinflammation 18 (2021), 1–13.
Gupta, N.K., Thaker, A.I., Kanuri, N., et al. Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity. Inflamm Bowel Dis 18 (2012), 1214–1220.
Arijs, I., Wollants, W.-J., Clarke, G., et al. P096 Analysis of the tryptophan metabolism and indoleamine 2, 3-dioxygenase expression (IDO) in patients with inflammatory bowel disease before and after infliximab treatment. J Crohns Colitis, 8, 2014 S102–S102.
Bosi, A., Banfi, D., Bistoletti, M., et al. Tryptophan metabolites along the microbiota-gut-brain axis: an interkingdom communication system influencing the gut in health and disease. Int J Tryptophan Res, 13, 2020, 1178646920928984.
Nikolaus, S., Schulte, B., Al-Massad, N., et al. Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases. Gastroenterology 153 (2017), 1504–1516.e2.
Sofia, M.A., Ciorba, M.A., Meckel, K., et al. Tryptophan metabolism through the kynurenine pathway is associated with endoscopic inflammation in ulcerative colitis. Inflamm Bowel Dis 24 (2018), 1471–1480.
Yamamoto, S., Ouchi, Y., Onoe, H., et al. Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport 15 (2004), 2571–2574.
Agus, A., Planchais, J., Sokol, H., Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23 (2018), 716–724.
Iskandar, H.N., Linan, E.E., Patel, A., et al. Self-reported sleep disturbance in Crohn's disease is not confirmed by objective sleep measures. Sci Rep, 10, 2020, 1980.
Lamas, B., Richard, M.L., Leducq, V., et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 22 (2016), 598–605.
Monteleone, I., Rizzo, A., Sarra, M., et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141 (2011), 237–248 248.e1.
Rothhammer, V., Mascanfroni, I.D., Bunse, L., et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22 (2016), 586–597.
Lieben, C.K., Blokland, A., Westerink, B., et al. Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat. Neurochem Int, 44, 2004 9–6.
Williams, W.A., Shoaf, S.E., Hommer, D., et al. Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J Neurochem 72 (1999), 1641–1647.
Pusceddu, M.M., Barboza, M., Keogh, C.E., et al. Nod-like receptors are critical for gut-brain axis signalling in mice. J Physiol 597 (2019), 5777–5797.
Ogawa, S., Fujii, T., Koga, N., et al. Plasma l-tryptophan concentration in major depressive disorder: new data and meta-analysis. J Clin Psychiatry 75 (2014), e906–e915.
Kurz, K., Fiegl, M., Holzner, B., et al. Fatigue in patients with lung cancer is related with accelerated tryptophan breakdown. PloS One, 7, 2012, e36956.
Schroecksnadel, K., Fiegl, M., Prassl, K., et al. Diminished quality of life in patients with cancer correlates with tryptophan degradation. J Cancer Res Clin Oncol 133 (2007), 477–4785.
Ormstad, H., Verkerk, R., Amthor, K.F., et al. Activation of the kynurenine pathway in the acute phase of stroke and its role in fatigue and depression following stroke. J Mol Neurosci 54 (2014), 181–187.
Borren, N.Z., Plichta, D., Joshi, A.D., et al. Alterations in fecal microbiomes and serum metabolomes of fatigued patients with quiescent inflammatory bowel diseases. Clin Gastroenterol Hepatol 19 (2021), 519–527.e5.
Turner, E.H., Loftis, J.M., Blackwell, A.D., Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther 109 (2006), 325–338.
Caruso, I., Puttini, P.S., Cazzola, M., et al. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med Res 18 (1990), 201–209.
Puttini, P.S., Caruso, I., Primary fibromyalgia syndrome and 5-hydroxy-l-tryptophan: a 90-day open study. J Int Med Res 20 (1992), 182–189.
Klusmann, B., Fleer, J., Tovote, K.A., et al. Trajectories of fatigue in inflammatory bowel disease. Inflamm Bowel Dis 27 (2021), 1919–1930.
Borren, N.Z., Tan, W., Colizzo, F.P., et al. Longitudinal trajectory of fatigue with initiation of biologic therapy in inflammatory bowel diseases: a prospective cohort study. J Crohns Colitis 14 (2020), 309–315.
Wolfe, F., Fatigue assessments in rheumatoid arthritis: comparative performance of visual analog scales and longer fatigue questionnaires in 7760 patients. J Rheumatol 31 (2004), 1896–1902.
Grimstad, T., Norheim, K.B., Isaksen, K., et al. Fatigue in newly diagnosed inflammatory bowel disease. J Crohns Colitis 9 (2015), 725–730.
Pollard, L., Choy, E., Gonzalez, J., et al. Fatigue in rheumatoid arthritis reflects pain, not disease activity. Rheumatology 45 (2006), 885–889.
Dass, S., Bowman, S.J., Vital, E.M., et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis 67 (2008), 1541–1544.
Keszthelyi, D., Troost, F., Jonkers, D., et al. Visceral hypersensitivity in irritable bowel syndrome: evidence for involvement of serotonin metabolism–a preliminary study. Neurogastroenterol Motil 27 (2015), 1127–1137.
Tinsley, A., Macklin, E.A., Korzenik, J.R., et al. Validation of the functional assessment of chronic illness therapy-fatigue (FACIT-F) in patients with inflammatory bowel disease. Aliment Pharmacol Ther 34 (2011), 1328–1336.
Lovibond, P.F., Lovibond, S.H., The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behav Res Ther 33 (1995), 335–343.
Vogelaar, L., van't Spijker, A., Timman, R., et al. Fatigue management in patients with IBD: a randomised controlled trial. Gut 63 (2014), 911–918.
Artom, M., Czuber-Dochan, W., Sturt, J., et al. Cognitive-behavioural therapy for the management of inflammatory bowel disease-fatigue: a feasibility randomised controlled trial. Pilot Feasibility Stud, 5, 2019, 145.
Barberio, B., Zamani, M., Black, C.J., et al. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 6 (2021), 359–370.
Cheema, M., Mitrev, N., Hall, L., et al. Depression, anxiety and stress among patients with inflammatory bowel disease during the COVID-19 pandemic: Australian national survey. BMJ Open Gastroenterol, 8, 2021, e000581.
Mules, T.C., Swaminathan, A., Hirschfeld, E., et al. The impact of disease activity on psychological symptoms and quality of life in patients with inflammatory bowel disease—results from the Stress, Anxiety and Depression with Disease Activity (SADD) Study. Aliment Pharmacol Ther 55 (2022), 201–211.
Keefer, L., Ballou, S.K., Drossman, D.A., et al. A Rome working team report on brain-gut behavior therapies for disorders of gut–brain interaction. Gastroenterology 162 (2022), 300–315.
Fairbrass, K.M., Gracie, D.J., Ford, A.C., Longitudinal follow-up study: effect of psychological co-morbidity on the prognosis of inflammatory bowel disease. Aliment Pharmacol Ther 54 (2021), 441–450.
Fairbrass, K.M., Lovatt, J., Barberio, B., et al. Bidirectional brain–gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis. Gut 71 (2022), 1773–1780.
Yu, H., MacIsaac, D., Wong, J.J., et al. Market share and costs of biologic therapies for inflammatory bowel disease in the USA. Aliment Pharmacol Ther 47 (2018), 364–370.
Vogelaar, L., de Haar, C., Aerts, B.R., et al. Fatigue in patients with inflammatory bowel disease is associated with distinct differences in immune parameters. Clin Exp Gastroenterol 10 (2017), 83–90.
Jangid, P., Malik, P., Singh, P., et al. Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr 6 (2013), 29–34.
Kaptchuk, T.J., Kelley, J.M., Conboy, L.A., et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336 (2008), 999–1003.
Bruera, E., Valero, V., Driver, L., et al. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 24 (2006), 2073–2078.
Gijsman, H.J., van Gerven, J.M., de Kam, M.L., et al. Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers. J Clin Psychopharmacol 22 (2002), 183–189.
Dass, S., Bowman, S.J., Vital, E.M., et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis 67 (2008), 1541–1544.
Birdsall, T.C., 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev 3 (1998), 271–280.
Arijs, I., Wollants, W.-J., Clarke, G., et al. P096 Analysis of the tryptophan metabolism and indoleamine 2, 3-dioxygenase expression (IDO) in patients with inflammatory bowel disease before and after infliximab treatment. J Crohn Colitis, 8, 2014 S102–S102.
Van Praag, H., Studies in the mechanism of action of serotonin precursors in depression. Psychopharmacol Bull 20 (1984), 599–602.
