Tryptophan Metabolism in Obesity: Pathways, Mechanisms, and Therapeutic Perspectives

Abstract

Obesity is a common noncommunicable disease characterized by persistent low-grade chronic inflammation and is associated with various metabolic disturbances, including insulin resistance and diabetes. The search for effective obesity treatments has led to growing interest in the role of amino acids in metabolic regulation. Tryptophan (TRP), an essential amino acid, participates in several biological pathways, including the kynurenine, 5-hydroxytryptamine (5-HT, also known as serotonin), and indole pathways. Recent evidence underscores the significance of TRP metabolism in obesity, showing that various metabolites and enzymes in its metabolic pathways are altered in individuals with obesity. These changes influence physiological processes, mood regulation, and overall metabolic health. This review provides a comprehensive overview of TRP metabolism. It highlights the potential of targeting TRP metabolism as a therapeutic strategy for managing obesity and its related metabolic and psychological comorbidities.

Keywords

Obesity / Tryptophan metabolism / Kynurenine pathway / 5-Hydroxytryptamine pathway (Serotonin) / Indole pathway / Gut microbiota / Inflammation / Therapeutic target

References

[1] Lin X, Li H. Obesity: epidemiology, pathophysiology, and therapeutics. Front Endocrinol., 2021, 12 706978

[2] Hruby A, Hu FB. The epidemiology of obesity: a big picture. PharmacoEconomics., 2015, 33(7): 673-689

[3] Cussotto S, Delgado I, Anesi A, et al.. Tryptophan metabolic pathways are altered in obesity and are associated with systemic inflammation. Front Immunol., 2020, 11: 557

[4] Sorgdrager FJH, Naudé PJW, Kema IP, et al.. Tryptophan metabolism in inflammaging: from biomarker to therapeutic target. Front Immunol., 2019, 10: 2565

[5] Zhao J, Bai X, Du J, et al.. Tryptophan metabolism: From physiological functions to key roles and therapeutic targets in cancer (Review). Oncol Rep., 2025, 54(1): 86

[6] Favennec M, Hennart B, Caiazzo R, et al.. The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity (Silver Spring)., 2015, 23(102066-2074

[7] Yan J, Chen D, Ye Z, et al.. Molecular mechanisms and therapeutic significance of Tryptophan Metabolism and signaling in cancer. Mol Cancer., 2024, 23(1241

[8] Farup PG, Hamarsland H, Mølmen KS, et al.. The kynurenine pathway in healthy subjects and subjects with obesity, depression and chronic obstructive pulmonary disease. Pharmaceuticals (Basel)., 2023, 16(3351

[9] Luo Z, Liu Y, Wang X, et al.. Exploring tryptophan metabolism: The transition from disturbed balance to diagnostic and therapeutic potential in metabolic diseases. Biochem Pharmacol., 2024, 230(Pt 1 116554

[10] Badawy AA. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int J Tryptophan Res., 2017, 10: 1178646917691938

[11] Kubacka J, Staniszewska M, Sadok I, et al.. The kynurenine pathway in obese middle-aged women with normoglycemia and type 2 diabetes. Metabolites., 2022, 12(6492

[12] Wolowczuk I, Hennart B, Leloire A, et al.. Tryptophan metabolism activation by indoleamine 2, 3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone. Am J Physiol Regul Integr Comp Physiol., 2012, 303(2R135-R143

[13] Tsuji A, Ikeda Y, Yoshikawa S, et al.. The tryptophan and kynurenine pathway involved in the development of immune-related diseases. Int J Mol Sci., 2023, 24(65742

[14] Nunzi E, Pariano M, Costantini C, et al.. Host-microbe serotonin metabolism. Trends Endocrinol Metab., 2025, 36(183-95

[15] Tanaka M, Szabó Á, Vécsei L. Redefining roles: a paradigm shift in tryptophan-kynurenine metabolism for innovative clinical applications. Int J Mol Sci., 2024, 25(23): 12767

[16] Christensen MHE, Fadnes DJ, Røst TH, et al.. Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery. PLoS One., 2018, 13(2 e0192169

[17] Gao J, Yang T, Song B, et al.. Abnormal tryptophan catabolism in diabetes mellitus and its complications: Opportunities and challenges. Biomedecine Pharmacother., 2023, 166 115395

[18] Gao K, Mu CL, Farzi A, et al.. Tryptophan metabolism: a link between the gut microbiota and brain. Adv Nutr., 2020, 11(3709-723

[19] Martin-Gallausiaux C, Larraufie P, Jarry A, et al.. Butyrate produced by commensal bacteria down-regulates indolamine 2, 3-dioxygenase 1 (IDO-1) expression via a dual mechanism in human intestinal epithelial cells. Front Immunol., 2018, 9: 2838

[20] Liu M, Nieuwdorp M, de Vos WM, et al.. Microbial tryptophan metabolism tunes host immunity, metabolism, and extraintestinal disorders. Metabolites., 2022, 12(9): 834

[21] Meléndez-Oliva E, Martínez-Pozas O, Sinatti P, et al.. Relationship between the gut microbiome, tryptophan-derived metabolites, and osteoarthritis-related pain: a systematic review with meta-analysis. Nutrients., 2025, 17(2264

[22] Sánchez Romero EA, Meléndez Oliva E, Alonso Pérez JL, et al.. Relationship between the gut microbiome and osteoarthritis pain: review of the literature. Nutrients., 2021, 13(3716

[23] Mangge H, Summers KL, Meinitzer A, et al.. Obesity-related dysregulation of the tryptophan-kynurenine metabolism: role of age and parameters of the metabolic syndrome. Obesity (Silver Spring)., 2014, 22(1195-201

[24] Theofylaktopoulou D, Midttun Ø, Ulvik A, et al.. A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study. Clin Exp Immunol., 2013, 173(1121-130

[25] Moore SC, Matthews CE, Sampson JN, et al.. Human metabolic correlates of body mass index. Metabolomics., 2014, 10(2): 259-269

[26] Perng W, Gillman MW, Fleisch AF, et al.. Metabolomic profiles and childhood obesity. Obesity (Silver Spring)., 2014, 22(12): 2570-2578

[27] Huang T, Song J, Gao J, et al.. Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling. Nat Commun., 2022, 13(1): 3489

[28] Laurans L, Venteclef N, Haddad Y, et al.. Genetic deficiency of indoleamine 2, 3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat Med., 2018, 24(81113-1120

[29] Lischka J, Schanzer A, Baumgartner M, et al.. Tryptophan metabolism is associated with BMI and adipose tissue mass and linked to metabolic disease in pediatric obesity. Nutrients., 2022, 14(2): 286

[30] Yeung KTD, Penney N, Whiley L, et al.. The impact of bariatric surgery on serum tryptophan-kynurenine pathway metabolites. Sci Rep., 2022, 12(1294

[31] Tan KM, Tint MT, Kothandaraman N, et al.. The kynurenine pathway metabolites in cord blood positively correlate with early childhood adiposity. J Clin Endocrinol Metab., 2022, 107(6e2464-e2473

[32] Murphy MC, Mosler AB, Rio EK, et al.. Can quantitative sensory testing predict treatment outcomes in hip and knee osteoarthritis A systematic review and meta-analysis of individual participant data. Pain., 2025, 166(10): 2261-2280

[33] Liu XG. Normalization of neuroinflammation: a new strategy for treatment of persistent pain and memory/emotional deficits in chronic pain. J Inflamm Res., 2022, 15: 5201-5233

[34] Höglund E, Øverli Ø, Winberg S. Tryptophan metabolic pathways and brain serotonergic activity: a comparative review. Front Endocrinol., 2019, 10: 158

[35] Some M, Helander A. Urinary excretion patterns of 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol in various animal species: implications for studies on serotonin metabolism and turnover rate. Life Sci., 2002, 71(20): 2341-2349

[36] Xue C, Li G, Zheng Q, et al.. Tryptophan metabolism in health and disease. Cell Metab., 2023, 35(81304-1326

[37] Li G, Dong S, Liu C, et al.. Serotonin signaling to regulate energy metabolism: a gut microbiota perspective. Life Metab., 2025, 4(2): loae039

[38] Yabut JM, Crane JD, Green AE, et al.. Emerging roles for serotonin in regulating metabolism: new implications for an ancient molecule. Endocr Rev., 2019, 40(41092-1107

[39] Yano JM, Yu K, Donaldson GP, et al.. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell., 2015, 161(2): 264-276

[40] Reigstad CS, Salmonson CE, Iii JFR, et al.. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J., 2015, 29(4): 1395-1403

[41] Xiao L, Yan J, Yang T, et al.. Fecal microbiome transplantation from children with autism spectrum disorder modulates tryptophan and serotonergic synapse metabolism and induces altered behaviors in germ-free mice. mSystems., 2021, 6(2): e01343–20

[42] Sjögren K, Engdahl C, Henning P, et al.. The gut microbiota regulates bone mass in mice. J Bone Miner Res., 2012, 27(61357-1367

[43] Hartstra AV, Schüppel V, Imangaliyev S, et al.. Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome. Mol Metab., 2020, 42 101076

[44] Hata T, Asano Y, Yoshihara K, et al.. Regulation of gut luminal serotonin by commensal microbiota in mice. PLoS One., 2017, 12(7 e0180745

[45] Liu B, Fan L, Wang Y, et al.. Gut microbiota regulates host melatonin production through epithelial cell MyD88. Gut Microbes., 2024, 16(1): 2313769

[46] Ahmadi S, Taghizadieh M, Mehdizadehfar E, et al.. Gut microbiota in neurological diseases: Melatonin plays an important regulatory role. Biomedecine Pharmacother., 2024, 174 116487

[47] Breum L, Rasmussen MH, Hilsted J, et al.. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr., 2003, 77(51112-1118

[48] Groer M, Fuchs D, Duffy A, et al.. Associations among obesity, inflammation, and tryptophan catabolism in pregnancy. Biol Res Nurs., 2018, 20(3): 284-291

[49] Crane JD, Palanivel R, Mottillo EP, et al.. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med., 2015, 21(2): 166-172

[50] Young RL, Lumsden AL, Keating DJ. Gut serotonin is a regulator of obesity and metabolism. Gastroenterology., 2015, 149(1): 253-255

[51] Oh CM, Namkung J, Go Y, et al.. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat Commun., 2015, 6: 6794

[52] Shong KE, Oh CM, Namkung J, et al.. Serotonin regulates de novo lipogenesis in adipose tissues through serotonin receptor 2A. Endocrinol Metab (Seoul)., 2020, 35(2): 470-479

[53] Pagire SH, Pagire HS, Park KY, et al.. Identification of new non-BBB permeable tryptophan hydroxylase inhibitors for treating obesity and fatty liver disease. Molecules., 2022, 27(113417

[54] Son JV, Koekkoek LL, La Fleur SE, et al.. The role of the gut microbiota in the gut-brain axis in obesity: mechanisms and future implications. Int J Mol Sci., 2021, 22(62993

[55] Simansky KJ. Serotonergic control of the organization of feeding and satiety. Behav Brain Res., 1995, 73(1–237-42

[56] Liu H, Wang C, Yu M, et al.. TPH2 in the dorsal raphe nuclei regulates energy balance in a sex-dependent manner. Endocrinology., 2021, 162(1): bqaa183

[57] Breisch ST, Zemlan FP, Hoebel BG. Hyperphagia and obesity following serotonin depletion by intraventricularp-chlorophenylalanine. Science., 1976, 192(4237382-385

[58] Oh CM, Park S, Kim H. Serotonin as a new therapeutic target for diabetes mellitus and obesity. Diabetes Metab J., 2016, 40(2): 89-98

[59] Feijó FDEM, Bertoluci MC, Reis C. Serotonin and hypothalamic control of hunger: a review. Rev Assoc Med Bras (1992)., 2011, 57(1): 74-77

[60] Nonogaki K. The regulatory role of the central and peripheral serotonin network on feeding signals in metabolic diseases. Int J Mol Sci., 2022, 23(3): 1600

[61] Conde K, Fang S, Xu Y. Unraveling the serotonin Saga: from discovery to weight regulation and beyond - a comprehensive scientific review. Cell Biosci., 2023, 13(1143

[62] Melhem NJ, Taleb S. Tryptophan: from diet to cardiovascular diseases. Int J Mol Sci., 2021, 22(189904

[63] Virtue AT, McCright SJ, Wright JM, et al.. The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs. Sci Transl Med., 2019, 11(496eaav1892

[64] Natividad JM, Agus A, Planchais J, et al.. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab., 2018, 28(5737-749.e4

[65] Jennis M, Cavanaugh CR, Leo GC, et al.. Microbiota-derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo. Neurogastroenterol Motil., 2018, 30(2 e13178

[66] Knudsen C, Neyrinck AM, Leyrolle Q, et al.. Hepatoprotective effects of indole, a gut microbial metabolite, in leptin-deficient obese mice. J Nutr., 2021, 151(6): 1507-1516

[67] Postal BG, Ghezzal S, Aguanno D, et al.. AhR activation defends gut barrier integrity against damage occurring in obesity. Mol Metab., 2020, 39 101007

[68] Saponara E, Chen R, Reding T, et al.. Single or combined ablation of peripheral serotonin and p21 limit adipose tissue expansion and metabolic alterations in early adulthood in mice fed a normocaloric diet. PLoS One., 2021, 16(8 e0255687

[69] Guan Q, Wang Z, Cao J, et al.. Mechanisms of melatonin in obesity: a review. Int J Mol Sci., 2021, 23(1): 218

[70] Modoux M, Rolhion N, Mani S, et al.. Tryptophan metabolism as a pharmacological target. Trends Pharmacol Sci., 2021, 42(160-73

[71] Mondanelli G, Albini E, Orecchini E, et al.. Pathogenetic interplay between IL-6 and tryptophan metabolism in an experimental model of obesity. Front Immunol., 2021, 12 713989

[72] Betari N, Sahlholm K, Morató X, et al.. Inhibition of tryptophan hydroxylases and monoamine oxidase-a by the proton pump inhibitor, omeprazole-In vitro and in vivo investigations. Front Pharmacol., 2020, 11 593416

[73] Kenney LL, Chiu RS, Dutra MN, et al.. mRNA-delivery of IDO1 suppresses T cell-mediated autoimmunity. Cell Rep Med., 2024, 5(9 101717

[74] Kenski JCN, Huang X, Vredevoogd DW, et al.. An adverse tumor-protective effect of IDO1 inhibition. Cell Rep Med., 2023, 4(2 100941

[75] Kim CS, Jung S, Hwang GS, et al.. Gut microbiota indole-3-propionic acid mediates neuroprotective effect of probiotic consumption in healthy elderly: a randomized, double-blind, placebo-controlled, multicenter trial and in vitro study. Clin Nutr., 2023, 42(6): 1025-1033

[76] Strasser B, Berger K, Fuchs D. Effects of a caloric restriction weight loss diet on tryptophan metabolism and inflammatory biomarkers in overweight adults. Eur J Nutr., 2015, 54(1): 101-107

[77] Li D, Yu S, Long Y, et al.. Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders. Front Immunol., 2022, 13 985378

[78] Fernández-Carnero S, Martínez-Pozas O, Pecos-Martín D, et al.. Update on the detection of frailty in older adults: a multicenter cohort machine learning-based study protocol. Aging., 2025, 17(5): 1328-1339

[79] Shimi G, Sohouli MH, Ghorbani A, et al.. Correction: The interplay between obesity, immunosenescence, and insulin resistance. Immun Ageing., 2024, 21(131

[80] Usategui A, López A, Municio C, et al.. Role of tryptophan metabolism on senescent synovial fibroblasts. J Immunol., 2020, 204(1_Supplement79.14

[81] Kondrikov D, Elmansi A, Bragg RT, et al.. Kynurenine inhibits autophagy and promotes senescence in aged bone marrow mesenchymal stem cells through the aryl hydrocarbon receptor pathway. Exp Gerontol., 2020, 130 110805

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology