The Role of Gut Microbiota-derived Tryptophan Metabolites in Mycobacterium tuberculosis Infection: A Mini-Review

Novi Maulina, Zinatul Hayati, Kartini Hasballah, Zulkarnain Zulkarnain, Baidillah Zulkifli


The gut microbiota has a major contribution in human physiology and influences disease pathogenesis, including in tuberculosis (TB) lung infection. Gut-lung axis has demonstrated the interplay of these two organs, mediated by metabolites produced by the gut microbes or derived from host molecules transformation. Tryptophan (Trp) is one of the essential aromatic amino acids catabolized as kynurenine, serotonin (5-hydroxytryptamine), and indole derivatives, including indole propionic acid (IPA), via 3 pathways. The latter was microbiota-derived Trp catabolism, which has known to have an immunomodulatory role, as ligands for Aryl hydrocarbon Receptor (AhR). Intriguingly, Mycobacterium tuberculosis required Trp as a nitrogen source, especially in CD4+ T cells-generated stress, to survive in the phagosome of macrophage and to cause disease. Recently, IPA is identified as a new anti-mycobacterial compound, which is specific and has broad spectrum of anti-mycobacterial activity. The structural similarity of this gut microbiota-derived metabolite and Trp allows IPA to inhibit the TrpE anthranilate synthase in Trp biosynthesis pathway in Mtb. In this review, we summarize findings from recent work by focusing on the role of Trp metabolites in host cells in TB infection.  A better understanding of this chemical signal could potentially serve as a novel strategy for managing this chronic inflammatory disease.


Tryptophan; Indole; Kynurenine; Tuberculosis

Full Text:



Agus, A., Planchais, J. and Sokol, H. (2018) ‘Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease’, Cell Host and Microbe, 23(6), pp. 716–724. doi: 10.1016/j.chom.2018.05.003.

Albors-Vaquer, A. et al. (2020) ‘Active and prospective latent tuberculosis are associated with different metabolomic profiles: clinical potential for the identification of rapid and non-invasive biomarkers’, Emerging Microbes and Infections, 9(1), pp. 1131–1139. doi: 10.1080/22221751.2020.1760734.

Badawy, A. A. B. (2017) ‘Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects’, International Journal of Tryptophan Research, 10(1). doi: 10.1177/1178646917691938.

Borah, K. et al. (2019) ‘Intracellular Mycobacterium tuberculosis Exploits Multiple Host Nitrogen Sources during Growth in Human Macrophages’, Cell Reports, 29(11), pp. 3580-3591.e4. doi: 10.1016/j.celrep.2019.11.037.

Bussi, C. and Gutierrez, M. G. (2019) ‘Mycobacterium tuberculosis infection of host cells in space and time’, FEMS Microbiology Reviews, 43(4), pp. 341–361. doi: 10.1093/femsre/fuz006.

Clardy, Jon; Fischbach, Michael A; Currie, C. R. (2009) ‘The Natural History of Antibiotics’, Current Biology, 19(11), pp. 437–441.

Dodd, Dylan; Spitzer, Matthew H; Van Treyren, William, et al. (2017) ‘A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites’, Nature, 551, pp. 648–652.

Fernstrom, J. D. (2016) ‘A perspective on the safety of supplemental tryptophan based on its metabolic fates’, Journal of Nutrition, 146(12), pp. 2601S-2608S. doi: 10.3945/jn.115.228643.

Gautam, U. S. et al. (2018) ‘In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis’, Proceedings of the National Academy of Sciences of the United States of America, 115(1), pp. E62–E71. doi: 10.1073/pnas.1711373114.

Gopal, P. et al. (2020) ‘Pyrazinamide triggers degradation of its target aspartate decarboxylase’, Nature Communications, 11(1), pp. 1–10. doi: 10.1038/s41467-020-15516-1.

Gouzy, A. P. Y. N. O. (2014) ‘Nitrogen metabolism in Mycobacterium tuberculosis physiology and virulence’, Nature Reviews Microbiology, 12, pp. 729–737. Available at:

Gutiérrez-Vázquez, C. and Quintana, F. J. (2018) ‘Regulation of the Immune Response by the Aryl Hydrocarbon Receptor’, Immunity, 48(1), pp. 19–33. doi: 10.1016/j.immuni.2017.12.012.

JM;, Bashiri G.; Johnston; Evans GL, et al. (2015) ‘Structure and inhibition of subunit I of the anthranilate synthase complex of Mycobacterium tuberculosis and expression of the active complex’, in Acta Crystallographica, pp. 2297–2308.

Jones, L. A. et al. (2020) ‘The ever-changing roles of serotonin’, International Journal of Biochemistry and Cell Biology, 125(November 2019), p. 105776. doi: 10.1016/j.biocel.2020.105776.

Kanova, M. and Kohout, P. (2021) ‘Tryptophan: A unique role in the critically ill’, International Journal of Molecular Sciences, 22(21), pp. 1–21. doi: 10.3390/ijms222111714.

Konopelski, Piotr; Ufnal, M. (2018) ‘Indoles - Gut Bacteria Metabolites of Tryptophan with Pharmacotherapeutic Potential’, Current Drug Metabolism, 19(10), pp. 883–890.

Melhem, N. J., and Taleb, S. (2021) ‘Tryptophan: From diet to cardiovascular diseases’, International Journal of Molecular Sciences, 22(18). doi: 10.3390/ijms22189904.

Mwadumba, Henry C; Russel, David G; Nyirenda, H Mukanthu, et al. (2004) ‘Mycobacterium tuberculosis Resides in Nonacidi{ed Vacuoles in Endocytically Competent Alveolar Macrophages from Patients with Tuberculosis and HIV Infection’, Journal of Immunology, 172(7), pp. 4592–4598.

Negatu, DA; Yamada, Yoshiyuki; Xi, Yu, et al. (2019) ‘Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in Mycobacterium tuberculosis’, 10(2), pp. 1–15.

Negatu, D. A. et al. (2020) ‘crossm Whole-Cell Screen of Fragment Library Identifies Gut’, International Journal of Molecular Sciences, 22(18), pp. 1–21. doi: 10.3390/ijms222111714.

Nicolas, G. R. and Chang, P. V. (2019) ‘Deciphering the Chemical Lexicon of Host–Gut Microbiota Interactions’, Trends in Pharmacological Sciences, 40(6), pp. 430–445. doi: 10.1016/

Padayatchi, N. et al. (2019) ‘Tuberculosis: treatment failure, or failure to treat? Lessons from India and South Africa’, BMJ Global Health, 4(1), p. e001097. doi: 10.1136/bmjgh-2018-001097.

Pappolla, M. A. et al. (2021) ‘Indoles as essential mediators in the gut-brain axis. Their role in Alzheimer’s disease’, Neurobiology of Disease, 156(May), p. 105403. doi: 10.1016/j.nbd.2021.105403.

Parish, T. (2003) ‘Starvation Survival Response of Mycobacterium tuberculosis’, Journal of Bacteriology, 185(22), pp. 6702–6706. doi: 10.1128/JB.185.22.6702-6706.2003.

Parker, E. (2017) The Handbook of Microbial Metabolism of Amino Acids.

Parthasarathy, A. et al. (2018) ‘A Three-Ring circus: Metabolism of the three proteogenic aromatic amino acids and their role in the health of plants and animals’, Frontiers in Molecular Biosciences, 5(APR), pp. 1–30. doi: 10.3389/fmolb.2018.00029.

Peng, K. and Monack, D. M. (2010) ‘Indoleamine 2,3-dioxygenase 1 is a lung-specific innate immune defense mechanism that inhibits growth of Francisella tularensis tryptophan auxotrophs’, Infection and Immunity, 78(6), pp. 2723–2733. doi: 10.1128/IAI.00008-10.

Ren, Z. et al. (2019) ‘Nutritional intakes and associated factors among tuberculosis patients: A cross-sectional study in China’, BMC Infectious Diseases, 19(1), pp. 1–8. doi: 10.1186/s12879-019-4481-6.

Roager, H. M. and Licht, T. R. (2018) ‘Microbial tryptophan catabolites in health and disease’, Nature Communications, 9(1), pp. 1–10. doi: 10.1038/s41467-018-05470-4.

Rothhammer, Veit; Mascanfroni, Ivan D; Bunse, L. et al. (2016) ‘Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor’, Nature Medicine, 22, pp. 586–597.

Shaun Lott, J. (2020) ‘The tryptophan biosynthetic pathway is essential for Mycobacterium tuberculosis to cause disease’, Biochemical Society Transactions, 48(5), pp. 2029–2037. doi: 10.1042/BST20200194.

Shin, Ji Hyun; Yang, Ji-Young; Jeon, Bo-Yong, et al. (2011) ‘1H NMR-based Metabolomic Profiling in Mice Infected with Mycobacterium tuberculosis’, Journal of Proteome Research, 10(5), pp. 2238–2247.

Suzuki, Y. ; Miwa, S. ; Akamatsu, T. (2013) ‘Indoleamine 2,3-dioxygenase in the pathogenesis of tuberculous pleurisy’, The International Journal of Tuberculosis and Lung Disease, 17(11), pp. 1501–1506.

Suzuki, Y. et al. (2012) ‘Serum indoleamine 2,3-dioxygenase activity predicts prognosis of pulmonary tuberculosis’, Clinical and Vaccine Immunology, 19(3), pp. 436–442. doi: 10.1128/CVI.05402-11.

Weiner, J. et al. (2018) ‘Metabolite changes in blood predict the onset of tuberculosis’, Nature Communications, 9(1), pp. 1–12. doi: 10.1038/s41467-018-07635-7.

Wellington, S; Nag, Partha P; Mischalka, Karolina, et al. (2017) ‘A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase’, Nature Chemical Biology, 12, pp. 943–950.

WHO (2021) ‘Global Tuberculosis Report 2021’, in WHO (ed.) Global Tuberculosis Report, pp. 15–25.

Wikoff, W. R. et al. (2009) ‘Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites’, Proceedings of the National Academy of Sciences of the United States of America, 106(10), pp. 3698–3703. doi: 10.1073/pnas.0812874106.

Yisireyili, M. et al. (2017) ‘Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells’, Nagoya Journal of Medical Science, 79(4), pp. 477–486. doi: 10.18999/nagjms.79.4.477.

Zelante, Teresa; Fallarino, Francesco; Paolo, Bistoni, et al. (2009) ‘Indoleamine 2,3-dioxygenase in infection: the paradox of an evasive strategy that benefits the host’, Microbes and Infection, 11(1), pp. 133–141.

Zhang, Y. J. et al. (2013) ‘XTryptophan biosynthesis protects mycobacteria from CD4 T-Cell-mediated Killing’, Cell, 155(6), pp. 1296–1308. doi: 10.1016/j.cell.2013.10.045.


Article Metrics

Abstract view : 0 times
PDF - 0 times


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

 Indexed in: 

Copyright© 2016 | ISSN: 2503-4715 

Published by: 
The Faculty of Veterinary Medicine of Syiah Kuala University
In cooperation with: 
Center for Tropical Veterinary Studies of Syiah Kuala University
and Indonesian Veterinary Medical Association (PDHI)

Online Submissions & Guidelines Editorial Policies Contact |  Statistics  

Creative Commons License
is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.