Micronutrient Deficiency and Autophagy Dysregulation in Pulmonary Tuberculosis Pathogenesis: A Systematic Review

Authors

DOI:

https://doi.org/10.58545/jkki.v6i2.778

Abstract

Pulmonary tuberculosis remains a critical global health burden, with Indonesia ranking second in the world for the highest TB burden. Autophagy is an essential innate immune mechanism for eliminating intracellular Mycobacterium tuberculosis (Mtb) in macrophages, but it is susceptible to dysregulation by micronutrient deficiencies, which are highly prevalent in populations with active TB. This systematic review aims to synthesize scientific evidence on the effects of deficiencies in vitamin D, vitamin A, zinc, and selenium on the dysregulation of the autophagy pathway and its implications for the pathogenesis of pulmonary tuberculosis. Literature searches were performed in PubMed and ScienceDirect for studies published from 2006 to 2025, using a combination of MeSH terms and free-text keywords. A total of 11 studies were included in the final synthesis. The results of the synthesis indicate that vitamin D deficiency inhibits the transcription of autophagy genes (LC3, Beclin-1, ATG5) by disrupting VDR signaling. Combined zinc and vitamin D deficiency reduces autophagy capacity by up to 85% and correlates with worse clinical outcomes of TB. Specifically, zinc and vitamin D deficiencies act synergistically to inhibit autophagy, representing the most significant interaction. Micronutrient deficiencies were shown to dysregulate autophagy through distinct yet synergistic molecular pathways, facilitating Mtb persistence and exacerbating the pathogenesis of pulmonary TB. Micronutrient supplementation holds potential as an adjuvant host-directed therapy strategy in the management of pulmonary tuberculosis.

Keywords:

Pulmonary tuberculosis, Autophagy, Micronutrient deficiency

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Author Biographies

Salma Winda Aufa, Faculty of Medicine, Universitas Andalas, Indonesia

Public Health Doctoral Program

Delmi Sulastri, Faculty of Medicine, Universitas Andalas, Indonesia

Department of Public Health

References

Abhimanyu, Meyer, V., Jones, B. R., & Bornman, L. (2020). Autophagy efficacy and vitamin D status: Population effects. Cellular Immunology, 352, 104082. https://doi.org/10.1016/j.cellimm.2020.104082

Ahmed, A. K. K. (2026). The Zinc Paradox in Tuberculosis: A Systematic Review of Anti-Tuberculosis Drug–Induced Zinc Depletion and Its Implications for Optic Neuropathy and Visual Loss. Preprints. https://doi.org/10.20944/preprints202604.1545.v1

Amaral, E. P., Namasivayam, S., Queiroz, A. T. L., Fukutani, E., Hilligan, K. L., Aberman, K., Fisher, L., Bomfim, C. C. B., Kauffman, K., Buchanan, J., Santuo, L., Gazzinelli-Guimaraes, P. H., Costa, D. L., Teixeira, M. A., Barreto-Duarte, B., Rocha, C. G., Santana, M. F., Cordeiro-Santos, M., Barber, D. L., … Sher, A. (2023). BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility. Nature Microbiology, 9(1), 120–135. https://doi.org/10.1038/s41564-023-01523-7

Baum, M. K., Campa, A., Lai, S., Sales Martinez, S., Tsalaile, L., Burns, P., Farahani, M., Li, Y., van Widenfelt, E., Page, J. B., Bussmann, H., Fawzi, W. W., Moyo, S., Makhema, J., Thior, I., Essex, M., & Marlink, R. (2013). Effect of Micronutrient Supplementation on Disease Progression in Asymptomatic, Antiretroviral-Naive, HIV-Infected Adults in Botswana. JAMA, 310(20), 2154. https://doi.org/10.1001/jama.2013.280923

Bhargava, A., & Bhargava, M. (2020). Tuberculosis deaths are predictable and preventable: Comprehensive assessment and clinical care is the key. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 19, 100155. https://doi.org/10.1016/j.jctube.2020.100155

Campbell, G. R., & Spector, S. A. (2012). Vitamin D Inhibits Human Immunodeficiency Virus Type 1 and Mycobacterium tuberculosis Infection in Macrophages through the Induction of Autophagy. PLoS Pathogens, 8(5), e1002689. https://doi.org/10.1371/journal.ppat.1002689

Carlberg, C. (2022). Vitamin D and Its Target Genes. In Nutrients (Vol. 14, Number 7). MDPI. https://doi.org/10.3390/nu14071354

Chen, W., Liu, Z., Zheng, Y., Wei, B., Shi, J., Shao, B., & Wang, D. (2021). Selenium donor restricts the intracellular growth of Mycobacterium tuberculosis through the induction of c-Jun-mediated both canonical autophagy and LC3-associated phagocytosis of alveolar macrophages. Microbial Pathogenesis, 161, 105269. https://doi.org/10.1016/j.micpath.2021.105269

Coleman, M. M., Basdeo, S. A., Coleman, A. M., Cheallaigh, C. N., Peral de Castro, C., McLaughlin, A. M., Dunne, P. J., Harris, J., & Keane, J. (2018). All-trans Retinoic Acid Augments Autophagy during Intracellular Bacterial Infection. American Journal of Respiratory Cell and Molecular Biology, 59(5), 548–556. https://doi.org/10.1165/rcmb.2017-0382OC

Deretic, V., Saitoh, T., & Akira, S. (2013). Autophagy in infection, inflammation and immunity. Nature Reviews Immunology, 13(10), 722–737. https://doi.org/10.1038/nri3532

Dow, A., Sule, P., O’Donnell, T. J., Burger, A., Mattila, J. T., Antonio, B., Vergara, K., Marcantonio, E., Adams, L. G., James, N., Williams, P. G., Cirillo, J. D., & Prisic, S. (2021). Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis. PLOS Pathogens, 17(5), e1009570. https://doi.org/10.1371/journal.ppat.1009570

Feleke, B. E., Feleke, T. E., Mekonnen, D., & Beyene, M. B. (2019). Micronutrient levels of tuberculosis patients during the intensive phase, a prospective cohort study. Clinical Nutrition ESPEN, 31, 56–60. https://doi.org/10.1016/j.clnesp.2019.03.001

Grobler, L., Nagpal, S., Sudarsanam, T. D., & Sinclair, D. (2016). Nutritional supplements for people being treated for active tuberculosis. Cochrane Database of Systematic Reviews, 2016(6). https://doi.org/10.1002/14651858.CD006086.pub4

Keflie, T. S., & Biesalski, H. K. (2021). Micronutrients and bioactive substances: Their potential roles in combating COVID-19. Nutrition, 84, 111103. https://doi.org/10.1016/j.nut.2020.111103

Kim, E. W., De Leon, A., Jiang, Z., Radu, R. A., Martineau, A. R., Chan, E. D., Bai, X., Su, W.-L., Montoya, D. J., Modlin, R. L., & Liu, P. T. (2019). Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis. mSphere, 4(3). https://doi.org/10.1128/mSphere.00327-19

Kumar, S., Nanduri, R., Bhagyaraj, E., Kalra, R., Ahuja, N., Chacko, A. P., Tiwari, D., Sethi, K., Saini, A., Chandra, V., Jain, M., Gupta, S., Bhatt, D., & Gupta, P. (2021). Vitamin D3-VDR-PTPN6 axis mediated autophagy contributes to the inhibition of macrophage foam cell formation. Autophagy, 17(9), 2273–2289. https://doi.org/10.1080/15548627.2020.1822088

Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa, M. T., Schauber, J., Wu, K., Meinken, C., Kamen, D. L., Wagner, M., Bals, R., Steinmeyer, A., Zügel, U., Gallo, R. L., Eisenberg, D., Hewison, M., Hollis, B. W., … Modlin, R. L. (2006). Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response. Science, 311(5768), 1770–1773. https://doi.org/10.1126/science.1123933

Liuzzi, J. P., Guo, L., Yoo, C., & Stewart, T. S. (2014). Zinc and autophagy. BioMetals, 27(6), 1087–1096. https://doi.org/10.1007/s10534-014-9773-0

Marcantonio, E., Burger, A. D., Chang, K. H., Hoffmann, F. W., Fu, Y., Khadka, V. S., Smagghe, B. J., Deng, Y., Hoffmann, P. R., & Prisic, S. (2025). Zinc-limited Mycobacterium tuberculosis stimulate distinct responses in macrophages compared with standard zinc-replete bacteria. Infection and Immunity, 93(3). https://doi.org/10.1128/iai.00578-24

Martineau, A. R., Timms, P. M., Bothamley, G. H., Hanifa, Y., Islam, K., Claxton, A. P., Packe, G. E., Moore-Gillon, J. C., Darmalingam, M., Davidson, R. N., Milburn, H. J., Baker, L. V, Barker, R. D., Woodward, N. J., Venton, T. R., Barnes, K. E., Mullett, C. J., Coussens, A. K., Rutterford, C. M., … Griffiths, C. J. (2011). High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. The Lancet, 377(9761), 242–250. https://doi.org/10.1016/S0140-6736(10)61889-2

Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, n71. https://doi.org/10.1136/bmj.n71

Paik, S., Kim, J. K., Chung, C., & Jo, E.-K. (2019). Autophagy: A new strategy for host-directed therapy of tuberculosis. Virulence, 10(1), 448–459. https://doi.org/10.1080/21505594.2018.1536598

Panda, S., Tiwari, A., Luthra, K., Sharma, S. K., & Singh, A. (2019). Association of Fok1 VDR polymorphism with Vitamin D and its associated molecules in pulmonary tuberculosis patients and their household contacts. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-51803-8

Pellegrini, J. M., Tateosian, N. L., Morelli, M. P., & García, V. E. (2022). Shedding Light on Autophagy During Human Tuberculosis. A Long Way to Go. In Frontiers in Cellular and Infection Microbiology (Vol. 11). Frontiers Media S.A. https://doi.org/10.3389/fcimb.2021.820095

Rathored, J., Sharma, S. K., Chauhan, A., Singh, B., Banavaliker, J. N., Sreenivas, V., & Srivastava, A. K. (2023). Low serum vitamin D in North Indian multi-drug resistant pulmonary tuberculosis patients: the role of diet and sunlight. Annals of Medicine, 55(2). https://doi.org/10.1080/07853890.2023.2291554

Tang, J., Gu, L., Luo, J., Luo, H., Zeng, Q., & Jiang, Y. (2022). 1,25(OH)2D3 promotes the elimination of Klebsiella pneumoniae infection by inducing autophagy through the VDR-ATG16L1 pathway. International Immunopharmacology, 112, 109266. https://doi.org/10.1016/j.intimp.2022.109266

Verway, M., Bouttier, M., Wang, T.-T., Carrier, M., Calderon, M., An, B.-S., Devemy, E., McIntosh, F., Divangahi, M., Behr, M. A., & White, J. H. (2013). Vitamin D Induces Interleukin-1β Expression: Paracrine Macrophage Epithelial Signaling Controls M. tuberculosis Infection. PLoS Pathogens, 9(6), e1003407. https://doi.org/10.1371/journal.ppat.1003407

Wagnew, F., Alene, K. A., Eshetie, S., Wingfield, T., Kelly, M., & Gray, D. (2022). Effects of zinc and vitamin A supplementation on prognostic markers and treatment outcomes of adults with pulmonary tuberculosis: a systematic review and meta-analysis. BMJ Global Health, 7(9), e008625. https://doi.org/10.1136/bmjgh-2022-008625

Wang, F., Sun, N., Zeng, H., Gao, Y., Zhang, N., & Zhang, W. (2022). Selenium Deficiency Leads to Inflammation, Autophagy, Endoplasmic Reticulum Stress, Apoptosis and Contraction Abnormalities via Affecting Intestinal Flora in Intestinal Smooth Muscle of Mice. Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.947655

Xu, J., Gong, Y., Sun, Y., Cai, J., Liu, Q., Bao, J., Yang, J., & Zhang, Z. (2020). Impact of Selenium Deficiency on Inflammation, Oxidative Stress, and Phagocytosis in Mouse Macrophages. Biological Trace Element Research, 194(1), 237–243. https://doi.org/10.1007/s12011-019-01775-7

Zheng, Z., Xie, J., Ma, L., Hao, Z., Zhang, W., & Li, L. (2023). Vitamin D Receptor Activation Targets ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Hepatocytes in Cholestasic Mice. Cellular and Molecular Gastroenterology and Hepatology, 15(4), 887–901. https://doi.org/10.1016/j.jcmgh.2022.10.011

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Published

05-08-2026

How to Cite

Aufa, S. W., & Sulastri, D. (2026). Micronutrient Deficiency and Autophagy Dysregulation in Pulmonary Tuberculosis Pathogenesis: A Systematic Review. Jurnal Kesehatan Komunitas Indonesia, 6(2), 412–429. https://doi.org/10.58545/jkki.v6i2.778

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