We read with great interest the article by Soh et al. (1) regarding the associations of dietary intakes of antioxidant vitamins and carotenoids with the risk of developing active tuberculosis (TB). Through administration of a 165-item semiquantitative food frequency questionnaire and prospective tracking of a very sizable cohort through the Singaporean national TB notification registry, the investigators showed a consistent reduction in TB risk associated with higher dietary intakes of vitamin A and its precursor, β-carotene. A higher dietary intake of vitamin C was also associated with a lower risk of TB among current smokers (1). Oxidative stress has increasingly been shown to be related to bacterial persistence and phenotypic tolerance to antibiotics (2). Recent evidence has also highlighted the importance of toxin-antitoxin genes as possible contributors to such phenomena in Mycobacterium tuberculosis (3). The mycobacterial persisters probably have a central role in the propensity for reactivation of TB (disease) from latent infection due to M. tuberculosis (4). Such a scenario would be of particular concern in some populations, notably persons with diabetes mellitus (5) or human immunodeficiency virus infection (6), culminating in a higher risk of reactivated TB in latently infected subjects and suboptimal outcomes of treatment of TB in patients with these specific comorbid conditions. Vitamins C and E have been amply shown to have antioxidative capacity (7–9), and the capacity of the former has been quite appropriately echoed by the findings of this present study (1). Although the antioxidative effect of vitamin A has been shown in some studies, its role as an antioxidant is not unequivocal (10–12); indeed, the ability of this vitamin to induce oxidative stress has also been shown in rat models (13, 14). In an investigation in which researchers addressed the associations of fruit and vegetable consumption (and related vitamins) with inflammatory and oxidative stress markers in prediabetic subjects, significant associations were found with fruits and vegetables and with vitamins C and E but not specifically with provitamin A carotenoids (15). This might beg the question whether there are other constituent micronutrients in fruits and vegetables that at least partially account for the putative antioxidative capacity of vitamin A. Alternatively, can vitamin A have other mechanisms underlying its protective role regarding reactivation of TB? The immune modulation of retinoic acid, a metabolite of vitamin A, might also appear different in the steady and inflammatory states (16). On the other hand, vitamin D has consistently offered a biologically plausible mechanism for the amelioration of TB reactivation from latent infection due to M. tuberculosis based on epidemiologic data and laboratory findings. Activation and modulation of the cell-mediated immunity of the host and antimicrobial activity of the peptide cathelicidin are likely involved in the protection (17–22). As acknowledged in the epidemiologic investigation by Soh et al., the role of vitamin D in preventing TB reactivation cannot be adequately assessed just by measuring the dietary intake of that vitamin, especially in a tropical area. Because of the inherent difficulty in specifically controlling the dietary intakes of individual micronutrients in human subjects, suitable animal models may need to be developed to verify the putative antimycobacterial role of vitamin A and β-carotene at physiological dose ranges and to elucidate the underlying mechanism(s). This is especially relevant in a benefit-risk analysis in which potentially toxic pharmacological dosages of vitamin A are considered for administration (23, 24). Acknowledgments Conflict of interest: none declared. References 1 Soh AZ , Chee CBE , Wang YT , et al. . Dietary intake of antioxidant vitamins and carotenoids and risk of developing active tuberculosis in a prospective population-based cohort . Am J Epidemiol . 2017 ; 186 ( 4 ): 491 – 500 . Google Scholar CrossRef Search ADS PubMed 2 Grant SS , Hung DT . Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response . Virulence . 2013 ; 4 ( 4 ): 273 – 283 . Google Scholar CrossRef Search ADS PubMed 3 Korch SB , Malhotra V , Contreras H , et al. . The Mycobacterium tuberculosis relBE toxin:antitoxin genes are stress-responsive modules that regulate growth through translation inhibition . J Microbiol . 2015 ; 53 ( 11 ): 783 – 795 . 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Effects of vitamin E, C and D supplementation on inflammation and oxidative stress in streptozotocin-induced diabetic mice . Int J Vitam Nutr Res . 2013 ; 83 ( 3 ): 168 – 175 . Google Scholar CrossRef Search ADS PubMed 9 Bouamama S , Merzouk H , Medjdoub A , et al. . Effects of exogenous vitamins A, C, E and NADH supplementation on proliferation, cytokines release, and cell redox status of lymphocytes from healthy aged subjects . Appl Physiol Nutr Metab . 2017 ; 42 ( 6 ): 579 – 587 . Google Scholar CrossRef Search ADS PubMed 10 Schwarz KB , Cox JM , Sharma S , et al. . Possible antioxidant effect of vitamin A supplementation in premature infants . J Pediatr Gastroenterol Nutr . 1997 ; 25 ( 4 ): 408 – 414 . Google Scholar CrossRef Search ADS PubMed 11 Palace VP , Khaper N , Qin Q , et al. . Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease . Free Radic Biol Med . 1999 ; 26 ( 5–6 ): 746 – 761 . Google Scholar CrossRef Search ADS PubMed 12 Meerza D , Iqbal S , Zaheer S , et al. . Retinoids have therapeutic action in type 2 diabetes . Nutrition . 2016 ; 32 ( 7–8 ): 898 – 903 . Google Scholar CrossRef Search ADS PubMed 13 Gasparotto J , Petiz LL , Girardi CS , et al. . Supplementation with vitamin A enhances oxidative stress in the lungs of rats submitted to aerobic exercise . Appl Physiol Nutr Metab . 2015 ; 40 ( 12 ): 1253 – 1261 . Google Scholar CrossRef Search ADS PubMed 14 Petiz LL , Girardi CS , Bortolin RC , et al. . Vitamin A oral supplementation induces oxidative stress and suppresses IL-10 and HSP70 in skeletal muscle of trained rats . Nutrients . 2017 ; 9 ( 4 ): E353 . Google Scholar CrossRef Search ADS PubMed 15 Folchetti LD , Monfort-Pires M , de Barros CR , et al. . Association of fruits and vegetables consumption and related-vitamins with inflammatory and oxidative stress markers in prediabetic individuals . Diabetol Metab Syndr . 2014 ; 6 ( 1 ): 22 . Google Scholar CrossRef Search ADS PubMed 16 Raverdeau M , Millis KH . Modulation of T cell and innate immune responses by retinoic acid . J Immunol . 2014 ; 192 ( 7 ): 2953 – 2958 . Google Scholar CrossRef Search ADS PubMed 17 Liu PT , Stenger S , Tang DH , et al. . Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin . J Immunol . 2007 ; 179 ( 4 ): 2060 – 2063 . Google Scholar CrossRef Search ADS PubMed 18 Sita-Lumsden A , Lapthorn G , Swaminathan R , et al. . Reactivation of tuberculosis and vitamin D deficiency: the contribution of diet and exposure to sunlight . Thorax 2007 ; 62 ( 11 ): 1003 – 1007 . Google Scholar CrossRef Search ADS PubMed 19 Ní Cheallaigh C , Keane J , Lavelle EC , et al. . Autophagy in the immune response to tuberculosis: clinical perspectives . Clin Exp Immunol . 2011 ; 164 ( 3 ): 291 – 300 . Google Scholar CrossRef Search ADS PubMed 20 Fabri M , Stenger S , Shin DM , et al. . Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages . Sci Transl Med . 2011 ; 3 ( 104 ): 104ra102 . Google Scholar CrossRef Search ADS PubMed 21 Andersen R , Brot C , Jakobsen J , et al. . Seasonal changes in vitamin D status among Danish adolescent girls and elderly women: the influence of sun exposure and vitamin D intake . Eur J Clin Nutr . 2013 ; 67 ( 3 ): 270 – 274 . Google Scholar CrossRef Search ADS PubMed 22 Wingfield T , Schumacher SG , Sandhu G , et al. . The seasonality of tuberculosis, sunlight, vitamin D, and household crowding . J Infect Dis . 2014 ; 210 ( 5 ): 774 – 783 . Google Scholar CrossRef Search ADS PubMed 23 Bjelakovic G , Nikolova D , Gluud LL , et al. . Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases . Cochrane Database Syst Rev . 2012 ;( 3 ): CD007176 . 24 Rutkowski M , Grzegorczyk K . Adverse effects of antioxidative vitamins . Int J Occup Med Environ Health . 2012 ; 25 ( 2 ): 105 – 121 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
American Journal of Epidemiology – Oxford University Press
Published: Jan 12, 2018
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