Fasting Ramadan During COVID-19 Pandemic: Immunomodulatory Effect
Taghreed Abunada
Hanan Abunada
Hatem Zayed- 1Biomedical Science Department, College of Health Sciences, QU-Health, Qatar University, Doha, Qatar
- 2Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
As of April 24, 2020, more than 1. 6 billion Muslims observe the holy fasting month of Ramadan worldwide. The safety of fasting of healthy adult Muslims during the COVID-19 era is debatable. In this perspective, we discuss the available scientific evidence of the advantages of fasting against COVID-19.
Fasting Ramadan During COVID-19 Pandemic
As of April 24, more than 1.6 billion Muslims are celebrating the fasting month of Ramadan worldwide, where healthy adult Muslims practice diurnal intermittent fasting and refrain from eating and drinking from dawn to sunset (1). The safety of fasting of healthy Muslims is debatable as some argue that fasting will render them vulnerable to the severe consequences of COVID-19 (2–4), especially after the WHO recommendations for adult people to get a balanced diet and drink plenty of water throughout the day as protective measures against COVID-19 (5). Although following such measures would not eliminate the risk rather than improve the symptoms in case of infection, the recommendations might be misinterpreted to encourage some Muslims to stop fasting during Ramadan. Ramadan fasting is only required of healthy adult Muslims who are physically able to fast (6, 7). Therefore, Muslims are legally exempted from fasting if their health status would not enable them to fast. On the contrary, they are then required not to perform Ramadan fasting (2).
There are many patterns of intermittent fasting practiced worldwide, such as complete alternate day fasting, modified fasting regimens, and time-restricted fasting (8). Apart from the diurnal intermittent fasting of Muslims during the month of Ramadan, fasting is practiced by Christians, Jews, and other people worldwide for religious, spiritual, and health purposes (8).
Fasting Immunomodulatory Effect in Experimental Studies
Alternate day fasting is an intermittent fasting approach that shows benefits on strengthening the immune system, alters the gut microbiota, and enhances antioxidative microbial metabolic pathways (9, 10). Alternate fasting–refeeding of BALB/c mice maintains the immune dynamics and hemostasis of B cells (11) and induces the migration of naïve B cells to the bone marrow, ready for combat (11–13). Alternate fasting–refeeding nutritional signals mediate this process and regulate it by CXCL13 expression (11). The CXCL13 chemokine reflects the germinal center activity where high-affinity antibody maturation and interaction with Th-cells occur (10). Diet restriction by 30% and 3 days of water-only fasting in C57Bl/6 mice increases the number of recirculating mature B cells in the bone marrow (14). A study by Nagai et al. examined the effect of alternate fasting/re-feeding for 24–36 h on BALB/c mice gut and found that such type of fasting decreases the number of Peyer's patches lymphocytes, while refeeding selectively restored naïve—but not germinal center and IgA class switched—B cells. The germinal center B cells underwent massive apoptosis during fasting due to downregulation of mTORC1 signaling, whereas naïve B cells shuttle between Peyer's patches and the bone marrow during these fasting–refeeding cycles in a CXCL-13-dependent manner (11). Calorie restriction and short-term fasting with access to water only for 48 h induce the cell cycle arrest of immature hematopoietic stem cells (HSCs) and increase the number of naïve CD8+/CD4+ T cells in the bone marrow of C57Bl/6 mice (15). Diet restriction by 30% and 3 days of water-only fasting increase mature CD3+ T cells in the bone marrow of C57Bl/6 mice (14). Diet restriction by 50% of C57BL/6NTac mice triggers memory T cell homing to the bone marrow and enhances their rapid protective function thereafter (16). Free access to water with food deprivation for 1 or 3 days augments the cytolytic activity of TRAIL-natural killer cells against virus-infected cells in C57BL/6J mice (17). Another study by Contreras et al. investigated the effect of calorie restriction in both mice and human and found that, during fasting, the T-lymphocytes redistribute and, upon re-feeding, undergo homeostatic proliferation, presumably to fill the void left by the redistributing cells in response to homeostatic cytokine, IL-7 (18). Cheng et al. examined the effect of prolonged fasting on murine HSCs and showed that prolonged fasting induced self-renewal and lineage-balanced regeneration of long-term HSCs and niche cells. This effect was mediated by many signal transduction changes of IGF1 and PKP activity (19, 20). Thus, these studies suggest that different fasting patterns preserve and improve the immunity by immune cell rejuvenation. Supplementary Table 1 describes the immunomodulatory effect of different fasting patterns in experimental studies.
Actually, intermittent fasting exerts well-being effect on different body organs and leads to a better metabolic health status in humans (21). Apart from its well-documented beneficial effects on the brain, heart, liver, intestine, and muscles, recent studies show that it ameliorates the immune system by rejuvenation and regeneration of stem cells, reducing inflammation and oxidative stress, reducing autoimmunity, improving cell repair (autophagy), and promoting healthy aging (21). These benefits encourage many physicians to recommend it as an alternative treatment for patients with asthma, hypertension, diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and even cancer (21, 22).
Of interest is that diurnal intermittent fasting and its model of Ramadan affect the immunity by changing the body's response toward infection, inflammation, and oxidative stress (23). For instance, Ramadan fasting reduces the pathogenicity of Mycobacterium tuberculosis by increasing the macrophage number and INF-γ secretion in fasting volunteers (23). It was demonstrated to be safe for patients infected with HIV and on antiretroviral therapy (23). It decreases C-reactive protein, pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6, and IL-8 (24–27), and pro-inflamatory CXC chemokines such as CXCL1, CXCL10, and CXCL12 (27). It has beneficial effects on nitric oxide and glutathione levels in women with polycystic ovary syndrome (28). It has a potential protective role against oxidative stress and inflammation by increasing the expression of three antioxidant genes (TFAM, SOD2, and Nrf2) (29). A systemic review by Adawi et al. illustrated a graphical explanation of the mechanism related to Ramadan intermittent fasting and the immune system (6).
Fasting Potential Favorable Effect Against COVID-19
The high mortality and morbidity from many respiratory diseases (30), including COVID-19, is attributed to sustained uncontrolled inflammatory infiltrates, antibody-dependent enhancement, and excessive cytokine production (cytokine storm) that lead eventually to lung tissue damage (31). The cytokine storm in COVID-19 patients is characterized by increased (IL)-1β and IL-6, IL-17, IFN-α, and INF-β, along with IL-37 and IL-38 (31). On the other hand, Ramadan diurnal intermittent fasting has a positive effect on the overall inflammatory status of the human body (24–27) and tends to decrease such pro-inflammatory cytokines, particularly IL-6, IL-1β (6, 7), and proinflammatory chemokines CXCL1, CXCL10, and CXCL12 (24–27), which might alleviate lung tissue damage. Ramadan intermittent fasting has a modulatory effect on macrophages and render them to produce low amounts of cytokines (32), previously proven to positively affect asthma patients (33). Of note is that fasting restored the balance of renin–angiotensin system (34, 35), which is crucial to reduce the effect of angiotensin II, pro-inflammatory cytokines, and fibrosis in the lung tissue (30). Taken together, these findings suggest that Ramadan diurnal intermittent fasting might have a favorable effect against COVID-19.
It should be noted that the beneficial effects of Ramadan intermittent fasting on immunity might be reduced by the sleep pattern practiced in the blessed month of Ramadan. Several studies showed that total sleep time significantly decreased by about 1 h in Ramadan nights, while daytime sleepiness increased (23, 36). Partial sleep deprivation is associated with increased susceptibility to viral infections (23, 37). It impairs the immune functions, decreases cytokine release, and reduces the infection-fighting antibodies and cells (38). Wilder-Smith et al. examined the effect of sleep deprivation on the immune markers of 52 healthy volunteers and showed its association with transiently impaired mitogen proliferation, decreased HLA-DR, upregulated CD14, and variations in CD4 and CD8 (39). A study by Bahijri et al. addressed the combined effect of Ramadan intermittent fasting and disturbed sleep to decrease the IgG level significantly in 23 healthy volunteers (40). Taken together, it is worth to state that the beneficial immunomodulatory effects of Ramadan intermittent fasting might be influenced by the disturbance of the sleep–wake cycle of fasting individuals.
Periodic Fasting Preserves and Improves the Immunity
Recent studies showed that periodic fasting and time-restricted re-feeding would make the immune system stronger. Of note is that Muller et al. showed that the clinical use of periodic fasting reduces the symptoms of rheumatoid arthritis when followed by a vegetarian diet (41). Understanding the mechanistic link between nutrients and fasting benefits leads to the identification of fasting-mimicking diets (FMD) that achieve changes similar to those caused by fasting (41). Cheng et al. demonstrated the effect of periodic fasting in promoting a HSC-dependent regeneration of mice immune cells, leading to a rejuvenated immune phenotype and elevation of mesenchymal stem and progenitor cells (MSPC), even at a relatively old mice age (19, 41). Cycles of fasting and refeeding have been shown to modulate gut microbiota, ameliorate pathology in various mouse autoimmunity models, and promote T cell-dependent killing of cancer cells (42). Dang et al. showed that fasting enhances TRAIL-mediated liver natural killer cell activity against neoplastic cells through upregulation of HSP70 (17). In agreement with the anti-inflammatory effect of FMD in mice, Brandhorst et al. showed that the MSPC levels were transiently elevated during FMD in human subjects (41, 43). Interestingly, this intermittent fasting was practiced by Mohammed, the prophet of Islam, about 1,500 years ago.
Concluding Remark
In light of the scientific evidence presented here, healthy adult Muslims will reap benefits from fasting and will improve body wellness and performance of the immune system, which will be a valuable asset in fighting against COVID-19 and is expected to expedite the healing process for patients with COVID-19.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Author Contributions
HZ conceptualized the perspective idea, drafted the outline, and revised the text. TA and HA created the original perspective draft. All authors reviewed and commented on the subsequent drafts of the perspective and declare that the content has not been published elsewhere. All authors read and approved the final version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2020.557025/full#supplementary-material
References
1. Husain S, Zafar M, Ullah R. Ramadan and public health: a bibliometric analysis of top cited articles from 2004 to 2019. J Infect Public Health. (2020) 13:275–80. doi: 10.1016/j.jiph.2019.11.006
2. Health – Gulf News. Ramadan During COVID-19: What clerics and Health Experts Say. (2020). Available online at: https://gulfnews.com/uae/health/ramadan-during-covid-19-what-clerics-and-health-experts-say-1.1586508552717 (accessed April 21, 2020).
3. Diet Doctor. Boosting Your Immune System to Fight the Coronavirus: What You Need to Know. (2020). Available online at: https://www.dietdoctor.com/coronavirus (accessed March 17, 2020).
4. Mubasher Aljazeera Net. Corona: A Former Algerian Minister Calls for the Suspension of Ramadan Fasting this year. (2020). Available online at: https://translate.google.com/translate?hl=en&sl=ar&u=http://mubasher.aljazeera.net/node/303054&prev=search (accessed April 21, 2020).
5. World Health Organization. Nutrition Advice for Adults During the COVID-19 Outbreak. (2020). Available online at: http://www.emro.who.int/nutrition/nutrition-infocus/nutrition-advice-for-adults-during-the-covid-19-outbreak.html (accessed April 21, 2020).
6. Adawi M, Watad A, Brown S, Aazza K, Aazza H, Zouhir M, et al. Ramadan fasting exerts immunomodulatory effects: insights from a systematic review. Front Immunol. (2017) 8:1144. doi: 10.3389/fimmu.2017.01144
8. Patterson RE, Sears DD. Metabolic effects of intermittent fasting. Annu Rev Nutr. (2017) 37:371–93. doi: 10.1146/annurev-nutr-071816-064634
9. Cignarella F, Cantoni C, Ghezzi L, Salter A, Dorsett Y, Chen L, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab. (2018) 27:1222–35.e6. doi: 10.1016/j.cmet.2018.05.006
10. Cabrera-Mulero A, Tinahones A, Bandera B, Moreno-Indias I, Macías-González M, Tinahones FJ. Keto microbiota: a powerful contributor to host disease recovery. Rev Endocr Metab Disord. (2019) 20:415–25. doi: 10.1007/s11154-019-09518-8
11. Nagai M, Noguchi R, Takahashi D, Morikawa T, Koshida K, Komiyama S, et al. Fasting-refeeding impacts immune cell dynamics and mucosal immune responses. Cell. (2019) 178:1072–87.e14. doi: 10.1016/j.cell.2019.07.047
12. Ahluwalia B, Magnusson MK, Öhman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad. Scand J Gastroenterol. (2017) 52:1185–93. doi: 10.1080/00365521.2017.1349173
13. Jung C, Hugot JP, Barreau F. Peyer's patches: the immune sensors of the intestine. Int J Inflam. (2010) 2010:823710. doi: 10.4061/2010/823710
14. Shushimita S, de Bruijn MJ, de Bruin RW, IJzermans JN, Hendriks RW, Dor FJ. Dietary restriction and fasting arrest B and T cell development and increase mature B and T cell numbers in bone marrow. PLoS ONE. (2014) 9:e87772. doi: 10.1371/journal.pone.0087772
15. Takakuwa T, Nakashima Y, Koh H, Nakane T, Nakamae H, Hino M. Short-term fasting induces cell cycle arrest in immature hematopoietic cells and increases the number of naïve t cells in the bone marrow of mice. Acta Haematol. (2019) 141:189–98. doi: 10.1159/000496096
16. Collins N, Han SJ, Enamorado M, Link VM, Huang B, Moseman EA, et al. The bone marrow protects and optimizes immunological memory during dietary restriction. Cell. (2019) 178:1088–101.e15. doi: 10.1016/j.cell.2019.07.049
17. Dang VT, Tanabe K, Tanaka Y, Tokumoto N, Misumi T, Saeki Y, et al. Fasting enhances TRAIL-mediated liver natural killer cell activity via HSP70 upregulation. PLoS ONE. (2014) 9:e110748. doi: 10.1371/journal.pone.0110748
18. Contreras NA, Fontana L, Tosti V, Nikolich-Žugich J. Calorie restriction induces reversible lymphopenia and lymphoid organ atrophy due to cell redistribution. Geroscience. (2018) 40:279–91. doi: 10.1007/s11357-018-0022-2
19. Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. (2014) 14:810–23. doi: 10.1016/j.stem.2014.04.014
20. Mendelsohn AR, Larrick JW. Prolonged fasting/refeeding promotes hematopoietic stem cell regeneration and rejuvenation. Rejuvenation Res. (2014) 17:385–9. doi: 10.1089/rej.2014.1595
21. Armutcu F. Fasting may be an alternative treatment method recommended by physicians. Electron J General Med. (2019) 16:em138. doi: 10.29333/ejgm/104620
22. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. (2014) 19:181–92. doi: 10.1016/j.cmet.2013.12.008
23. Faris MA, Salem M, Jahrami H, Madkour M, BaHammam AS. Ramadan intermittent fasting and immunity: an important topic in the era of COVID-19. Ann Thorac Med. (2020) 15:125–33. doi: 10.4103/atm.ATM_151_20
24. Faris MA, Kacimi S, Al-Kurd RA, Fararjeh MA, Bustanji YK, Mohammad MK, et al. Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects. Nutr Res. (2012) 32:947–55. doi: 10.1016/j.nutres.2012.06.021
25. Almeneessier AS, BaHammam AA, Alzoghaibi M, Olaish AH, Nashwan SZ, BaHammam AS. The effects of diurnal intermittent fasting on proinflammatory cytokine levels while controlling for sleep/wake pattern, meal composition and energy expenditure. PLoS ONE. (2019) 14:e0226034. doi: 10.1371/journal.pone.0226034
26. Aksungar FB, Topkaya AE, Akyildiz M. Interleukin-6, C-reactive protein and biochemical parameters during prolonged intermittent fasting. Ann Nutr Metab. (2007) 51:88–95. doi: 10.1159/000100954
27. Akrami Mohajeri F, Ahmadi Z, Hassanshahi G, Akrami Mohajeri E, Ravari A, Ghalebi SR. Dose ramadan fasting affects inflammatory responses: evidences for modulatory roles of this unique nutritional status via chemokine network. Iran J Basic Med Sci. (2013) 16:1217–22.
28. Asemi Z, Samimi M, Taghizadeh M, Esmaillzadeh A. Effects of ramadan fasting on glucose homeostasis, lipid profiles, inflammation and oxidative stress in women with polycystic ovary syndrome in Kashan, Iran. Arch Iran Med. (2015) 18:806–10.
29. Madkour MI, T El-Serafi A, Jahrami HA, Sherif NM, Hassan RE, Awadallah S, et al. Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT1, SIRT3) gene expressions in subjects with overweight and obesity. Diabetes Res Clin Pract. (2019) 155:107801. doi: 10.1016/j.diabres.2019.107801
30. Kaparianos A, Argyropoulou E. Local renin-angiotensin II systems, angiotensin-converting enzyme and its homologue ACE2: their potential role in the pathogenesis of chronic obstructive pulmonary diseases, pulmonary hypertension and acute respiratory distress syndrome. Curr Med Chem. (2011) 18:3506–15. doi: 10.2174/092986711796642562
31. Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. (2020) 10:102–8. doi: 10.1016/j.jpha.2020.03.001
32. Sun D, Muthukumar AR, Lawrence RA, Fernandes G. Effects of calorie restriction on polymicrobial peritonitis induced by cecum ligation and puncture in young C57BL/6 mice. Clin Diagn Lab Immunol. (2001) 8:1003–11. doi: 10.1128/CDLI.8.5.1003-1011.2001
33. Han K, Nguyen A, Traba J, Yao X, Kaler M, Huffstutler RD, et al. A pilot study to investigate the immune-modulatory effects of fasting in steroid-naive mild asthmatics. J Immunol. (2018) 201:1382–8. doi: 10.4049/jimmunol.1800585
34. Badreh F, Joukar S, Badavi M, Rashno M. Restoration of the renin-angiotensin system balance is a part of the effect of fasting on cardiovascular rejuvenation: role of age and fasting models. Rejuvenation Res. (2019) 23:302–12. doi: 10.1089/rej.2019.2254
35. Butkus NE, Burman KD, Smallridge RC. Angiotensin-converting enzyme activity decreases during fasting. Horm Metab Res. (1987) 19:76–9. doi: 10.1055/s-2007-1011743
36. Faris MAE, Jahrami HA, Alhayki FA, Alkhawaja NA, Ali AM, Aljeeb SH, et al. Effect of diurnal fasting on sleep during Ramadan: a systematic review and meta-analysis. Sleep Breath. (2020) 24:771–82. doi: 10.1007/s11325-019-01986-1
37. Bryant PA, Trinder J, Curtis N. Sick and tired: does sleep have a vital role in the immune system? Nat Rev Immunol. (2004) 4:457–67. doi: 10.1038/nri1369
38. Yousfi N, Bragazzi NL, Briki W, Zmijewski P, Chamari K. The COVID-19 pandemic: how to maintain a healthy immune system during the lockdown – a multidisciplinary approach with special focus on athletes. Biol Sport. (2020) 37:211–6. doi: 10.5114/biolsport.2020.95125
39. Wilder-Smith A, Mustafa FB, Earnest A, Gen L, Macary PA. Impact of partial sleep deprivation on immune markers. Sleep Med. (2013) 14:1031–4. doi: 10.1016/j.sleep.2013.07.001
40. Bahijri SM, Ajabnoor GM, Borai A, Al-Aama JY, Chrousos GP. Effect of Ramadan fasting in Saudi Arabia on serum bone profile and immunoglobulins. Ther Adv Endocrinol Metab. (2015) 6:223–32. doi: 10.1177/2042018815594527
41. Longo VD, Panda S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. (2016) 23:1048–59. doi: 10.1016/j.cmet.2016.06.001
42. Buono R, Longo VD. When fasting gets tough, the tough immune cells get going-or die. Cell. (2019) 178:1038–40. doi: 10.1016/j.cell.2019.07.052
Keywords: fasting Ramadan, COVID-19, immune, diet, restriction
Citation: Abunada T, Abunada H and Zayed H (2020) Fasting Ramadan During COVID-19 Pandemic: Immunomodulatory Effect. Front. Nutr. 7:557025. doi: 10.3389/fnut.2020.557025
Received: 30 April 2020; Accepted: 07 September 2020;
Published: 05 November 2020.
Edited by:
Reinaldo B. Oria, Federal University of Ceara, BrazilReviewed by:
Ahmed S. BaHammam, King Saud University, Saudi ArabiaHamdi Chtourou, University of Sfax, Tunisia
Copyright © 2020 Abunada, Abunada and Zayed. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hatem Zayed, hatem.zayed@qu.edu.qa
†These authors have contributed equally to this work