Can the gastrointestinal system alter liver damage caused by COVID-19?

Abstract

Our gastrointestinal system, often referred to as our "second brain," is grappling with the devastating effects of COVID-19, a disease that has plagued recent years. Researchers are investigating how bacteria in the intestinal microflora may contribute to or mitigate liver damage caused by COVID-19. Despite the limited number of studies, the fight against liver organ damage by the gastrointestinal system, which is our second brain is important. All original articles published in English until March 01, 2020, were retrieved via a library-assisted literature search from PubMed/MEDLINE, Excerpta Medica Database (EMBASE), and Web of Science. A total of nine articles (2.188 patients) were found eligible for inclusion. Effect size and 95% confidence interval were evaluated in this study. The randomized trials exhibit a noteworthy level of heterogeneity (p<0.05), and upon scrutinizing the funnel plot, there is no discernible indication of publication bias. According to the meta-analysis tree graph, the weights of the studies are significantly to the right of the 2 vertical lines. The confidence interval of each study has significant weights. According to the study findings, the interaction of the intestinal flora and the immune system showed us that there is an area that we need to investigate against the COVID-19 disease. For many years, research has tried to explain how the signaling pathways in the intestinal tract are related to the brain. The study revealed that our digestive system plays a crucial role as an auxiliary component of our brain. Future studies should uncover the main ways of this communication.

Keywords

• Second brain
• Gut brain axis
• COVID-19 and microbiome
• COVID-19 liver effect

References

1. Matijašić M., Meštrović T., Paljetak HČ, Perić M, Barešić A. & Verbanac D. (2020). Gut Microbiota beyond Bacteria-Mycobiome, Virome, Archaeome, and Eukaryotic Parasites in IBD. International journal of molecular sciences, 11;21(8):2668. https://doi.org/ 10.3390/ijms21082668
2. Vemuri R., Shankar E.M., Chieppa M., Eri R. & Kavanagh K. (2020). Beyond Just Bacteria: Functional Biomes in the Gut Ecosystem Including Virome, Mycobiome, Archaeome and Helminths. Microorganisms, 8(4):483. https://doi.org/ 10.3390/microorganisms8040483
3. Davis C.D. (2016). The Gut Microbiome and Its Role in Obesity. Nutrition today, 51(4):167-174. https://doi.org/ 10.1097/NT.0000000000000167
4. Tomasello G., Mazzola M., Jurjus A., Cappello F., Carini F. & Damiani P. (2017). The fingerprint of the human gastrointestinal tract microbiota: a hypothesis of molecular mapping. Journal of Biological Regulators and Homeostatic Agents, 31(1):245-249. https://doi.org/ 28337900
5. Dill-McFarland K.A., Tang Z.Z., Kemis J.H., Kerby R.L., Chen G. & Palloni A. (2019). Close social relationships correlate with human gut microbiota composition. Scientific reports, 24;9(1):703. https://doi.org/ 10.1038/s41598-018-37298-9
6. Rees T., Bosch T. & Douglas A.E. (2018). How the microbiome challenges our concept of self. PLoS Biology, 9;16(2):e2005358. https://doi.org/ 10.1371/journal.pbio.2005358
7. Conlon M.A. & Bird A.R. (2014). The impact of diet and lifestyle on gut microbiota and human health. Nutrients, 24;7(1):17-44. https://doi.org/ 10.3390/nu7010017
8. Krajmalnik-Brown R., Ilhan Z.E., Kang D.W. & DiBaise J.K. (2012). Effects of gut microbes on nutrient absorption and energy regulation. Nutrition in Clinical Practice, 27(2):201-14. https://doi.org/ 10.1177/0884533611436116

9. Morowitz M.J., Carlisle E.M. & Alverdy J.C. (2011). Contributions of intestinal bacteria to nutrition and metabolism in the critically ill. Surgical oncology clinics of North America, 91(4):771-85, https://doi.org/ 10.1016/j.suc.2011.05.001
10. Clapp M., Aurora N., Herrera L., Bhatia M., Wilen E. & Wakefield S. (2017). Gut microbiota's effect on mental health: The gut-brain axis. International journal of clinical practice. 15;7(4):987. https://doi.org/ 10.4081/cp.2017.987
11. Butler M.I., Mörkl S., Sandhu K.V., Cryan J.F. & Dinan T.G. (2019). The Gut Microbiome and Mental Health: What Should We Tell Our Patients?: Le microbiote Intestinal et la Santé Mentale : que Devrions-Nous dire à nos Patients? The Canadian Journal of Psychiatry, 64(11):747-760. https://doi.org/ 10.1177/0706743719874168
12. Taylor V.H. (2019). The microbiome and mental health: Hope or hype? Journal of Psychiatry and Neuroscience, 1;44(4):219-222. https://doi.org/ 10.1503/jpn.190110
13. Dantzer R. (2018). Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiological reviews, 1;98(1):477-504. https://doi.org/ 10.1152/physrev.00039.2016
14. Rivest S. (2009). Regulation of innate immune responses in the brain. Nature reviews immunology, 9(6):429-39. https://doi.org/ 10.1038/nri2565
15. Hanke M.L. & Kielian T. (2011). Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clinical science, 121(9):367-87. https://doi.org/ 10.1042/CS20110164
16. Nobel Y.R., Phipps M. & Verna E.C. (2021). COVID-19 and Effect on Liver Transplant. Current treatment options in gastroenterology,19(3):483-499. https://doi.org/ 10.1007/s11938-021-00355-w
17. Choudhary N.S., Dhampalwar S., Saraf N. & Soin A.S. (2021). Outcomes of COVID-19 in Patients with Cirrhosis or Liver Transplantation. Journal of Clinical and Experimental Hepatology, 11(6):713-719. https://doi.org/ 10.1016/j.jceh.2021.05.003
18. Schult D., Reitmeier S., Koyumdzhieva P., Lahmer T., Middelhoff M. & Erber J. (2022). Gut bacterial dysbiosis and instability is associated with the onset of complications and mortality in COVID-19. Gut Microbes, 14(1):2031840. https://doi.org/ 10.1080/19490976.2022.2031840
19. Cheemerla S. & Balakrishnan M. (2021). Global Epidemiology of Chronic Liver Disease. Clin Liver Dis (Hoboken), 4;17(5):365-370. https://doi.org/ 10.1002/cld.1061
20. Mallet V., Beeker N., Bouam S., Sogni P. & Pol S. (2021). Demosthenes research group. Prognosis of French COVID-19 patients with chronic liver disease: A national retrospective cohort study for 2020. Journal of hepatology, 75(4):848-855. https://doi.org/ 10.1016/j.jhep.2021.04.052
21. Chadalavada P., Padbidri V., Garg R., Alomari M., Babar A., Kewan T. Et al. (2020). Transaminases are Potential Biomarkers of Disease Severity in COVID-19 Patients: A Single-Center Experience. Cureus, 18;12(11):e11555. https://doi.org/ 10.7759/cureus.11555
22. Kaneko S., Kurosaki M., Nagata K., Taki R., Ueda K. & Hanada S. (2020). Liver injury with COVID-19 based on gastrointestinal symptoms and pneumonia severity. PLoS One, 4;15(11):e0241663. https://doi.org/ 10.1371/journal.pone.0241663
23. Pott-Junior H., Bittencourt N.Q.P., Chacha S.F.G., Luporini R.L., Cominetti M.R. & Anibal F.F. (2021). Elevations in Liver Transaminases in COVID-19: (How) Are They Related? Frontiers of medicine, 15;8:705247. https://doi.org/ 10.3389/fmed.2021.705247
24. Schnabl B. & Brenner D.A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology, 146(6):1513-24. https://doi.org/ 10.1053/j.gastro.2014.01.020
25. Belkaid Y. & Hand T.W. (2014). Role of the microbiota in immunity and inflammation. Cell, 27;157(1):121-41. https://doi.org/ 10.1016/j.cell.2014.03.011
26. Newsome R.C., Gauthier J., Hernandez M.C., Abraham G.E., Robinson T.O., Williams H.B. Et al. (2021). The gut microbiome of COVID-19 recovered patients returns to uninfected status in a minority-dominated United States cohort. Gut Microbes, 13(1):1-15. https://doi.org/10.1080/19490976.2021.1926840
27. Carabotti M., Scirocco A., Maselli M.A. & Severi C. (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of gastroenterology, 28(2):203-209. https://doi.org/ 25830558
28. Martin C.R., Osadchiy V., Kalani A. & Mayer E.A. (2018). The Brain-Gut-Microbiome Axis. Cellular and Molecular Gastroenterology and Hepatology, 12;6(2):133-148. https://doi.org/ 10.1016/j.jcmgh.2018.04.003
29. Fung T.C., Olson C.A. & Hsiao E.Y. (2017). Interactions between the microbiota, immune and nervous systems in health and disease. Nature neuroscience, 20(2):145-155. https://doi.org/ 10.1038/nn.4476
30. Wang Y. & Kasper L.H. (2014). The role of microbiome in central nervous system disorders. Brain, Behavior, and Immunity, 38:1-12. https://doi.org/ 10.1016/j.bbi.2013.12.015
31. Maeda Y., Motooka D., Kawasaki T., Oki H., Noda Y. & Adachi Y. (2022). Longitudinal alterations of the gut mycobiota and microbiota on COVID-19 severity. BMC infectious diseases, 24;22(1):572. https://doi.org/ 10.1186/s12879-022-07358-7
32. Galland L. (2014). The gut microbiome and the brain. Journal of medicinal food. 17(12):1261-72. https://doi.org/ 10.1089/jmf.2014.7000
33. Madison A. & Kiecolt-Glaser J.K. (2019). Stress, depression, diet, and the gut microbiota: human-bacteria interactions at the core of psychoneuroimmunology and nutrition. Current Opinion in Behavioral Sciences, 28:105-110. https://doi.org/ 10.1016/j.cobeha.2019.01.011
34. Napolitano M. & Covasa M. (2020). Microbiota Transplant in the Treatment of Obesity and Diabetes: Current and Future Perspectives. Frontiers in microbiology, 12;11:590370. https://doi.org/ 10.3389/fmicb.2020.590370
35. Chinna Meyyappan A., Forth E., Wallace C.J.K. & Milev R. (2020). Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review. BMC Psychiatry, 15;20(1):299. https://doi.org/ 10.1186/s12888-020-02654-5
36. Sharon G., Sampson T.R., Geschwind D.H. & Mazmanian S.K. (2016). The Central Nervous System and the Gut Microbiome. Cell, 3;167(4):915-932. https://doi.org/ 10.1016/j.cell.2016.10.027
37. Wiertsema S.P., van Bergenhenegouwen J., Garssen J. & Knippels L.M.J. (2021). The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies. Nutrients, 13(3):886. https://doi.org/ 10.3390/nu13030886
38. Kho Z.Y. & Lal SK. (2018). The Human Gut Microbiome - A Potential Controller of Wellness and Disease. Frontiers in microbiology, 14;9:1835. https://doi.org/ 10.3389/fmicb.2018.01835
39. Martin A.M., Sun E.W., Rogers G.B. & Keating D.J. (2019). The Influence of the Gut Microbiome on Host Metabolism Through the Regulation of Gut Hormone Release. Frontiers in Physiology, 16;10:428. https://doi.org/ 10.3389/fphys.2019.00428
40. Gilbert J.A., Blaser MJ, Caporaso JG, Jansson JK, Lynch SV & Knight R. (2018). Current understanding of the human microbiome. Nature medicine, 10;24(4):392-400. https://doi.org/ 10.1038/nm.4517
41. Conlon M.A. & Bird A.R. (2014). The impact of diet and lifestyle on gut microbiota and human health. Nutrients, 24;7(1):17-44. https://doi.org/ 10.3390/nu7010017
42. Kelly S.A., Nzakizwanayo J., Rodgers A.M., Zhao L., Weiser R. & Tekko I.A. (2021). Antibiotic Therapy and the Gut Microbiome: Investigating the Effect of Delivery Route on Gut Pathogens. ACS infectious diseases, 14;7(5):1283-1296. https://doi.org/ 10.1021/acsinfecdis.1c00081
43. Ramirez J., Guarner F., Bustos Fernandez L., Maruy A., Sdepanian V.L. & Cohen H. (2020). Antibiotics as Major Disruptors of Gut Microbiota. Frontiers in cellular and infection microbiology, 24;10:572912. https://doi.org/ 10.3389/fcimb.2020.572912
44. Ceccarelli G., Borrazzo C., Pinacchio C., Santinelli L., Innocenti G.P., Cavallari E.N. et al. (2021). Oral Bacteriotherapy in Patients With COVID-19: A Retrospective Cohort Study. Frontiers in Nutrition, 11;7:613928. https://doi.org/ 10.3389/fnut.2020.613928
45. Looft T. & Allen H.K. (2012). Collateral effects of antibiotics on mammalian gut microbiomes. Gut Microbes, 3(5):463-7. https://doi.org/ 10.4161/gmic.21288
46. Khlevner J., Park Y. & Margolis K.G. (2018). Brain-Gut Axis: Clinical Implications. Gastrointestinal endoscopy clinics of North America, 47(4):727-739. https://doi.org/ 10.1016/j.gtc.2018.07.002
47. Sasselli V., Pachnis V. & Burns A.J. (2012). The enteric nervous system. (2014). Dev Biol, 366(1): 64-73. https://doi.org/ 10.1016/j.ydbio.2012.01.012
48. Furness J.B., Callaghan B.P., Rivera L.R. & Cho H.J. (2014). The enteric nervous system and gastrointestinal innervation: integrated local and central control. Advances in Experimental Medicine and Biology, 817:39-71. https://doi.org/ 10.1007/978-1-4939-0897-4_3
49. Li J.H., Duan R., Li L., Wood J.D., Wang X.Y. & Shu Y. [Unique characteristics of "the second brain" - The enteric nervous system]. Sheng Li Xue Bao, 2020 Jun 25;72(3):382-390. https://doi.org/ 10.3389/fnagi.2021.698988
50. Arneth B.M. (2018). Gut-brain axis biochemical signalling from the gastrointestinal tract to the central nervous system: gut dysbiosis and altered brain function. Postgraduate medical journal, 94(1114):446-452. https://doi.org/ 10.1136/postgradmedj-2017-135424
51. D'Agata A.L., Wu J., Welandawe MKV, Dutra SVO, Kane B & Groer MW. (2019). Effects of early life NICU stress on the developing gut microbiome. Developmental psychobiology. 61(5):650-660. https://doi.org/ 10.1002/dev.21826
52. Shen H.H. News Feature: Microbes on the mind. (2015). The Proceedings of the National Academy of Sciences, 28;112(30):9143-5. https://doi.org/ 10.1073/pnas.1509590112
53. Gutiérrez-Castrellón P., Gandara-Martí T., Abreu A.T., Nieto-Rufino C.D., López-Orduña E. & Jiménez-Escobar I. (2022). Probiotic improves symptomatic and viral clearance in COVID19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial. Gut Microbes, 14(1):2018899. https://doi.org/ 10.1080/19490976.2021.2018899.
54. Bathina S. & Das U.N. (2015). Brain-derived neurotrophic factor and its clinical implications. Archives of medical sciences, 10;11(6):1164-78. https://doi.org/ 10.5114/aoms.2015.56342
55. Binder D.K. & Scharfman H.E. (2004). Brain-derived neurotrophic factor. Growth Factors, 22(3):123-31. https://doi.org/ 10.1080/08977190410001723308
56. Rodriguez D.M., Benninghoff A.D., Aardema N.D.J., Phatak S. & Hintze K.J. (2019). Basal Diet Determined Long-Term Composition of the Gut Microbiome and Mouse Phenotype to a Greater Extent than Fecal Microbiome Transfer from Lean or Obese Human Donors. Nutrients, 17;11(7):1630. https://doi.org/ 10.3390/nu11071630
57. Luo Y., Zeng B., Zeng L., Du X., Li B. & Huo R. (2018). Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus. Translational psychiatry, 7;8(1):187. https://doi.org/ 10.1038/s41398-018-0240-5
58. Argou-Cardozo I. & Zeidán-Chuliá (2018). F. Clostridium Bacteria and Autism Spectrum Conditions: A Systematic Review and Hypothetical Contribution of Environmental Glyphosate Levels. Medical Sciences, 4;6(2):29. https://doi.org/10.3390/medsci6020029
59. Wasilewska J. & Klukowski M. (2015). Gastrointestinal symptoms and autism spectrum disorder: links and risks- a possible new overlap syndrome. Pediatric Health, Medicine and Therapeutics, 6:153-166. https://doi.org/ 10.2147/PHMT.S85717
60. Dunn A.B., Jordan S., Baker B.J. & Carlson N.S. (2017). The Maternal Infant Microbiome: Considerations for Labor and Birth. MCN The American Journal of Maternal Child Nursing, 42(6):318-325. https://doi.org/ 10.1097/NMC.0000000000000373
61. Suganya K. & Koo B.S. (2020). Gut-Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions. International journal of molecular sciences, 21(20):7551. https://doi.org/ 10.3390/ijms21207551
62. Chowdhury M.A., Hossain N., Kashem M.A., Shahid M.A. & Alam A. (2020). Immune response in COVID-19: A review. Journal of infection prevention, 13(11):1619-1629. https://doi.org/ 10.1016/j.jiph.2020.07.001
63. Farsi Y., Tahvildari A., Arbabi M., Vazife F., Sechi L.A. & Shahidi Bonjar A.H. (2022). Diagnostic, Prognostic, and Therapeutic Roles of Gut Microbiota in COVID-19: A Comprehensive Systematic Review. Frontiers in cellular and infection microbiology, 4;12:804644. https://doi.org/ 10.3389/fcimb.2022.804644
64. Gagliardi A., Totino V., Cacciotti F., Iebba V., Neroni B. & Bonfiglio G. (2018). Rebuilding the Gut Microbiota Ecosystem. International journal of environmental health research, 7;15(8):1679. https://doi.org/
65. Sun Z., Song Z.G., Liu C., Tan S., Lin S., Zhu J. Et al. (2022). Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients. BMC Medicine, 20;20(1):24. https://doi.org/ 10.1186/s12916-021-02212-0
66. Somsouk M., Estes J.D., Deleage C., Dunham R.M., Albright R. & Inadomi J.M. (2015). Gut epithelial barrier and systemic inflammation during chronic HIV infection. AIDS, 29(1):43-51. https://doi.org/
67. Gold J.E., Okyay R.A., Licht W.E. & Hurley D.J. (2021). Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens, 17;10(6):763. https://doi.org/ 10.3390/pathogens10060763
68. Carvalho T., Krammer F. & Iwasaki A. (2021). The first 12 months of COVID-19: a timeline of immunological insights. Nature reviews Immunology, 21(4):245-256. https://doi.org/ 10.1038/s41577-021-00522-1
69. D'Andrea G. (2015). Quercetin: A flavonol with multifaceted therapeutic applications? Fitoterapia, 106:256-71. https://doi.org/ 10.1016/j.fitote.2015.09.018
70. Górski A., Międzybrodzki R., Żaczek M. & Borysowski J. (2020). Phages in the fight against COVID-19? Future Microbiol, 15:1095-1100. https://doi.org/ 10.2217/fmb-2020-0082
71. Sharma J.N., Al-Omran A. & Parvathy S.S. (2007). Role of nitric oxide in inflammatory diseases. Inflammopharmacology, 15(6):252-9. https://doi.org/ 10.1007/s10787-007-0013-x
72. Vázquez-Torres A. & Bäumler A.J. (2016). Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens. Current Opinion in Microbiology, 29:1-8. https://doi.org/ 10.1016/j.mib.2015.09.002
73. Thota R.N., Acharya S.H. & Garg M.L. (2019). Curcumin and/or omega-3 polyunsaturated fatty acids supplementation reduces insulin resistance and blood lipids in individuals with high risk of type 2 diabetes: a randomised controlled trial. Lipids in Health and Disease, 18(1):31. https://doi.org/ 10.1186/s12944-019-0967-x
74. Davie J.R. (2003). Inhibition of histone deacetylase activity by butyrate. The Journal of Nutrition, 133(7 Suppl):2485S-2493S. https://doi.org/ 10.1093/jn/133.7.2485S
75. Wei Y. & Melas P.A. Wegener G, Mathé A.A., Lavebratt C. (2014). Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene. International Journal of Neuropsychopharmacology, 31;18(2). https://doi.org/ 10.1093/ijnp/pyu032
76. Madempudi R.S., Ahire JJ, Neelamraju J, Tripathi A. & Nanal S. (2019). Randomized clinical trial: the effect of probiotic Bacillus coagulans Unique IS2 vs. placebo on the symptoms management of irritable bowel syndrome in adults. Scientific reports, 21;9(1):12210. https://doi.org/ 10.1038/s41598-019-48554-x
77. Liu Q., Mak J.W.Y., Su Q., Yeoh Y.K., Lui G.C. & Ng S.S.S. (2022). Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. Gut, 71(3):544-552. https://doi.org/ 10.1136/gutjnl-2021-325989
78. Hrncir T. (2022). Gut Microbiota Dysbiosis: Triggers, Consequences, Diagnostic and Therapeutic Options. Microorganisms. 10(3):578-643. doi: 10.3390/microorganisms10030578.
79. Tilg H, Adolph TE, Trauner M (2022). Gut-liver axis: Pathophysiological concepts and clinical implications. Microorganism. 34(11):1700-1718. doi: 10.1016/j.cmet.2022.09.017.
80. An C, Chon H, Ku W, Eom S, Seok M, Kim S et al., (2022). Bile Acids: Major Regulator of the Gut Microbiome. Microorganisms. 10(9):1792. doi: 10.3390/microorganisms10091792.
81. Arias N, Arboleya S, Allison J, Kaliszewska A, Higarza SG, Gueimonde M et al., (2020). The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases. Nutrients. 12(8):2340. doi: 10.3390/nu12082340.
82. Latif A, Shehzad A, Niazi S, Zahid A, Ashraf W, Iqbal MW et al., (2023). Probiotics: mechanism of action, health benefits and their application in food industries. Frontiers in Microbiology. 14(1): 21-67. doi: 10.3389/fmicb.2023.1216674.
83. Bax L., Yu L.M., Ikeda N & Moons KGA. (2007). systematic comparison of software dedicated to meta-analysis of causal studies. BMC medical research methodology, 10;7:40. https://doi.org/ 10.1186/1471-2288-7-40
84. Chelakkot C., Ghim J. & Ryu S.H. (2018). Mechanisms regulating intestinal barrier integrity and its pathological implications. Experimental and Molecular Medicine, 16;50(8):1-9. https://doi.org/ 10.1038/s12276-018-0126-x
85. Chowdhury M.A., Hossain N., Kashem M.A., Shahid M.A. & Alam A. (2020). Immune response in COVID-19: A review. Journal of infection prevention, 13(11):1619-1629. https://doi.org/ 10.1016/j.jiph.2020.07.001
86. Dill-McFarland K.A., Tang Z.Z., Kemis J.H., Kerby R.L., Chen G. & Palloni A. (2019). Close social relationships correlate with human gut microbiota composition. Scientific reports, 24;9(1):703. https://doi.org/ 10.1038/s41598-018-37298-9
87. Jin X., Lian J.S., Hu J.H., Gao J., Zheng L. & Zhang Y.M. (2020). Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut, 69(6):1002-1009. https://doi.org/ 10.1136/gutjnl-2020-320926
88. Suárez-Reyes A. & Villegas-Valverde C.A. (2021). Implications of Low-grade Inflammation in SARS-CoV-2 Immunopathology. MEDICC Review, 23(2):42. https://doi.org/ 10.37757/MR2021.V23.N2.4
89. Yeoh Y.K., Zuo T., Lui G.C., Zhang F. & Liu Q. (2021). Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut, 70(4):698-706. https://doi.org/10.1136/gutjnl-2020-323020