Is the increased risk for MAFLD patients to develop severe COVID-19 linked to perturbation of the gut-liver axis?
Authors: Gabriella Assante, Roger Williams, Neil Alexander Youngson
Journal: Journal of Hepatology (2020)

Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective studyJournal of HepatologyVol. 73Issue 2PreviewLiver injury has been observed in patients with COVID-19, at an incidence ranging from 14–53%.1–3 We examined the liver injury patterns and implication of non-alcoholic fatty liver diseases (NAFLD) on clinical outcomes in Chinese patients with COVID-19. Full-Text PDF Two recent studies in the Journal of Hepatology suggest that metabolic dysfunction-associated fatty liver disease (MAFLD) is a risk factor for progression to severe COVID-19. A Chinese study of 202 patients with COVID-19 found that those with indicators of MAFLD had a higher risk of respiratory disease progression than patients without MAFLD.[1]Ji D. Qin E. Xu J. Zhang D. Cheng G. Wang Y. et al.Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study.J Hepatol. 2020; 73: 451-453Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar A subsequent study of 327 patients, also from China, found increased risk for COVID-19 progression in younger (<60 years old) patients with MAFLD but not in older ones.[2]Zhou Y.J.Z. Wang K.I. Yan X.B. Sun H.D. Pan Q.F. Wang K.H. et al.Younger patients with MAFLD are at increased risk of severe COVID-19 illness: a multicenter preliminary analysis.J Hepatol. 2020; 73: 719-721Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar More studies are required to confirm this, especially in cohorts of patients with COVID-19 and imaging or biopsy-proven MAFLD prior to infection. However, it potentially adds MAFLD to a list of risk factors that also includes obesity, type 2 diabetes (T2D), chronic lung disease, inflammatory bowel disease (IBD), asthma, cardiovascular disease, immunodeficiency, and renal failure. There are likely to be several contributing (and overlapping) explanations for an increased risk for severe COVID-19 in patients with MAFLD. These include an additive strain on an already stressed immune system, hepatic functional impairment in those with clinically significant disease at baseline, infection of the liver itself, or an indirect association due to comorbidities such as obesity and insulin resistance. More studies are urgently needed to separate MAFLD from its comorbidities, and to identify the factors that causally drive COVID-19 progression in individuals with dysmetabolism. However, herein, we wish to highlight the possibility that the increased risk observed in patients with MAFLD is driven by SARS CoV-2 infection of the gut, which exacerbates an existing state of intestinal permeability and mucosal inflammation, thereby contributing to the systemic immune dysfunction characteristic of severe COVID-19. Indeed, this process may also explain the increased risk for COVID-19 progression in obesity, T2D and even IBD which are associated with similar gut microbiota, intestinal inflammation and barrier integrity disturbances. Multiple studies have reported that gastrointestinal symptoms such as diarrhoea, vomiting, and abdominal pain are common in patients with COVID-19.[3]Pan L. Mu M. Yang P. Sun Y. Wang R. Yan J. et al.Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study.Am J Gastroenterol. 2020; 115: 766-773Crossref PubMed Scopus (1187) Google Scholar The severity of digestive symptoms increases alongside respiratory symptoms and liver injury.[3]Pan L. Mu M. Yang P. Sun Y. Wang R. Yan J. et al.Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study.Am J Gastroenterol. 2020; 115: 766-773Crossref PubMed Scopus (1187) Google Scholar,[4]Xiao F. Tang M. Zheng X. Liu Y. Li X. Shan H. Evidence for gastrointestinal infection of SARS-CoV-2.Gastroenterology. 2020; 158: 1831-1833.e3Abstract Full Text Full Text PDF PubMed Scopus (1990) Google Scholar ACE-2 is abundantly expressed on enterocytes in the small intestine,[4]Xiao F. Tang M. Zheng X. Liu Y. Li X. Shan H. Evidence for gastrointestinal infection of SARS-CoV-2.Gastroenterology. 2020; 158: 1831-1833.e3Abstract Full Text Full Text PDF PubMed Scopus (1990) Google Scholar and the high level of virus in faeces and the intestinal lumen suggests that the organ is a site of viral infection and inflammation. It is currently unclear whether this induces high levels of cell death and/or increases the permeability of the gut barrier. However, the gut symptoms correlate with markers of liver damage,[3]Pan L. Mu M. Yang P. Sun Y. Wang R. Yan J. et al.Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study.Am J Gastroenterol. 2020; 115: 766-773Crossref PubMed Scopus (1187) Google Scholar which supports the notion of increased transmission of pathogen-associated molecular patterns (PAMPs) to the liver. This process could increase the severity of COVID-19 by either sequestering immune resources away from the lungs to the gut and liver, or by 'priming' the liver and systemic immune systems to hyperactivity (cytokine storm). The latter explanation may be supported by similarities in the range of circulating proinflammatory cytokines that are induced by non-alcoholic steatohepatitis and severe COVID-19, such as IL-1β, IL-6, and TNF-α.[5]Giamarellos-Bourboulis E.J. Netea M.G. Rovina N. Akinosoglou K. Antoniadou A. Antonakos N. et al.Complex immune dysregulation in COVID-19 patients with severe respiratory failure.Cell Host Microbe. 2020; 27: 992-1000.e3Abstract Full Text Full Text PDF PubMed Scopus (1437) Google Scholar,[6]Li X. Xu S. Yu M. Wang K. Tao Y. Zhou Y. et al.Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.J Allergy Clin Immunol. 2020; 146: 110-118Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar Furthermore, priming of toll-like receptor (TLR)-mediated proinflammatory release from circulating immune cells has been observed with an initial exposure to malarial parasites[7]Franklin B.S. Parroche P. Ataide M.A. Lauw F. Ropert C. de Oliveira R.B. et al.Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function.Proc Natl Acad Sci U S A. 2009; 106: 5789-5794Crossref PubMed Scopus (145) Google Scholar or respiratory syncytial virus infection,[8]Monick M.M. Yarovinsky T.O. Powers L.S. Butler N.S. Carter A.B. Gudmundsson G. et al.Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin.J Biol Chem. 2003; 278: 53035-53044Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar and a subsequent exposure to a TLR agonist (lipopolysaccharide, LPS). MAFLD has been shown to increase levels of TLRs in liver,[9]Kanuri G. Ladurner R. Skibovskaya J. Spruss A. Konigsrainer A. Bischoff S.C. et al.Expression of toll-like receptors 1-5 but not TLR 6-10 is elevated in livers of patients with non-alcoholic fatty liver disease.Liver Int. 2015; 35: 562-568Crossref PubMed Scopus (49) Google Scholar so could that 'first-hit' prime liver immune cells to hyperactivity upon a 'second-hit' of PAMPs such as LPS from a SARS-CoV2-infected gut? As the liver contains the largest population (~80%) of all tissue-resident macrophages (Kupffer cells), a strong immune response from that organ would be able to cause large alterations to systemic inflammation. Research is needed to confirm whether intestinal permeability increases in COVID-19, whether the particular pro-inflammatory cytokines entering circulation from the gut and liver overlap between MAFLD, T2D, IBD, obesity and COVID-19, and whether immune cell numbers are reduced in the lungs when the gut and liver are inflamed. If gut-liver axis alterations due to metabolic diseases are a key contributor to progression to severe COVID-19 then this information can be used to guide treatment of a large sector of society. Global prevalence rates are estimated at 24% for MAFLD, 13% for obesity and 8.5% for T2D. These subgroups are major contributors to the overall number of patients with COVID-19 that require hospitalisation (up to 25–35% in Western countries[10]Docherty A.B. Harrison E.M. Green C.A. Hardwick H.E. Pius R. Norman L. et al.Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol.MedRxiv. 2020; https://doi.org/10.1101/2020.04.23.20076042Crossref Scopus (0) Google Scholar). Trials of treatments that restore gut barrier integrity are also supported by this disease mechanism. For instance, therapeutics that have been developed for IBD, including probiotics and modulators of gut mucosal protection/regeneration, could reduce the number of patients with MAFLD/obesity/T2D that progress to severe COVID-19. Moreover, caution may have to be taken with drugs that disturb intestinal microbiota composition or abundance. The authors received no financial support to produce this manuscript. NAY and GA wrote the letter, RW revised and approved the final version of the letter. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.16 MB) Help with pdf files disclosures.pdf