Is the increased risk for MAFLD patients to develop severe COVID-19 linked to perturbation of the gut-liver axis?

Abstract

Two recent studies in the Journal of Hepatology suggest that MAFLD is a risk factor for progression to severe COVID-19. A Chinese study of 202 COVID-19 patients found that those with indicators of MAFLD had a higher risk of respiratory disease progression than non-MAFLD patients [1]. A subsequent study of 327 patients, also from China, found increased risk for COVID-19 progression in younger (<60 years old) MAFLD patients but not in older ones [2]. More studies are required to confirm this, especially in cohorts of COVID-19 patients with imaging or biopsy-proven MAFLD from 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 MAFLD patients. 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, here we wish to highlight the possibility that the increased risk observed in MAFLD patients 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 of COVID-19. Indeed, this process may also explain 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 COVID-19 patients [3]. The severity of digestive symptoms increases alongside others including respiratory symptoms and liver injury [3, 4]. The small intestine has abundant expression of ACE-2 on enterocytes [4], and the high level of virus in feces and 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], which supports the notion of an increase of transmission of pathogen-associated molecular patterns (PAMPs) to the liver. This process could increase severity of COVID-19 by either sequestration of immune resources away from the lungs to gut and liver, or by ‘priming’ the liver and systemic immune systems to hyperactivity of the cytokine storm. The latter explanation may be supported by similarities in the range of circulating proinflammatory cytokines that are induced by NASH and severe COVID-19, such as IL-1β, IL-6, and TNF-α [5, 6]. Futhermore, priming of toll-like receptor (TLR)-mediated proinflammatory release from circulating immune cells has been observed with an initial exposure to malarial parasites [7] or respiratory syncytial virus infection [8], and a subsequent exposure to a TLR agonist (lipopolysaccharide, LPS). MAFLD has been shown to increase levels of TLRs in liver [9], 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 increases in intestinal permeability in COVID-19, that 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 COVID patients that require hospitalisation (up to 25-35% in Western countries [10]). Trials of treatments that restore gut barrier integrity are also supported by this disease mechanism. For instance, therapeutics that have been developed for inflammatory bowel diseases, including probiotics and modulators of gut mucosal protection/regeneration, could reduce the number of MAFLD/obese/T2D patients that progress to severe COVID-19. Moreover, caution may have to be taken with drugs, that disturb intestinal microbiota composition or abundance.