Chronic inflammation in post-acute sequelae of COVID-19 modulates gut microbiome: a review of literature on COVID-19 sequelae and gut dysbiosis

Abstract

Background: Long COVID or Post-acute sequelae of COVID-19 is an emerging syndrome, recognized in COVID-19 patients who suffer from mild to severe illness and do not recover completely. Most studies define Long COVID, through symptoms like fatigue, brain fog, joint pain, and headache prevailing four or more weeks post-initial infection. Global variations in Long COVID presentation and symptoms make it challenging to standardize features of Long COVID. Long COVID appears to be accompanied by an auto-immune multi-faceted syndrome where the virus or viral antigen persistence causes continuous stimulation of the immune response, resulting in multi-organ immune dysregulation.

Main text: This review is focused on understanding the risk factors of Long COVID with a special emphasis on the dysregulation of the gut-brain axis. Two proposed mechanisms are discussed here. The first mechanism is related to the dysfunction of angiotensin-converting enzyme 2 receptor due to Severe Acute Respiratory Syndrome Corona Virus 2 infection, leading to impaired mTOR pathway activation, reduced AMP secretion, and causing dysbiotic changes in the gut. Secondly, gut-brain axis dysregulation accompanied by decreased production of short-chain fatty acids, impaired enteroendocrine cell function, and increased leakiness of the gut, which favors translocation of pathogens or lipopolysaccharide in circulation causing the release of pro-inflammatory cytokines. The altered Hypothalamic-Pituitary-Adrenal axis is accompanied by the reduced level of neurotransmitter, and decreased stimulation of the vagus nerve, which may cause neuroinflammation and dysregulation of serum cortisol levels. The dysbiotic microbiome in Long COVID patients is characterized by a decrease in beneficial short chain fatty acid-producing bacteria (Faecalibacterium, Ruminococcus, Dorea, and Bifidobacterium) and an increase in opportunistic bacteria (Corynebacterium, Streptococcus, Enterococcus). This dysbiosis is transient and may be impacted by interventions including probiotics, and dietary supplements.

Conclusions: Further studies are required to understand the geographic variation, racial and ethnic differences in phenotypes of Long COVID, the influence of viral strains on existing and emerging phenotypes, to explore long-term effects of gut dysbiosis, and gut-brain axis dysregulation, as well as the potential role of diet and probiotics in alleviating those symptoms.

Keywords: COVID-19; Gut-brain axis; Inflammation; Long COVID; Microbiota; PASC.

Fig. 1

The suggested mechanism of possible gut dysbiosis and persistent SARS-CoV-2 infection in Long COVID. Long COVID-mediated ACE2 dysfunction is characterized by the persistent presence of SARS-CoV-2 (1), which leads to internalization of the ACE2-B⁰AT1 complex (2), resulting in decreased tryptophan absorption (3). This leads to decreased mTOR activation which is needed for AMP and TJ formation. Reduced levels of AMPs affect the normal bacterial composition and decreased TJ functioning allows for bacterial translocation, resulting in bacterial imbalance (4). The subsequent dysbiosis is characterized by an increase in the number of opportunistic pathogens, including species belonging to Clostridium, Micrococcus, and Veillonella, with a decrease in beneficial SCFAs producing bacteria including those belonging to species Bifidobacterium, Faecalibacterium, and Eubacterium (5). SCFA, namely butyrate, acetate, and propionate, which are reduced in Long COVID, are responsible for maintaining intestinal homeostasis and immune function (6). SCFAs inhibit histone deacetylase (HDAC) while simultaneously activating histone acetylase (HACT). Imbalance in this acetylation process leads to dysregulation of NF-Kb function, resulting in increased production of pro-inflammatory cytokines. SCFA act on their G-protein coupled receptors (GPR43, GPR41, GPR109A) to carry out anti-inflammatory actions. Decreased activation of these pathways include reduced NLRP3 inflammasome activation, and hence reduced IL-18, needed for innate immunity. Levels of FOXP3 regulatory T cells are also decreased. SCFA typically act as energy sources for intestinal epithelial cells and B cells. Reduced levels lead to less energy for the synthesis of mucosal IgA antibodies by the B cells. Intestinal permeability is increased due to reduced TJ formation, and mucin formation by the goblet cells is also reduced because of decreased SCFA. Additionally, these effects due to decreased SCFA are exacerbated by reduced ACE2 (2), which leads to reduced conversion of Ang ll to Ang 1-7 (3), resulting in pro-inflammatory effects and tissue injury (4). SCFA (Short chain fatty acid), HDAC (histone deactylase), HCAT (histone acetylase), TJ (tight junctions), AMP (antimicrobial peptide), TMPRSS2 (Trans membranous protease serine 2), NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)

Fig. 2

Contribution of microbiota-gut-brain-axis in causing the neurological symptoms of Long COVID. Persistent levels of SARS-CoV-2 in the gastrointestinal wall (1) leads to reduced production of SCFA, as discussed earlier (2). Decreased serum levels of SCFA results in lower production of TJ for the blood-brain barrier, resulting in increased permeability of the brain capillaries (3). As a result, pro inflammatory cytokines [IL-17, IL-6, and IL-1] produced in the gut by opportunistic pathogens (4) can cross the blood brain barrier and activate resident macrophages (5). At the same time, reduced SCFA results in reduced neurotransmitter production in the enteroendocrine cells. This leads to reduced stimulation of the vagus nerve afferents, and consequently, less Ach released on the macrophages. Ach is responsible for inhibiting the production of TNF-α by macrophages. Thus, the collective effect of the opportunistic pathogens and reduced vagal stimulation leads to increased proinflammatory cytokine production by the macrophages (6). The resultant neuroinflammation (7) of the brain parenchyma affects the hypothalamus, which affects the HPA axis (8). Cortisol production increases, which acts in the prefrontal cortex and hippocampus due to their abundant GR (9). This affects synaptic connection and neuronal integrity, which is hypothesized to explain the neurological symptoms of Long COVID, such as depression (10). SCFA (Short chain fatty acids), TJ (tight junctions), NT (neurotransmitter), HPA (hypothalamic pituitary adrenal) axis, EEC (enteroendocrine cell), GR (glucocorticoid receptor), Ach (Acetyl Choline)