COVID-19-associated encephalopathy: connection between neuroinflammation and microbiota-gut-brain axis

Abstract

While neurological complications of COVID-19, such as encephalopathy, are relatively rare, their potential significant impact on long-term morbidity is substantial, especially given the large number of infected patients. Two proposed hypotheses for the pathogenesis of this condition are hypoxia and the uncontrolled release of proinflammatory cytokines. The gut microbiota plays an important role in regulating immune homeostasis and overall gut health, including its effects on brain health through various pathways collectively termed the gut-brain axis. Recent studies have shown that COVID-19 patients exhibit gut dysbiosis, but how this dysbiosis can affect inflammation in the central nervous system (CNS) remains unclear. In this context, we discuss how dysbiosis could contribute to neuroinflammation and provide recent data on the features of neuroinflammation in COVID-19 patients.

Keywords: COVID-19; butyrate; cytokine; encephalopathy; gut microbiome; gut-brain axis; inflammation; probiotic.

Figure 1

Pathogenesis of SARS-CoV-2-induced neuroinflammation. Two main theories explain the neuroinflammation observed in COVID-19 patients. The first theory is attributed to reduced systemic oxygenation, which leads to cerebral hypoxia and secondary brain damage, known as brain-lung crosstalk. The second theory involves the direct invasion of SARS-CoV-2, which triggers a hyperinflammatory response, causing a cytokine storm with inflammatory mediators such as IL-1β, IL-6, and TNF. This storm damages the blood–brain barrier (BBB), allowing immune cells and proinflammatory molecules to enter the brain. As a result, microglia and astrocytes become reactive. Microglia increase the production of reactive oxygen species, cytokines, and chemokines while reducing brain-derived neurotrophic factor (BDNF). Astrocytes increase glial fibrillary acidic protein (GFAP) and vimentin expression, leading to structural changes and reduced neurotransmitter recycling.

Figure 2

Overview of Pathogens that Cause Neuroinflammation. Neuroinflammation, a secondary inflammatory response in the brain, can occur as a result of peripheral infections caused by viruses, bacteria, or parasites. Inflammatory mediators that affect the brain endothelium and parenchyma as well as the subsequent response of brain cells to these mediators mediate this response.

Figure 3

The Potential Impact of the Gut Microbiota on Neuroinflammation. Coronaviruses actively replicate in enterocytes since they highly express ACE2. The available data support a change in the microbiota in COVID-19 patients. Altered microbiota can cause intestinal barrier damage, systemic translocation of microbial products, and systemic inflammation. Additionally, the microbiota is connected to the brain via the vagus nerve and is referred to as the gut–brain axis.

Figure 4

Treatment Options for COVID-19-associated Encephalopathy. Supportive therapy includes supplemental oxygen to address hypoxemia and immune modulation with high-dose corticosteroids and intravenous immunoglobulin to manage the systemic inflammatory response. Plasmapheresis can help reduce proinflammatory marker levels and improve consciousness in severe cases. Immunomodulation involves tocilizumab, which may reduce the need for mechanical ventilation in some patients but does not guarantee improved survival. Probiotic therapy with strains such as Lactobacillus plantarum and Pediococcus acidilactici has shown potential in reducing viral load and improving symptoms. Studies suggest that probiotic-supplemented patients may have shorter hospital stays and better outcomes.