The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature

Abstract

The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.

Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms

“…It does, however, unify several other hypotheses for the pathogenesis of PACS and its neurocognitive symptoms, including innate immune dysregulation, impact on microbiota, as well as endothelial and epithelial damage and dysfunction that can lead to degradation of brain and intestinal barriers, respectively (Arthur et al, 2021;Haffke et al, 2022;Davis et al, 2023). Similar models along the gut-brain axis have been described previously (Vakili et al, 2022;Gareau and Barrett, 2023), and while our narrative for the initiation and maintenance of neurocognitive symptomology reflects these existing models, we also elaborate on the specific metrics that can be quantified experimentally to assess each component of the model. The described mechanism of gut-brain pathology has been described extensively in other disorders, such as depression (Valles-Colomer et al, 2019), anxiety (Kim and Shin, 2018), neurodegenerative conditions (Ryman et al, 2023), and other chronic multi-symptom illnesses such as Gulf War illness (Alhasson al., 2017;Bajaj et al, 2019;Keating et al, 2019).…”

“…It does, however, unify several other hypotheses for the pathogenesis of PACS and its neurocognitive symptoms, including innate immune dysregulation, impact on microbiota, as well as endothelial and epithelial damage and dysfunction that can lead to degradation of brain and intestinal barriers, respectively ( Arthur et al, 2021 ; Haffke et al, 2022 ; Davis et al, 2023 ). Similar models along the gut-brain axis have been described previously ( Vakili et al, 2022 ; Gareau and Barrett, 2023 ), and while our narrative for the initiation and maintenance of neurocognitive symptomology reflects these existing models, we also elaborate on the specific metrics that can be quantified experimentally to assess each component of the model.…”

The Role of Gut Dysbiosis in the Loss of Intestinal Immune Cell Functions and Viral Pathogenesis

“…Intestinal homeostasis is intricately connected to the central nervous system (CNS) through the physiological contributions of gut microbiota, regulation of intestinal barrier function, and activity of peripheral neurons. Referred to as the “microbiome–gut–brain axis”, the communication between the gut and brain has recently garnered much interest in the context of long-term neurological symptoms of COVID-19 [ 124 ], which include chronic fatigue, anxiety, olfactory and gustatory dysfunction, dementia, depression, anxiety, memory impairment, stroke, and encephalitis.…”

“…The complex bidirectional communication pathway between the GI tract and CNS involves a network of neural, hormonal, and immunological pathways that allow for coordinated responses to changes in the gut environment, such as exposure to pathogenic viruses. For instance, gut dysfunction and systemic inflammation driven by chronic HIV infection lead to neurological symptoms such as cognitive impairment, depression, and anxiety [ 124 , 126 ]. Furthermore, the development of HIV-associated neuroinflammation and cognitive impairment has been directly linked to gut dysbiosis and increased intestinal permeability [ 127 ].…”

The microbiome in post-acute infection syndrome (PAIS)

“…A range of pathogens (Coronaviruses, HIV, Zika virus, Enteroviruses, Rotaviruses, Influenza virus, and others) are known to cause GBA disturbance by affecting gut bacteriome, virome and mycobiome, which further regulate the brain activity. Driven by the alteration of microbiome, GBS-associated key modulators, including short-chain fatty acids, 5-hydroxytryptamine, cytokine, cholecystokinin, and LPS have been found altered in different PASC and ME/CFS studies [72] . Furthermore, as one of the potential outcomes, fatigue appears to be linked to neuroinflammation, which is a main clinical manifestation in the PAIS [73] .…”