Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein–Barr virus and the gut–brain axis

Nature The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in a serious public health burden worldwide. In addition to respiratory, heart, and gastrointestinal symptoms, patients infected with SARS-CoV-2 experience a number of persistent neurological and psychiatric symptoms, known as long COVID or “brain fog”. Studies of autopsy samples from patients who died from COVID-19 detected SARS-CoV-2 in the brain. Furthermore, increasing evidence shows that Epstein–Barr virus (EBV) reactivation after SARS-CoV-2 infection might play a role in long COVID symptoms. Moreover, alterations in the microbiome after SARS-CoV-2 infection might contribute to acute and long COVID symptoms. In this article, the author reviews the detrimental effects of COVID-19 on the brain, and the biological mechanisms (e.g., EBV reactivation, and changes in the gut, nasal, oral, or lung microbiomes) underlying long COVID. In addition, the author discusses potential therapeutic approaches based on the gut–brain axis, including plant-based diet, probiotics and prebiotics, fecal microbiota transplantation, and vagus nerve stimulation, and sigma-1 receptor agonist fluvoxamine. Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to threaten public health worldwide. COVID-19 patients frequently experience sequelae such as shortness of breath or dyspnea, and fatigue or exhaustion [1,2,3]. A number of neurological and psychiatric symptoms have also been linked to COVID-19, including anosmia (or loss of smell), ageusia (or loss of taste), cognitive impairment, depression, anxiety, and sleep disturbance [1,2,3]. Long-lasting symptoms following SARS-CoV-2 infection are known as long COVID or post-COVID conditions [4,5,6]. The World Health Organization reported that long COVID is defined as the symptoms that usually occur 3 months after infection of SARS-CoV-2, with symptoms lasting for at least 2 months [7]. Long COVID has impacts on multiple tissues, including respiratory and non-respiratory organs such as the heart, kidney, immune system, pancreas, gastrointestinal (GI) tract, and brain (Fig. 1) [3, 6, 8]. However, the precise biological mechanisms underlying long COVID remain elusive. At present, there are several hypothesized mechanisms, including immune dysregulation, dysbiosis of the gut microbiome, autoimmunity, clotting and endothelial abnormalities, and altered neurological signaling [3]. Unfortunately, current diagnostic and treatment options are insufficient.

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