The Gut-Brain Axis May Mediate Gastrointestinal and Neurological Symptoms of COVID-19

June 2, 2020 by Sam Bazzi

The gut microbiome and the gut-brain connection are currently hot topics in neuroimmunology, so I am constantly on the lookout for studies describing dysbiosis in COVID-19 patients. There are currently no large-scale studies on changes to the microbiome after SARS-CoV-2 infection, but there have been some interesting theories posed as to how the gut microflora and gut-brain axis may be mediating neurological and gastrointestinal (GI) symptoms.

Writing in Inflammatory Bowel Disease, Mehmet Bostancıklıoğlu hypothesizes that after the initial respiratory symptom onset, the neurological and GI symptoms that develop at nearly the same time during the course of the infection may be interlinked via the gut-brain axis. The author starts by describing the incidence of GI symptoms in cases of COVID-19. Despite initial studies demonstrating low incidence of GI symptoms, more recent estimates place the incidence at 11.4%-24.2% (Bostancıklıoğlu, 2020). He then cites a study in China that revealed GI symptoms from COVID-19 do not necessarily correlate with RNA shedding into the feces (Lin et al., 2020). Out of the 95 patients studied, 11 had GI symptoms upon admission and 47 developed symptoms upon hospitalization, with the most common symptoms being diarrhea (24.2%), anorexia (17.9%), and nausea (17.9%). They then analyzed the fecal samples of patients with and without GI symptoms for the presence of SARS-CoV-2 RNA and found there was not a significant difference. Based on this result, Mehmet Bostancıklıoğlu claims that this discrepancy can be explained by gut-brain crosstalk.

The most direct proposed mechanism for SARS-CoV-2-related GI symptoms is the direct invasion of the virus via ACE2, which is expressed in the gut. This explanation does not provide the full picture because of the discrepancy mentioned above, as we would expect that all GI distress associated with viral inflammation would lead to viral shedding. Instead, the author describes the possibility that the virus can invade the lateral hypothalamic nuclei, which would lead to GI symptoms such as anorexia and nausea without viral infection of the gut. This would explain why GI symptoms occur without viral RNA shedding. Alternatively, the virus may invade the GI tract and cause inflammation and gut microbiome dysbiosis. This would then lead to viral RNA shedding into the feces, as other studies have demonstrated intestinal inflammation during COVID-19 is correlated with the presence of viral RNA in fecal samples (Effenberger et al., 2020). Additionally, the author goes on to say that proinflammatory mediators from the gut can then reach the brain via the lymph or blood, or perhaps through activation of the vagal nerve, which would go on to cause neurological symptoms.

This opinion piece brings up a lot of interesting questions that have yet to be answered. So far, there are no studies on how GI symptoms develop during COVID-19, so I wonder how the virus is entering the GI tract. From what I’ve read, it seems like no one has been able to isolate and culture viable, intact virus from patient blood, so perhaps the virus is entering via the oral route – maybe from eating infected food or swallowing a significant amount of infected aerosol droplets. It will be interesting to see if anyone is able to isolate and culture viable virus from the digestive tract of COVID-19 patients. Additionally, it will be interesting to see if COVID-19 patients (with varying severities of GI and neurological symptoms) have dysbiotic gut microbiomes and then look at which bacterial species are over- and under-represented across the spectrum of symptom severity. Perhaps this may offer some insight into how different gut microbiome compositions may affect clinical outcomes for COVID-19. Finally, more studies need to be done on the neuroinvasive potential of SARS-CoV-2, and how this hypothesized invasion of the CNS may mediate symptoms in other organ systems.

Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
6/2/2020