COVID-19 and Its Sequelae on the Gut-Brain Axis

Written by: Shruthi Aravindan
Edited by: Esther Melamed

COVID-19 infection is often characterized by a cytokine storm which contributes to the high levels of inflammation. While COVID-19 is most commonly a respiratory infection, there are often symptoms that manifest in other parts of the body and in conjunction with multiple organ failure in severe cases. One of the often-overlooked effects of COVID-19 is on the enteric nervous system (ENS), which is composed of neurons that line the walls of the gastrointestinal (GI) tract.

The gut microbiome is a collection of microbes that live in the GI tract and play an important role in stabilizing the body’s metabolic processes. Since the maintenance of normal gut flora is essential to maintaining the body’s homeostasis, a disruption in the gut microbiota, also called gut dysbiosis, can result in metabolic diseases and increased systemic and neurological inflammation. The GI system is tightly connected to the nervous system through the Gut-Brain Axis, and leads to bidirectional communication between the gut and the brain, influencing the body’s metabolism, immune, and neurological functions.

As a result of  COVID-19, patients already experience increased inflammation and reduced efficiency of anti-inflammatory mechanisms. These two effects in conjunction with gut dysbiosis due to COVID-19 can lead to the magnification of clinical symptoms as well as cause further shifts in the gut microbiota, such as affecting gut bacterial diversity and lower production of the body’s beneficial metabolites. From a GI perspective, these changes can lead to disruptions in the digestive processes and overall metabolism. In addition, due to the bidirectional connection between the central and enteric nervous systems through the gut-brain axis, the shifts in the gut flora result in changes within the gut that are governed by the autonomic nervous system, such as visceral hypersensitivity, slowing or increase in GI motility (leading to constipation or diarrhea),  or abdominal pain. Although these symptoms are more commonly observed in neurological disorders such as  Alzheimer’s, Parkinson’s disease, or Multiple Sclerosis,  there is emerging evidence of these symptoms in patients with COVID-19 and Long-COVID syndrome. 

Importantly, shifts in gut flora can also affect diseases such as hypertension, kidney failure, and cancer and contribute to worse outcomes in COVID-19 patients with these co-morbidities.  In turn, these diseases can be exacerbated due to COVID-19. Further, shifts in the gut microbiota have been reported as a risk factor for thrombosis due to COVID-19. The presumed mechanism is that gut dysbiosis may lead to the escape of endotoxins and bacteria from the gut into the bloodstream, which in turn could contribute to local inflammation in blood vessels leading to the formation of thrombi. The higher propensity for thrombus formation can in turn contribute to deep vein thrombosis, pulmonary embolism, and stroke. 

Nevertheless, there is a ray of hope in that the Gut-Brain Axis can be targeted to affect the outcomes of COVID-19 by modulating gut flora and reversing gut dysbiosis.  To this end, fecal transplants and probiotics have been proposed as possible ways to reverse gut dysbiosis The effectiveness of these methods could be measured through the levels of gut bacteria and gut bacterial metabolite production. Of course, further research is required to better understand which bacterial species may be beneficial.