Therapeutic implications of SARS-CoV-2 dysregulation of the gutbrain-lung axis

The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19(COVID-19)pandemic.Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms,including fever,cough,fatigue,and loss of smell and taste.However,many individuals develop pneumonia,acute respiratory distress syndrome,septic shock,and multiorgan dysfunction.In addition to these primarily respiratory symptoms,SARS-CoV-2 can also infiltrate the central nervous system,which may damage the blood-brain barrier and the neuron's synapses.Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves,leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions.Additionally,SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier.As a result,this exacerbates pro-inflammatory responses both locally and systemically,resulting in impaired clinical outcomes.Recent evidence has highlighted the complex interactions that mutually modulate respiratory,neurological,and gastrointestinal function.In this review,we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis.We further highlight targeting specific responses to SARS-CoV-2 for the development of novel,urgently needed therapeutic interventions.Finally,we propose a prospective related to the individuals from Low-and Middle-Income countries.Here,the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.