Impact of intestinal dysbiosis and microbiota-derived extracellular vesicles on the pathogenesis and clinical manifestations of long COVID

It is estimated that 14.8% of Canadians who had COVID-19 will have complications lasting beyond 12 weeks after the initial infection (i.e., long COVID). Long COVID can be debilitating and last for years. Some of the most common and long-lasting symptoms are neuropsychological and include extreme fatigue, brain fog, and symptoms of depression and/or anxiety. The causes of long COVID are poorly understood, and as a result, diagnostic blood tests and effective treatments are lacking. Our previous studies suggest that long COVID is associated with a disruption of the intestinal microbiota (i.e., community of bacteria that live in the gut) which causes leaky gut and inflammation. We hypothesize that these perturbations of the microbiota contribute to the development and persistence of the neuropsychological manifestations of long COVID. However, the mechanisms by which changes in the intestinal microbiota can cause these neuropsychological complications are unknown. Bacteria have been shown to shed parts of themselves in the form of circular structures that pinch off like knobs of dough called extracellular vesicles (EVs). EVs contain several molecules that can have an impact on different cells in the body. Given that the microbiota is mostly composed of bacteria, we believe that microbiota-derived EVs can cause inflammation in the gut leading to leakiness which allows for microbiota-derived EVs to transfer from the gut into the bloodstream thereby causing inflammation in the brain. We will test this hypothesis using mice that have been exposed to stool or microbiota-derived EVs from patients with and without long COVID. We will also evaluate the impact of microbiota-derived EVs isolated from the blood and stool of patients with long COVID on human gut, blood and neural cells. We expect that these studies will help us identify new ways to diagnose and possibly treat long COVID by targeting the gut microbiota and microbiota-derived EVs.