The long-term goals of this research are to determine the mechanisms that underlie Post-Acute Sequelae of SARSCoV-2 (PASC)-related symptoms in Veterans and to develop targeted and personalized treatments. PASC is a condition of long-term symptom burden following coronavirus disease 2019 (COVID-19) that is having serious adverse effects among Veteran populations. Known colloquially as Long-COVID, symptoms of pain, fatigue, irritable bowel, and cognitive impairment overlap considerably with chronic multisymptom illnesses (CMIs) such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf War illness (GWI). Critically, all three conditions report that physical activity worsens their illness, a characteristic of CMIs known as post-exertional malaise (PEM). As with CMIs, PEM is a promising model for studying Long-COVID in Veterans because, as we have shown in ME/CFS and GWI, PEM reveals pathophysiology not apparent at rest by challenging multiple physiological systems. The causes of PEM/CMIs are currently unknown, but converging evidence suggests that gut-microbiome perturbations and neuroinflammation act to sustain/worsen symptoms. Our central hypothesis is that neuroinflammation and gut-microbiome perturbations act to produce and maintain symptoms, and that dysfunction among these systems is best studied using an exercise challenge model. Our pilot data indicate that those with CMI: 1) report moderate-to-large symptom changes and worsened cognitive performance following a standardized exercise challenge; 2) show disturbed gut microbiome at rest and differential responses to exercise compared to controls, and 3) that peripheral inflammation (interleukin-6) is associated with augmented brain activity during fatiguing cognition in ME/CFS compared to controls. We intend to extend our exercise challenge research in CMI to PASC with the following specific aims: Aim 1: To determine the effects of a standardized exercise challenge on PEM (symptoms and cognition). Aim 2: To determine the effects of a standardized exercise challenge on gut microbiome structure and function. Aim 3: To determine the effects of a standardized exercise challenge on neuroinflammation. This study will significantly enhance our understanding of PASC and will begin to determine the pathophysiological mechanisms that underlie symptoms at rest and symptom worsening with physical effort. The COVID-19 pandemic offers a unique window of opportunity to evaluate pathophysiology early in disease development and with known proximity to the initiating event – i.e., COVID-19 infection. This is a rare occurrence in CMI research, and one that can provide critical mechanistic insight to aid in the development of targeted and personalized therapies.

Post-Acute Sequelae of SARSCoV-2 (PASC), a chronic multisymptom illness, is affecting an alarming number of Veterans infected by the COVID-19 virus. PASC symptoms are often debilitating and can include various combinations of fatigue, pain, irritable bowel, and brain fog, severely impacting health quality. Importantly, exercise is reported to worsen the symptoms of PASC, a condition of post-exertional malaise (PEM), which interferes with recovery. The causes of PASC symptoms and their exacerbation with exercise are unknown, limiting treatment options. Two candidate mechanisms are disturbed gut microbiome and neuroinflammation. The proposed research will test whether Veterans with PASC exhibit PEM and whether exercise disrupts the gut microbiome and augments neuroinflammation. This research will improve our understanding of the causes of PASC-related symptoms and begin a path towards individualized treatment. These goals are directly in line with the mission of the Department of Veterans Affairs to care for those who have served this country.