# Genetic predictors, pathophysiological mechanisms, and functional consequences of post-acute sequelae of SARS-CoV-2: Exercise challenge of gut microbiome and neuroinflammation in PASC

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10611031
- **Project number:** 1I01CX002616-01
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** DANE B. COOK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10611031

## Citation

> US National Institutes of Health, RePORTER application 10611031, Genetic predictors, pathophysiological mechanisms, and functional consequences of post-acute sequelae of SARS-CoV-2: Exercise challenge of gut microbiome and neuroinflammation in PASC (1I01CX002616-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10611031. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*