Abstract

Long COVID has emerged as a significant public health challenge with no effective treatments currently available, yet the pathophysiological mechanisms underlying its persistent gastrointestinal (GI) symptoms remain poorly understood. Here, integrating clinical data with transgenic animal models, we discover a critical role for impaired intestinal epithelial repair in the local intestinal etiology of long COVID. Mechanistically, we show that intestinal SARS-CoV-2 reservoirs disrupt very-long-chain fatty acid (VLCFA) metabolism, suppressing activation of peroxisome proliferator-activated receptor (PPAR) signaling and reducing peroxisome abundance. This disruption impairs intestinal stem cell differentiation and epithelial regeneration, resulting in prolonged GI symptoms including diarrhea, inflammation, and microbiota dysbiosis. Importantly, the FDA-approved sodium phenylbutyrate (NaPB) and fenofibrate alleviate these symptoms by promoting peroxisome proliferation and restoring epithelial repair. These findings provide insights into the GI pathogenesis of long COVID and highlight the therapeutic potential of enhancing the VLCFA-PPAR-peroxisome axis to mitigate persistent GI complications.