Elevated HMGB1 mediates microbiome-immune axis dysregulation underlying reduced neutralization capacity in obesity-related post-acute sequelae of SARS-CoV-2

While obesity is a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC, "long-COVID"), the mechanism(s) underlying this phenomenon is poorly understood. To address this gap in knowledge, we performed a 6-week longitudinal study to examine immune activity and gut microbiome dysbiosis in post-acute stage patients recovering from SARS-CoV-2 infection. Self-reported symptom frequencies and blood samples were collected weekly, with plasma assessed by ELISA and Luminex for multiple biomarkers and immune cell profiling. DNA from stool samples were collected at the early stage of recovery for baseline assessments of gut microbial composition and diversity using 16S-based sequencing. Multiple regression analyses revealed obesity-related PASC linked to a proinflammatory immune profile and reduced adaptive immunity, corresponding with gut microbial dysbiosis. In particular, the high mobility group box 1 (HMGB1) protein was found to be a central mediator of this dysregulation, with its upregulated levels in plasma associated with significantly impaired viral neutralization that was exacerbated with obesity. Plasma levels of HMGB1 also negatively correlated with B-cell activating factor (BAFF), while inducing pro-inflammatory nitric oxide. These findings strongly implicate HMGB1 as a candidate biomarker of PASC, with potential applications for risk assessment and targeted therapies.