Emerging data show that SARS-CoV-2 infection causes gut microbiome changes strongly associated with Post-Acute Sequelae of SARS-CoV-2 (PASC). The investigators and others have established that an orally ingested probiotic (Lactobacillus plantarum 299v, Lp299v) reduces circulating levels of cell-free mitochondrial DNA (cf-mtDNA), decreases toll-like receptor 9 (TLR9) activation [and downstream interleukin (IL-6)], and improves micro- and macrovascular (brachial artery) endothelial dysfunction [as measured by flow-mediated dilation (FMD%)] in humans. Recently published data also report impaired brachial FMD% and increased vascular stiffness post-SARS-CoV-2 infection. Based on these data, the investigators hypothesize that supplementation with Lp299v will attenuate SARS-CoV-2 associated endothelial dysfunction by reducing cf-mtDNA, TLR9 activation, and inflammation.

The intestinal immune system plays a critical role in systemic immunity, and its interaction with the systemic immune system plays a crucial role in determining the severity and outcomes of common pulmonary infections. SARS-CoV-2 infection alters the composition and metabolism of the gut microbiome. Greater losses of beneficial species in the human gut microbiome of SARS-CoV-2 patients are associated with severe disease and greater systemic inflammation. These pathological alterations are observed at least 6 months post-infection and are associated with greater residual systemic inflammation and PASC symptoms.

Six weeks of Lp299v supplementation in otherwise healthy smokers reduces circulating levels of the pro-inflammatory IL-6 and reduces monocyte adhesion to endothelial cells. IL-6 is elevated in patients with PASC and strongly correlates with TLR9 activation in disease states with high circulating cf-mtDNA levels. We published trial data showing once daily Lp299v supplementation (20 billion colony forming units/day) in men with coronary artery disease (CAD) improves endothelium-dependent vasodilation in the brachial artery and NO-dependent vasodilation of resistance arterioles from CAD patients. Further, preliminary data suggest Lp299v reduces circulating levels of cf-mtDNA (Fig. 2B). We also published data showing that 6 weeks of Lp299v has a significant anti-inflammatory effect on PBMC gene transcription, with gene ontology analyses indicating Lp299v supplementation inhibits TLR9 activation (z-score -3.48, P<0.0000000023). Combining the evidence that Lp299v reduces (1) circulating cf-mtDNA; (2) TLR9 activation; and (3) IL-6 levels while improving micro- and macrovascular endothelial function make Lp299v an excellent candidate to test as an intervention to improve vascular function in PASC patients.

Therefore, we will recruit subjects ages ≥18-89 who carry a clinical diagnosis of PASC and are within a window of 30-180-day post-acute symptom resolution into an 8-week, double-blind, randomized, placebo-controlled clinical trial of Lp299v supplementation. Measurements of micro- and macrovascular function, systemic inflammation, and stool microbiota composition will be made.

Inclusion Criteria:

• Ages 18 to 89 years
• 30-180 days post-COVID-19 diagnosis
• PASC diagnosed based on symptom report/expert physician judgement

Exclusion Criteria:

• Antibiotics within four weeks of enrollment
• History of chronic diseases (renal insufficiency, liver dysfunction, cancer requiring systemic treatment within 3 years of enrollment)
• History of cognitive impairment/inability to follow study procedures
• Short gut syndrome, inflammatory bowel disease, or an ileostomy.
• Subjects currently taking Vitamin K antagonists such as coumadin or warfarin
• Pregnant at the time of screening
• Unstable coronary artery disease (new symptoms or event within 30 days of enrollment)
• Daily alcohol use (may interfere with Lp299v's action)

Within 1 year of completion of all studies procedures.