impact of lp299v on vascular function in patients with pasc

Conditions: COVID-19

Summary: 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.

Eligibility criteria:
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)

Keywords: endothelial function pasc covid-19 inflammation microbiome