Abstract 229: Mucosal Immunity Shapes the Lipoprotein Small-RNA Fingerprint from Commensal, Dietary and Environmental Microbiota

Abstract

Cardiovascular disease (CVD) is a leading cause of mortality in developed countries and is a frequent comorbidity of numerous metabolic and inflammatory diseases that demands more effective therapies. Dyslipidemias are a classical risk factor for CVD, but emerging alternative functions of lipoproteins have implicated them in novel narratives for the pathophysiology of many diseases that warrant further study. Our lab has identified functional, intercellular gene regulatory networks mediated by extracellular transport of microRNAs (miRNA) by lipoproteins. Here, we quantified the landscape of small RNAs (sRNA) on human and animal lipoproteins and discovered that most lipoprotein-sRNAs are derived from microorganisms of multiple kingdoms, primarily bacteria. Based on these observations, our over-arching hypothesis is that lipoprotein-sRNA signatures are shaped by the interface of host tissues with resident, environmental and dietary microbiota, and likely participate in unique gene regulation networks that contribute to complex (patho)physiological traits. To investigate this hypothesis, we developed a sRNA-sequencing analysis pipeline that identifies and quantifies both host and non-host sRNAs. Using this bioinformatic tool, we identified and validated a number of lipoprotein-sRNAs derived from bacteria that are similar in size to miRNAs with identical seed regions, termed Doppelganger (Dopl)-miRNAs. We hypothesized that mucosal immunity contributes to non-host sRNAs on lipoproteins, as mucosal linings are a primary interface between host tissues and microorganisms. To this end, we investigated the lipoprotein-sRNAs of mice lacking the polymeric immunoglobulin receptor (pIgR -/- ), which is devoid of polymeric IgA and IgM at mucosal linings and models human respiratory and intestinal diseases. We report a global increase in lipoprotein-miRNAs juxtaposed with a profound decrease in bacterial sRNA and Dopl-miRNAs from specific taxa. This work unfurls novel links between microbiota, mucosal immunity, and lipoprotein-sRNA gene networks and emphasizes the potential for novel nucleic-acid based therapeutics.