Abstract 398: Gut Microbiota Facilitates Apolipoprotein A1 and HDL Production Through Hepatic TLR5

Gut microbiota is considered as an external organ as these trillions of commensal microbes in our gut interact with our body to regulate various physiological responses. The pattern and composition of gut bacteria is subject to alteration by our diet. High fat diet not only decreases the β-diversity of gut microbiota but also increases gut permeability, leading to the leak of bacterial products into circulation, which aggravates various diseases including atherosclerosis by escalating inflammation. Paradoxically high fat intake can augment HDL level (J Clin Invest 91:1665-71, 1993). Moreover, gut microbiota was shown to contribute the variation of HDL but not LDL or total cholesterol level in a human study. (Circ Res 117: 817-24, 2015) We speculate that gut microbiota may provide an adaptive protection by upregulating HDL level. In this study, we investigated the possible underlying mechanism of how gut microbiota affects HDL level. C57BL/6J mice were fed a normal chow diet and a high fat diet (HFD, 45% fat kcal) for 10 weeks. Other than decreasing the β-diversity of gut microbiota, HFD increased the portion of flagellated bacteria, resulting in the increase of hepatic but not circulating level of flagellin, the ligand of toll-like receptor (TLR5). Deletion of TLR5 in mice suppressed HFD-stimulated HDL level. Treatment with flagellin in hepatocytes was able to stimulate apolipoprotein A1 (apoA), the primary apolipoprotein on HDL in TLR5-dependent manner. Blocking the downstream signaling of TLR5 by silencing MYD88 blocked the flagellin-induced apoA1 production in wild type hepatocytes. Lipopolysaccharides, another important bacterial product which can activate MYD88 signaling, failed to elicit the same effect. It might be due to the different degree of sensitivity of these TLRs in hepatocytes. In addition, supplementation of flagellin to atherogenic mice (apoE knockout mice) by oral gavage was able to elevate apoA1 and HDL levels in circulation, partially protecting against atherosclerosis. Our data provides a molecular explanation of how commensal bacteria in gut stimulate HDL production upon HFD, and such finding will provide an insight in developing alternative strategy to stimulate HDL production and prevent atherosclerosis.