PB1345 - Gut microbiota and diet as organotypic regulator of the microvascular endothelial transcriptome

Background: The mammalian gut harbors diverse microbial communities, which are shaped by diet and profoundly influence host physiology and vulnerability to diseases. Changes in the gut microbiome are implicated with alterations in endothelial function and thus play an essential role in impacting the microvascular system. Despite functional similarities, endothelial cells (ECs) of different organs present a highly specialized and organotypic phenotype. However, the involvement of the gut microbiota in shaping endothelial transcriptomes of remote organs at hyperlipidemic conditions is still limitedly understood.

Aims: In the present study, we aim to provide new insights on microbiome-induced changes of the endothelial cell transcriptome in liver, lung, visceral adipose tissue (VAT), and brain.

Methods: The low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model was kept germ-free (GF) or conventionally raised (CONV-R). Following 8 weeks of feeding with normal chow (ND) or high-fat diet (HFD), ECs from liver, lung, VAT, and brain were isolated using a magnetic cell separation technique. Following RNA isolation, whole-transcriptome sequencing analysis was performed.

Results: In CONV-R and GF Ldlr-/- mice, 8 weeks of HFD-feeding led to a complex regulation of different genes involved in angiogenesisis, vasculogenesis, and activation state of different EC types. For instance, microbiota-regulated genes in EC vasculogenesis included Asb4 or Kdr in liver while Ramp2 or Rras where highly regulated in lung ECs. Interestingly, we found an upregulation of the activation and cell adhesion marker E- and P-Selectin in liver ECs. However, this diet-dependent phenotype was not found in remote endothelial transcriptomes. In GF mice, E- and P-Selectin was found downregulated in brain and VAT whereas upregulated in the lung, indicating a heterogenous role of gut microbiota in the activation state of different microvascular endothelia.

Conclusion(s): Here, we report the gut microbiota is a complex and organ specific regulator of remote endothelial transcriptomes, affecting angiogenesis, EC activation, and genes involved in microvascular inflammation.