Abstract 1156: Akkermansia (Strain BAA835) And The Microbial ADP-heptose Pathway Are Associated With Reduced Neointimal Hyperplasia After Arterial Injury

Introduction: Despite advances in surgical therapy for atherosclerosis, up to 50% of procedures such as balloon angioplasty, stenting, and bypass fail due to restenosis from neointimal hyperplasia, a cell proliferative process potentiated by inflammation. We hypothesized that neointimal hyperplasia is associated with a distinct gut microbiome profile and can be modulated by fecal transplantation. Methods: We performed fecal transplantation (FT) of C57BL6 mice using donors with differential microbiome profiles and susceptibility to neointimal hyperplasia (Sprague-Dawley [SD] and Lewis [LE] rats, high and low susceptibility, respectively). In separate experiments, germ-free mice underwent FT using C57BL6 donors with and without Akkermansia muciniphila BAA835 ( Amuc ) prior to arterial injury. Microbial communities were characterized using 16S rRNA gene amplicon and shotgun metagenome sequencing. Arterial and immune effects were assessed using frozen arterial sections, multi-parameter flow cytometry of mesenteric lymph nodes, or multiplex cytokine assays after ex vivo stimulation of whole blood with lipopolysaccharide. Results: Paradoxically, neointimal hyperplasia after injury was 67.7% greater in FT recipients of low- compared to high-susceptibility stools (P=0.01). In fecal communities of both FT recipient groups, relative abundance of A. muciniphila (r=-0.66, P<0.001) and of the ADP-heptose biosynthesis pathway (r=-0.7, P<0.001) were negatively associated with neointimal hyperplasia. A. muciniphila was differentially elevated (P<0.001) in SD compared to LE FT recipients and was the main contributing taxa for the enrichment (P<0.001) of the ADP-heptose biosynthesis pathway in the SD recipient group. In mice colonized with communities that differed only by the presence of Amuc , neointimal hyperplasia was 57.8% greater in the Amuc - group compared to Amuc+ (P=0.01). Amuc+ recipients had lower levels of IL-12, MIP-1beta, and MCP-1 in unstimulated blood and higher IP-10 and MCP-1 levels in stimulated blood. Conclusion: A. muciniphila and microbial ADP-heptose biosynthesis pathway are inversely associated with neointimal hyperplasia and are potential targets for novel microbe-based strategies to mitigate restenosis risk.