Neuroimmune mechanisms recruited by salt-dependent hypertensive stimuli shape splenic and gut components to influence cardiac function

Background Hypertensive stimuli increase sympathetic drive to peripheral organs, contributing to blood pressure (BP) elevation and end organ damage. We previously demonstrated that the autonomic nervous system (ANS) influences immune responses relevant for BP regulation and cardiac remodeling, through the splenic innervation that in turn controls cardiac resident macrophages (CRM). However, the ANS in the splanchnic district controls the gut as well, and gut barrier defects are frequently observed in hypertension, suggesting that gut-derived signals could play an additional role. Purpose Whether ANS concomitantly influences immune and microbial components to dictate the fate of cardiac remodeling during hypertensive stimuli remains unknown. Here we have characterized the effect of two independent models of hypertension – Ang II or L-NAME + High Salt Diet (HSD) – on the ANS mediated modulation of spleen and gut, in relation to cardiac remodelling. Methods C57Bl/6J mice were treated with HSD 4% + L-NAME (0,5 g/L) in drinking water or with AngII in osmotic minipumps. BP was monitored by tail cuff, cardiac remodelling by echocardiography, ANS by microneurography, immune response by flow cytometry, dysbiosis by rRNA 16S of faecal pellet by Next Generation Sequencing (NGS). Results L-NAME/HSD and AngII induced the same BP elevation and cardiac hypertrophic remodelling. Both hypertensive stimuli induced a surge in splenic sympathetic nerve activity, paired with the release of Placental Growth Factor (PlGF) - a key element of neuroimmune activation in hypertension. However, the analysis of gut microbiota showed divergent phenotypes. While AngII did not significantly change microbial composition, L-NAME/HSD selectively expanded bacterial groups belonging to Verrucomicrobia phylum and Akkermansia Muciniphila species. Interestingly, while both models of hypertension led to CRM expansion, AngII influenced the subpopulation of CRM partially replenished by recruited cells, previously found by us as dependent on PlGF, instead L-NAME/HSD increased CRM expanding only through local proliferation. These results suggest that the two hypertensive hits could differently influence cardiac remodelling to hypertensive stress. To dissect the contribution of gut metabolite alterations, we executed a faecal microbiota transplantation (FMT) from L-NAME/HSD mice into recipient mice treated with antibiotics to deplete their commensal microbiota. FMT mice developed cardiac dysfunction in the absence of any hypertensive stimulus, suggesting that specific gut microbial metabolites could contribute to local milieu influencing the cardiac immune signature. Conclusion Our findings demonstrate that the crosstalk between the gut, spleen and heart is differently affected by AngII or L-NAME/HSD. Future studies will be needed to clarify which gut metabolite influences CRM responsible for the observed cardiac remodeling.