Influence of Early Postnatal Gut Microbiota on Immune System in SHR Hypertension

Abstract

Hypertension exhibits a prominent immunological component. We have recently shown that spontaneously hypertensive rats (SHR) have a genetic abnormality whereby they are born with a large population of proinflammatory CD161+ immune cells. Although early postnatal maternal environment is important for development of hypertension, its impact on the immune system is not known. Cross‐fostering SHR pups by normotensive Wistar‐Kyoto (WKY) dams lowers the blood pressure in adulthood only if the cross‐fostering is initiated at a very young age. In this study, we used SHR as a genetic model of hypertension to test whether early postnatal gut microbiota affect the immune system and blood pressure of SHR. Since cross‐fostering permanently changes the gut microbiota of the fostered offspring, we first examined the microbial populations in the fecal samples of SHR and normotensive control WKY using 16s rDNA sequencing. We found that the newborn SHR (1‐week old) have abnormal gut microbiota that is qualitatively and quantitatively different from the newborns of normotensive WKY. The representation of predominant bacterial phylum Proteobacteria was less in 1‐week old SHR pups (94% Proteobacteria in WKY vs. 65% in SHR neonates). Even within the phylum Proteobacteria, the colonizing genera in WKY and SHR differed dramatically. In contrast, the representation of phylum Fermicutes in the neonatal SHR gut was greater than WKY (5% Fermicutes in WKY vs. 31% in SHR). We also observed a dramatic shift in 1‐week old SHR gut microbiota when we cross‐fostered WKY and SHR pups beginning at 1‐day of age. Two major bacterial genera of phylum Proteobacteria present in self‐fostered SHR pups, but absent in WKY, were depleted after cross‐fostering, and were replaced by other bacteria predominant in WKY gut. Investigation of immune cells in the spleen of cross‐fostered SHR using cell surface markers and flow cytometry showed that there was a clear reduction in CD161+ cells (30.7% in self‐fostered SHR vs. 12.6% in cross‐fostered SHR at 30 weeks of age), a marker associated with inflammation. Thus, cross‐fostering of SHR pups by WKY dams shifted the composition of their gut microbiota toward WKY within one week. Additionally, preliminary results suggest lower systolic blood pressure (tail cuff pressure) in cross‐fostered SHR. In summary, SHR are born with a defect in their immune system that results in greater proinflammatory response associated with hypertension. Moreover, the gut microbiota of the SHR is remarkably different from that of normotensive WKY, and cross‐fostering of SHR by WKY dams favorably changes the gut microbiome and immune regulation.Support or Funding InformationNational Institutes of Health Program Project Grant to FMA (HL 14388) VA Merit Review Award to MWC (1 I01 BX001414), American Heart Association Innovative Research Grant to MVS (16IRG27260323).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.