Early Postnatal Gut Microbiota Determines SHR Hypertension

Abstract

Hypertension is regulated by immunological components. We have shown that spontaneously hypertensive rats (SHR) display a genetic abnormality in a large population of proinflammatory CD161+ immune cells. Although early postnatal gut microbiota is important for development of the immune system, this relationship has not been studied in hypertension. Cross‐fostering SHR pups by normotensive Wistar‐Kyoto (WKY) dams lowers the blood pressure in adulthood when cross‐fostering is initiated at a very young age. In this study, we tested whether early alteration in postnatal gut microbiota affect s the immune system and blood pressure of SHR. 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 the predominant bacterial phylum Proteobacteria was significantly less in 1‐week old SHR pups than in WKY (94% Proteobacteria in WKY vs. 65% in SHR neonates). Even within the phylum Proteobacteria, the colonizing genera in WKY and SHR differed dramatically. Whereas WKY microbiota was predominantly comprised of Escherichia‐Shigella (92.5%), SHR microbiota was represented by Klebsiella (34.7%) and Haemophilus (27.8%). 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 cross‐fostered newborn SHR pups by lactating WKY dams and measured the resulting changes in the gut microbiota, immune system and blood pressure. Cross‐fostering caused a dramatic shift in 1‐week old cross‐fostered SHR gut microbiota. The two major bacterial genera of phylum Proteobacteria, Klebsiella and Haemophilus, present in self‐fostered SHR pups, were depleted after cross‐fostering, and were replaced by the predominant genera of WKY (Escherichia‐Shigella). A proinflammatory CD161+ immune cell population in the spleen of cross‐fostered SHR was also reduced (30.7% in self‐fostered SHR vs. 12.6% in cross‐fostered SHR at 30 weeks of age) as was the systolic blood pressure in adult cross‐fostered SHR (SHR 204 mmHg vs. cross‐fostered SHR 177 mmHg, p= 0.02, n= 4 each group). Thus, cross‐fostering of SHR pups by WKY dams shifted the composition of their gut microbiota toward WKY within one week. Additionally, reduction in proinflammatory immune cells and lowering of systolic blood pressure were observed in cross‐fostered SHR. In summary, SHR have a congenital defect in their immune system that results in greater proinflammatory response associated with hypertension. Gut microbiota of the SHR is remarkably different from that of normotensive WKY, and likely contributes to SHR blood pressure by modulating early development of the immune system.Support or Funding InformationNational Institutes of Health Program Project Grant to FMA (HL 14388) VA Merit Review Award to MWC (1 I01BX001414), American Heart Association Innovative Research Grant to MVS (16IRG27260323).