Abstract P088: The Gut Microbiome Contributes To The Cerebral Small Vessel Disease Phenotype In Spontaneously Hypertensive Stroke Prone Rats

Abstract

In recent years, it has become apparent that the gut microbiome can influence the functioning and pathological states of organs and systems throughout the body. In this study we tested the hypothesis that the gut microbiome has a major role in the cascade of pathological events, including inflammation and hypertension, leading to the onset of cerebral small vessel disease (CSVD). To test this hypothesis, we used an animal model for hypertensive CSVD, the spontaneously hypertensive stroke prone rat (SHRSP). At birth, SHRSP pups were placed with foster dams of the SHRSP strain or dams of the WKY strain, the control strain that does not develop hypertensive CSVD. Similarly, WKY pups were placed with dams of the same or opposite strain. The rationale for cross fostering is that gut microbiomes are shaped by environmental bacteria of the foster dam and the nesting surroundings. Analysis of the bacterial genera in feces using 16S rRNA analysis demonstrated that the gut microbiome in the rat pups was strongly influenced by the foster dam. SHRSP offspring fostered on WKY dams had systolic blood pressures (SBPs) that were significantly decreased by 26 mmHg (P<0.001, N=5-7/group) at 20 weeks, compared to SHRSP offspring fostered on SHRSP dams. Similarly, WKY offspring fostered on SHRSP dams had significantly increased SBP compared to WKY offspring fostered on WKY dams, although the magnitude of SBP change was not as robust (9 mmHg, P<0.05, N=6-8/group). At ~20 weeks of age, rats fostered on SHRSP dams showed increased expression of IL-1a, TLR-2, E-CAD, Muc-2, and Il-17a in ileum regardless of the strain of the offspring (N=6/group, P<0.05). Loss of blood-brain barrier (BBB) integrity, an early marker of CSVD onset, was assessed by extravasation of IgG, which is confined to the plasma space under normal conditions. Extravasation of IgG was increased four-fold in SHRSP fostered on SHRSP dams compared to WKY rats fostered on WKY dams; however, extravasation of IgG was decreased in SHRSP fostered on WKY dams by ~ 50% (P=0.005, N=5/group). These findings demonstrate that although SHRSP is a genetic model for CSVD, the makeup of the gut microbiota has a major influence on gut and brain physiology, and ultimately in shaping the phenotype and onset of CSVD.