Gut dysbiosis in the development of cerebral small vessel disease
Authors: Nelson James Willard , Ganesh Priya , Ajami Nadim , Bryan Robert , Durgan David 
Published: June 2021

The importance of a healthy gut microbiota on host physiology is becoming increasingly evident. Recent studies suggest that alterations to the microbiota (i.e., dysbiosis) can have adverse effects beyond the GI tract, and has been linked to hypertension and stroke. We have demonstrated that the microbiota of the spontaneously hypertensive stroke prone rat (SHRSP), a model of cerebral small vessel disease (CSVD), is significantly different than that of WKY controls. Thus we hypothesized that gut dysbiosis contributes to the development of CSVD. Phenotypically, CSVD includes hypertension, vessel remodeling, BBB breakdown and neuroinflammation. If our hypothesis is valid, then creating a gut microbiota in a WKY rat that resembles one from an SHRSP rat should produce CSVD phenotypes. Conversely, creating a gut microbiota in a SHRSP rat that resembles one from a healthy WKY strain should abolish or attenuate the onset of CSVD phenotypes, including hypertension. Given that rat pups acquire their microbiota from their mother and the immediate environment, we used foster mothers to shape the microbiota of rat pups. WKY and SHRSP pups were removed from their birthing mother at 2–3 days of age and fostered on mothers of the same or opposite strain. Upon weening, fostered animals were co‐housed with animals of the same strain as their fostered mother. Systolic blood pressure (SBP) was measured using tail cuff plethysmography from 6–20 weeks of age. At 20 weeks of age, rats were sacrificed and brain and gut tissue were collected to assess for CSVD phenotypes and gene expression for inflammatory markers and toll‐like receptor signaling. Feces were collected at each BP measurement to evaluate the composition of the gut microbiota using 16s rRNA sequencing. Repeated measures two‐way ANOVA of SBP from week 6–20 showed a 15 mmHg increase in WKY rats fostered by an SHRSP mother (sWKY)compared to WKY fostered on WKY mothers (wWKY; p<.001), and a 7 mmHg decrease in SHRSPs fostered by a WKY mother (wSHRSP) compared to SHRSPs fostered by a SHRSP mother (sSHRSP) (p=.027). Independent of genotype, rats nursed by SHRSP mothers had evidence of brain and gut inflammation including increases in TLR2, TLR4, NF‐kB1, and Il‐1α expression in the brain and proximal colon mucosa, compared to animals fostered by WKYs (p<.01). Furthermore, by using IgG extravasation into the brain parenchyma as a marker for blood brain barrier integrity, we discovered that wSHRSP animals had improved blood brain barrier integrity as compared to sSHRSP (p<.05). Through sequencing of fecal 16s rRNA it was determined that cross‐fostering animals on opposite strains lead to significant alterations in the gut microbiota composition. Most striking was that animals nursing on SHRSP mothers led to significant decreases in Akkermansia, a genus associated with improving gut barrier integrity (p<.05). This study supports the hypothesis that gut dysbiosis contributes to the onset and development of CSVD, possibly by creating an inflammatory environment in the colon. Furthermore, maintaining a healthy gut microbiota in a CSVD strain has the potential to reduce CSVD phenotypes, gut inflammation and attenuate hypertension. These findings support the idea that the gut is a possible therapeutic target to treat CSVD and other cardiovascular diseases.Support or Funding InformationAHA Predoctoral Fellowship 16PRE29640005This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.