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

Cerebral small vessel disease (CSVD) includes hypertension, vessel remodeling, blood brain barrier (BBB) breakdown and neuroinflammation. Recent studies suggest that alterations in the gut microbiota are linked to hypertension and stroke. We have demonstrated a causal role for gut dysbiosis in the development of hypertension in the spontaneously hypertensive stroke prone rat (SHRSPs; a model of CSVD). Thus we hypothesized that gut dysbiosis may contribute to the development of CSVD. To test this hypothesis, we changed the gut microbiome of WKY and SHRSP pups by fostering them on mothers of the same or opposite strain. Upon weening, fostered animals were co‐housed with animals of the same strain of their fostered mother (4 groups: wWKY, wSHRSP, sWKY, sSHRSP; w and s indicate the strain of foster mother). Feces was collected after each systolic blood pressure (SBP) measurement to evaluate gut microbiota using 16s rRNA sequencing. At 20 weeks of age, rats were sacrificed, brain was collected to assess for CSVD phenotypes, and ileal tissue to asses local gut gene expression for inflammatory markers and toll‐like receptor signaling. Repeated measures two‐way ANOVA of systolic blood pressure (SBP) from 6–20 wks showed a 6 mmHg increase in sWKY compared to wWKY (p<.05), and a 22 mmHg decrease in wSHRSP compared to sSHRSP (n=6–8, p<.01). Independent of genotype, rats nursed by SHRSP mothers had evidence of brain and gut inflammation compared to animals nursed by WKYs, this included increased expression of Il‐1a, Il‐6 and TLR2 (n=6, p<.01). Furthermore, by using IgG extravasation into the brain parenchyma as a marker for BBB integrity, we observed improved BBB integrity in wSHRSP compared to sSHRSP (n=5, p<.05). Fecal 16s rRNA data showed that the gut microbiota of offspring was altered by cross‐fostering to closely resemble the foster mother. Interestingly, rats fostered by SHRSP mothers demonstrated a significant decrease in Akkermansia, a genus associated with improving gut barrier integrity (n=6–8, p<.05). To confirm the effect of gut microbiome switching in the cross‐fostering study, we gavaged male Germ Free (GF) rats (13wks) with cecal content from either WKY or SHRSP animals. GF rats gavaged with SHRSP content exhibited a 19 mmHg increase in SBP (18–25 wks; n=7–8, p<.05). Furthermore, we observed significantly lower abundance of Akkermansia in SHRSP gavaged, as compared to WKY gavaged germ‐free rats (18–23 wks; n=7–8, p<.05). Finally, to test if Akkermansia could play a therapeutic role against CSVD, we administered either Akkermansia muciniphila (Akk, ≈10^9 colony forming units, n=7) or vehicle to SHRSP rats weekly (oral gavage, starting at age of 3 weeks). At 16 wks animals treated with Akk experienced a significant decrease in SBP when compared to vehicle controls. We conclude that gut dysbiosis contributes to the onset and development of CSVD possibly by inducing inflammation in the colon, and that probiotic treatment may be a potential therapeutic approach to attenuate gut inflammation and hypertension in CVSD.Support or Funding InformationAHA Predoctoral Fellowship 16PRE29640005, NIH (R56) 2031201316 and NIH (R21) 2031201314.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.