The Gut Microbiota Can Protect Against The Onset Of Symptoms In An Animal Model Of Cerebral Small Vessel Disease.

It has become increasingly evident that disruption of the gut microbiota plays an important role in multiple host disease states. We hypothesize that maintaining a healthy gut microbiome protects against the development of cerebral small vessel disease (CSVD), an inflammatory disease accompanied by blood-brain barrier (BBB) breakdown and neuroinflammation. To test our hypothesis, we altered the gut microbiota of spontaneously hypertensive stroke-prone rats (SHRSPs), a model of CSVD associated with hypertension, to resemble that of healthy/asymptomatic WKY control rats. At birth SHRSP pups were removed from their birth moms and nursed by either WKY (SW rats) or SHRSP (SS) foster dams until 21 days of age. At 20 weeks, markers associated with neuroinflammation were significantly decreased in SW rats compared to SS rats (NF-κB1 by 68%, TLR-2 by 58%, and TLR-4 by 54%, P≤ 0.01, n=5-6/ group). When compared to SS rats, SW rats showed a 33% (P=0.045) decrease in IgG extravasation into brain indicating greater BBB integrity. Systolic blood pressure at 20 weeks in SW was 173±6 mm Hg compared to 201±6 mm Hg in SS rats (P=0.003) and these pressures remained stable for until at least 30 weeks. Analysis of microbiota in feces revealed that gut microbiota of SW rats were significantly different from SS rats (P<0.05, principal components analysis of weighted Unifrac distances, n=5-6), resembled the microbiome in WKY rats, and showed > 2-fold increase in the abundance of the genus, Akkermansia, in SW compared to SS rats (6.1% vs 3.0%, P=0.01). Akkermansia can enhance gut integrity by stimulating epithelial cell mucus production and enhancing tight junctions. We conclude that the gut microbiota can influence the onset of CSVD-like symptoms even in the genetic SHRSP model. Maintaining a microbiota similar to WKY control rats, which includes an increased abundance of Akkermansia, appears to protect against the onset of CSVD. Altering the gut microbiota in humans could be an effective prophylactic measure to protect against CSVD.