A Role For Gut Dysbiosis In The Progression Of Cerebral Small Vessel Disease

We tested the hypothesis that a pathological imbalance of the gut microbiota, or dysbiosis, contributes to the inflammation that drives the progression of cerebral small vessel disease (CSVD). To test our hypothesis, we used SHRSP rats, a model for hypertension-related CSVD, and their parent strain, WKY. We sought to alter the gut microbiota to affect the onset of CSVD. Given that the gut microbiome is strongly influenced by the nursing mother, we cross-fostered SHRSP and WKY pups with mothers of the same or different strain. All measures, except where noted, were made at 20 weeks. Relative abundance of bacterial genera in fecal samples (representing gut) was analyzed by sequencing the 16S rRNA bacterial gene. When SHRSPs were fostered on WKY mothers, the relative abundance of Akkermansia, a bacterial genus that maintains gut health and reduces GI inflammation, was increased by 107% (P=0.002, N=8/gp). Alternatively, when WKYs were fostered on SHRSP mothers, Akkermansia was decreased by 40% (P<0.05). Thus, the relative abundance of Akkermansia was increased, regardless of strain, when fostered on WKY mothers. Consistent with the relative abundance of Akkermansia, rats fostered on SHRSP mothers showed increased expression of IL-1α and NF-κB1 in the proximal colon regardless of the strain of the pup (P=0.003, N=5/gp). Blood-brain barrier disruption, as measured by IgG extravasation, was increased 2-fold (P<0.001, N=4/gp) in SHRSPs fostered on SHRSP mothers compared to WKYs fostered on WKY mothers. When SHRSPs were fostered on WKY mothers IgG extravasation decreased 31% (P<0.05). Gene expression for NF-κB1, TLR-2, and TLR-4 in brain increased 2.5 to 3 fold in SHRSPs fostered on SHRSP mothers compared to WKYs fostered on WKY mothers (P=0.003, N=5/gp) and was completely normalized when SHRSPs were fostered on WKY mothers. Blood pressure at 16 weeks was increased by ~ 25 mm Hg (P<0.001, N=11/g), regardless of strain, when fostered on SHRSP mothers compared to the same strain fostered on WKY mothers. Although SHRSPs are a genetic model for hypertensive CSVD, our studies demonstrate that gut dysbiosis has a significant contribution to the onset of CSVD. A decrease in the abundance of healthy gut bacteria likely contributes to CSVD onset and progression.