Abstract Body: Hypothesis Gut dysbiosis contributes to age-dependent hypertension (HTN) driven cognitive impairment (CI), that is attenuated by prebiotic dietary fiber supplementation.

Methods In 3 and 16 month old (M) male Sprague Dawley rats, 3M rats receiving a fecal microbiota transplant (FMT) from 16M rats, and 16M rats fed a 6 week high prebiotic fiber (HPF) diet (n=4-6), BP, cognition (novel object recognition), paraventricular nucleus (PVN) and hippocampal blood brain barrier (BBB) integrity (FITC extravasation) and neuroinflammation (IBA1 and GFAP), gut microbiota taxonomy (by WGS) and short chain fatty acid (SCFA) levels (by GC-MS) were assessed.

Results 16M rats exhibit gut dysbiosis, HTN, hippocampal BBB disruption and neuroinflammation, and CI. FMT to 3M rats evoked HTN and gut dysbiosis (3M vs 3M + FMT: Cecal Bray-Curtis b diversity PCoA Species Bacteria, P=<0.05). Linear Discriminant Analysis shows enrichment of cecal a) Lactobacillales (associated with lower BP) in 3M rats (LDA Log¹⁰ 4.69, P=0.022), b) Alistipes putrendenis in 16M rats (LDA Log¹⁰ 3.98, P=0.005), c) the Bacteroides genera (increased in HTN) in 3M + FMT rats (LDA Log¹⁰ 4.34, P=0.015). HPF attenuated gut dysbiosis (16M vs 16M + HPF: Fecal Bray-Curtis b Diversity PCoA Species Bacteria, P<0.05, PCoA MetaCyc, P<0.05; 16M pre vs post HPF: Fecal Bray-Curtis b Diversity PCoA Species Bacteria, P<0.05), increased SCFA levels, reduced BP, and improved PVN and hippocampal BBB disruption, hippocampal neuroinflammation and CI.

Conclusions Gut dysbiosis contributes to age-dependent HTN-driven CI. HPF supplementation, a readily implementable lifestyle intervention, attenuates HTN-driven CI via mechanisms independent of current antihypertensive medications.