The gut microbiome contributes to blood‐brain barrier disruption in spontaneously hypertensive stroke prone rats

Abstract

In recent years, it has become apparent that the gut microbiome can influence the functioning and pathological states of organs and systems throughout the body. In this study, we tested the hypothesis that the gut microbiome has a major role in the disruption of the blood-brain barrier (BBB) in the spontaneously hypertensive stroke prone rats (SHRSP), an animal model for hypertensive cerebral small vessel disease (CSVD). Loss of BBB is thought to be an early and initiating component to the full expression of CSVD in animal models and humans. To test this hypothesis, newly born SHRSP pups were placed with foster dams of the SHRSP strain or dams of the WKY strain, the control strain that does not demonstrate BBB dysfunction or develop hypertensive CSVD. Similarly, WKY pups were placed with foster dams of the same or opposite strain. The rationale for cross fostering is that the gut microbiomes are shaped by environmental bacteria of the foster dam and the nesting surroundings.Analysis of the bacterial genera in feces, using 16S rRNA analysis, demonstrated that the gut microbiome in the rat pups was influenced by the foster dam. SHRSP offspring fostered on WKY dams had systolic blood pressures (SBPs) that were significantly decreased by 26 mmHg (P < .001) from 16-20 weeks, compared to SHRSP offspring fostered on SHRSP dams. Similarly WKY offspring fostered on SHRSP dams had significantly increased SBP compared to WKY offspring fostered on WKY dams, although the magnitude of SBP change was not as robust. At ~20 weeks of age, rats fostered on SHRSP dams showed enhanced inflammation in distal ileum regardless of the strain of the offspring. Disruption of BBB integrity, an early marker of CSVD onset, was improved in SHRSPs that were fostered on WKY dams when compared to the SHRSP rats fostered on SHRSP dams. Although SHRSP is a genetic model for CSVD, environmental factors such as the gut microbiota of the foster dam have a major influence in the loss of BBB integrity.

Distinctive Gut Microbiota Alteration Is Associated with Poststroke Functional Recovery: Results from a Prospective Cohort Study

“…Dysregulation of the gut-microbiota-brain axis has been increasingly linked to the pathophysiology of stroke [ 14 , 15 ]. Interactions across gut microbiota and poststroke functional outcomes were mainly observed in animal models [ 16 , 17 ]. Nonetheless, the role of human gut microbiota is indeed somewhat different from animals [ 18 ].…”

Alterations of the gut microbial community structure and function with aging in the spontaneously hypertensive stroke prone rat

“…Fresh fecal pellets were collected into 1.5 mL tubes while handling rats, snap frozen, and stored at −80 °C. The samples were sent to the Center for Metagenomics and Microbiota Research (CMMR) at the Baylor College of Medicine where 16S rRNA gene sequence libraries were generated from the V4 primer region using the Illumina MiSeq platform 12 , 16 , 17 after extracting DNA using MO BIO PowerMag Soil Isolation Kit (MO BIO Laboratories). Reads were de-noised and merged into amplicon sequence variants (ASVs) by DADA2 pipeline in R 18 , 19 .…”

Gut Microbiota and Their Metabolites in Stroke: A Double-Edged Sword

“…An example is the use of cross-fostering to determine the role of the gut microbiota in the integrity of the blood-brain barrier. 40 It is important to highlight that these experiments can have their own limitations. Besides eliciting a physiological response, it is important to identify if changes in the gut microbiota composition are driving these responses and whether these changes are biologically relevant.…”

“…Gut dysbiosis is present in animals subjected to stroke, such as the middle cerebral artery occlusion (MCAO) model, 2,3 and in genetic models, such as the spontaneously hypertensive stroke-prone rat. 40,55 Several shifts in specific gut microbiota taxa have been reported in stroke models (transient filamentous MCAO and permanent distal MCAO), including an overall decreased in α-diversity, a metric for microbiome diversity within a sample 2,3 (see Table 1), as well as changes in the phyla Actinobacteria (now named Actinomycetota), Bacteroidetes (Bacteroidota), and Firmicutes (Bacillota). 2,3,53 At the phylum level, decreased Bacteroidetes and increased Proteobacteria (now named Pseudomonadota) in the overall gut microbiota was suggested to provide neuroprotection to brain injury.…”