Department of Anesthesiology, Baylor College of Medicine, Houston, TX, USA.
Integrated Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX, USA.
FASEB J. 2021 Feb;35(2):e21201. doi: 10.1096/fj.202001117R.
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.
近年来，人们已经认识到肠道微生物组可以影响全身各个器官和系统的功能和病理状态。在这项研究中，我们检验了这样一个假设，即肠道微生物组在自发性高血压卒中易感大鼠（SHRSP）的血脑屏障（BBB）破坏中起主要作用，SHRSP 是高血压性脑小血管病（CSVD）的动物模型。人们认为，BBB 的丧失是 CSVD 在动物模型和人类中完全表达的早期和起始组成部分。为了验证这一假设，新生的 SHRSP 幼崽被安置在 SHRSP 母鼠或 WKY 母鼠（不表现出 BBB 功能障碍或发生高血压性 CSVD 的对照品系）的代乳母鼠下。同样，WKY 幼崽被安置在相同或相反品系的代乳母鼠下。交叉寄养的原理是，代乳母鼠及其巢周围的环境细菌塑造了幼崽的肠道微生物组。使用 16S rRNA 分析对粪便中细菌属的分析表明，大鼠幼崽的肠道微生物组受到代乳母鼠的影响。与 SHRSP 幼崽寄养在 SHRSP 母鼠下相比，寄养在 WKY 母鼠下的 SHRSP 后代的收缩压（SBP）降低了 26mmHg（P<0.001），从 16 到 20 周。同样，与 WKY 幼崽寄养在 WKY 母鼠下相比，寄养在 SHRSP 母鼠下的 WKY 后代的 SBP 显著升高，尽管 SBP 变化的幅度并不那么显著。大约 20 周龄时，寄养在 SHRSP 母鼠下的大鼠无论后代的品系如何，远端回肠的炎症均增强。与寄养在 SHRSP 母鼠下的 SHRSP 大鼠相比，寄养在 WKY 母鼠下的 SHRSP 大鼠的 BBB 完整性破坏得到改善，这是 CSVD 发病的早期标志物。尽管 SHRSP 是 CSVD 的遗传模型，但代乳母鼠的肠道微生物群等环境因素对 BBB 完整性的丧失有重大影响。
