Microbial disruption in the gut promotes cerebral endothelial dysfunction

Abstract

Cerebrovascular disease is a group of conditions characterized by disorders of the cerebral vessels. Endothelial dysfunction renders the vasculature at risk of impaired blood flow and increases the potential of developing cerebrovascular disease. The gut microbiota has been recently identified as a possible risk factor of cerebrovascular disease. However, a direct link between gut microbiota and cerebral vascular function has not been established. Therefore, the aim of this study was to determine the effect of gut bacterial disruption on cerebral endothelial function. Male inbred Sprague‐Dawley rats were randomly assigned to receive either drinking water with (n = 4) or without (n = 4) a cocktail of nonabsorbable broad‐spectrum antibiotics (streptomycin, neomycin, bacitracin, and polymyxin B). Three weeks of antibiotic treatment resulted in a significant reduction in bacterial load and shifts within the bacterial sub‐populations as assessed using flow cytometry. Using pressure myography, we found that spontaneous tone significantly increased and L‐NAME‐induced vasoconstriction was significantly blunted in middle cerebral arteries (MCAs) harvested from antibiotic‐treated rats. ATP‐mediated dilations were significantly blunted in MCAs from antibiotic‐treated rats compared to their control counterparts. Immunoblotting revealed that the eNOS‐P/total eNOS ratio was significantly reduced in cerebral artery lysates from antibiotic‐treated rats compared to controls. Our findings suggest that disruption of the gut microbiota leads to cerebral endothelial dysfunction through reduction of eNOS activity. This study highlights the potential of the microbiota as a target to reverse endothelial dysfunction and a preventative approach to reducing risk of stroke and aneurysms.

16S rRNA gene amplicon-based gut microbiome signature in cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: A prospective nested case-control pilot study

“…However, according to Shade and colleagues 16 diversity is neither good nor bad, it simply "is", and its deviations can be utilized in clinical settings. In terms of CVS, there is evidence that gut microbiome alterations including bacterial sub-population diversity might result in endothelial dysfunction, which in turn is strongly linked to vasospasm 17 . Also, bacterial diversity alters levels of plasma trimethylamine N-oxide (TMAO) of bacterial origin 18 .…”

Gut microbiome in intracranial aneurysm growth, subarachnoid hemorrhage, and cerebral vasospasm: a systematic review with a narrative synthesis

“…Observational case–control study design prevailed (see Table 1 and Supplementary material 1 ). Although two studies (Rustia et al, 2021 ; Xiao et al, 2022 ) addressed cerebral ischemic complications due to endothelial dysfunction or cerebral hypoperfusion in subjects with altered microbiota, they were not in the setting of aneurysmal rupture. Therefore, they were not included in the systematic review but were discussed as a pathophysiological rationale for conducting a research study on associations between cerebral vasospasm and intestinal microbiome (see Cerebral vasospasm and delayed cerebral ischemia Section).…”

“…It has been shown that alteration of gut microbiome might lead to endothelial dysfunction which is one of the core mechanisms of vasospasm. Rustia et al ( 2021 ) presented an experimental animal study showing that antibiotic treatment disrupting gut microbiota leads to endothelial dysfunction by the reduction of phosphorylated endothelial nitric oxide synthase (eNOS-p) to total eNOS ratio (a surrogate marker to eNOS activity). The gut dysbiosis obtained via a 3-week antibiotic regimen also produced increased spontaneous tone of the endothelium, decreased response to NG-Nitro-l-Arginine Methyl Ester (L-NAME) which is a non-selective nitric oxide synthase, and diminished ATP-mediated luminal dilation.…”

GLP-1RAs and cardiovascular disease: is the endothelium a relevant platform?

“…Moreover, exposure to GLP-1 increases energy expenditure in muscle at least in part through the upregulation of fat oxidation [ 56 ]. Recently, disruption of the gut microbiota has been associated with a reduction of eNOS activity in cerebral ECs highlighting the potential of the microbiota as a target to reverse endothelial dysfunction [ 57 ]. There is evidence that GLP-1 may play a role in the function of the intestinal epithelium, correlating these effects with changes in gut microbiota.…”