Cerebrovascular damage caused by the gut microbe/host co-metabolitep-cresol sulfate is prevented by blockade of the EGF receptor

Abstract

Chronic kidney disease is linked to impaired cognitive function and increased neurovascular disease risk even after correction for classical risk factors. The mechanism(s) underlying these links are unclear but may involve interactions of uraemic toxins with the blood-brain barrier (BBB). Here, we studied how the major uraemic toxinp-cresol sulfate (pCS) could affect BBB integrity. Exposure of human hCMEC/D3 endothelial cells to pCS dose-dependently increased paracellular permeability and disrupted intercellular tight junctions, a permeabilising effect mirrored in mice. Whole brain RNAseq analysis identified pCS-mediated suppression of neuronal activity, transcription and mitochondrial respiration pathways.In vitrostudies identified pCS binding to the epidermal growth factor receptor (EGFR), leadingviaannexin A1 and STAT3 signalling to mobilisation of matrix metalloproteinase (MMP)-2/9. Confirming this pathwayin vivo, the BBB damaging effects of pCS were prevented by pre-treatment with the EGFR antagonist erlotinib or the MMP2/9 inhibitor SB-3CT. Finally, hCMEC/D3 cells exposed to haemodialysis patient serum, but not to that of healthy donors, showed an erlotinib-sensitive increase in paracellular permeability that closely correlated in size to the total serum pCS content. Overall, we define a pathway linking the uraemic toxin pCS with BBB damage suggesting that targeting the EGFR may be useful in mitigating against cerebrovascular damage in chronic kidney disease.Translational StatementPatients with chronic kidney disease (CKD) have increased risk of cognitive impairment and stroke, pathologies associated cerebromicrovascular disease, but it is not clear why. Here, we show that the uraemic toxin p-cresol sulfate impairs BBB functionin vitroandin vivothrough EGFR-dependent MMP mobilisation. Importantly, serum from haemodialysis patients can also impair permeability of anin vitroBBB model, an effect prevented by EGFR inhibition, and proportional in magnitude to serum pCS content. Our data suggest that existing EGFR inhibitory drugs might have utility in preventing cerebral small vessel disease in CKD patients.

Differences in gut microbiota associated with stress resilience and susceptibility to single prolonged stress in female rodents

“…We analyzed BBB permeability only at the end of the experiment, and we cannot determine whether the observed differences between the cohorts pre-existed or resulted from SPS exposure. Yet, recent studies reported elevated levels of toxic microbial metabolites, such as p-crestol, capable of disrupting BBB integrity, which coincided with trauma-induced gut microbial alterations ( Laudani et al, 2023 ; Shah et al, 2022 ). This further highlights the importance of gut microbial metabolites in the gut-brain communication axis.…”

Dietary (Poly)phenols and the Gut–Brain Axis in Ageing

“…This translates into increased production of p-cresol and lipopolysaccharides (LPS), as well as increased degradation of intestinal mucus, suggesting enhanced permeability of the gut cell wall. Of interest here, the uraemic toxin p-cresol sulfate (pCS) is known to increase endothelial permeability and has been recently linked to cerebrovascular damage due to its disruptive actions on BBB integrity [61,137]. Other studies, although lacking the molecular mechanisms linked to the GBA and related derived metabolites, have evaluated the effects of olive oil polyphenols, major components of the Mediterranean diet (Med Diet).…”

Impact of Pesticide Residues on the Gut-Microbiota–Blood–Brain Barrier Axis: A Narrative Review

“…Some of these metabolites are beneficial such as indoles that regulate the IB function and immune response, and bile acids and TMA that maintain glycolipid homeostasis. Contrarywise, others are detrimental such as LPS which is an immune system disrupter and circulating uremic toxins derived from the digestion of dietary amino acids that have recently been shown to impair BBB integrity and alter brain activity (p-cresol sulfate and 4-ethylphenyl sulfate) [ 58 , 59 ].…”