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

Shah, SN, Knausenberger, TB, Connell, E, Le Gall, G, Hardy, TAJ, Randall, DW, McCafferty, K, Yaqoob, MM, Solito, E, Müller, M, Stachulski, AV, Glen, RC, Vauzour, D, Hoyles, L ORCID: https://orcid.org/0000-0002-6418-342X and McArthur, S, 2024. Cerebrovascular damage caused by the gut microbe/host co-metabolite p-cresol sulfate is prevented by blockade of the EGF receptor. Gut Microbes, 16 (1): 2431651. ISSN 1949-0976

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Abstract

The gut microbiota-brain axis has been associated with the pathogenesis of numerous disorders, but the mechanism(s) underlying these links are generally poorly understood. Accumulating evidence indicates the involvement of gut microbe-derived metabolites. Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease (CKD), but whether this relationship is mechanistic is unclear. We hypothesized that pCS would impair the function of the blood–brain barrier (BBB), the primary brain vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitro and both acutely (≤6 hours) and chronically (28 days) in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately exerting a suppressive effect upon whole-brain transcriptomic activity. In vitro and in vivo mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signaling, sequentially activating the intracellular signaling proteins annexin A1 and STAT3 to induce mobilization of matrix metalloproteinase MMP-2/9 and disruption to the integrity of the BBB. This effect was confirmed as specific to the EGFR through the use of both pharmacological and RNA interference approaches. Confirming the translational relevance of this work, exposure of the cerebromicrovascular endothelia to serum from hemodialysis patients in vitro led to a significant increase in paracellular permeability, with the magnitude of permeabilization closely correlating with serum pCS, but not most other uremic toxin, content. Notably, this damaging effect of hemodialysis patient serum was prevented by pharmacological blockade of the EGFR. Our results define a pathway linking the co-metabolite pCS with BBB damage and suggest that targeting the EGFR may mitigate against cerebrovascular damage in CKD. This work further provides mechanistic evidence indicating the role of gut microbe-derived metabolites in human disease.

Item Type:	Journal article
Publication Title:	Gut Microbes
Creators:	Shah, S.N., Knausenberger, T.B., Connell, E., Le Gall, G., Hardy, T.A.J., Randall, D.W., McCafferty, K., Yaqoob, M.M., Solito, E., Müller, M., Stachulski, A.V., Glen, R.C., Vauzour, D., Hoyles, L. and McArthur, S.
Publisher:	Taylor & Francis
Date:	24 November 2024
Volume:	16
Number:	1
ISSN:	1949-0976
Identifiers:	Number Type 10.1080/19490976.2024.2431651 DOI 1651061 Other
Rights:	This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	18 Nov 2024 09:09
Last Modified:	25 Nov 2024 14:44
URI:	https://irep.ntu.ac.uk/id/eprint/52587

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