Defining the Role of Inflammation and Effective Therapies for the Commonest Cause of Stroke in Children: Cerebral Cavernous Malformation (CCM)

Sadegh, Hamidreza

Defining the Role of Inflammation and Effective Therapies for the Commonest Cause of Stroke in Children: Cerebral Cavernous Malformation (CCM)

Sadegh, Hamidreza

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Publication Type:: Thesis
Issue Date:: 2023

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Field	Value	Language
dc.contributor.author	Sadegh, Hamidreza
dc.date.accessioned	2024-06-18T22:55:58Z
dc.date.available	2024-06-18T22:55:58Z
dc.date.issued	2023
dc.identifier.uri	http://hdl.handle.net/10453/179555
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Cerebral cavernous malformations (CCMs) are enlarged blood vessels that develop abnormally, posing a non-cancerous but potentially life-threatening condition that can result in a haemorrhagic stroke. Therefore, there is an urgent requirement for innovative, non-surgical treatment alternatives for CCM. Recent studies have identified the dysbiosis of gut microbiome and the innate immune response (TLR4-MEKK3-KLF signalling pathway) as a critical stimulant of CCM in mouse models. The gut barrier has since been identified as a major determinant of the disease course in CCM, whereby its disruption augments CCM formation in mouse models. These studies provide strong evidence that a novel and innovative strategy to treat CCM is to target the gut microbiome. In this study, we established a CCM1 knockout mouse model through the utilization of Cdh5CreERT2 (hereafter referred to as Ccm1iECKO) to assess the impact of diet-induced modifications to the microbiome on CCM development across two distinct temporal phases: short-term and long-term. Evaluation of brain lesion burden encompassed measurements of size and quantity through micro-CT imaging, while histological analysis was employed to examine gut morphology and integrity. Metagenomics and metabolomics sequencing were performed on collected faecal samples to track alterations in the gut microbiome and associated metabolites. Lastly, blood LPS levels were scrutinized following dietary interventions to elucidate the role of LPS in CCM. In summary, a diet rich in plant-based fats leads to a reduction in CCM lesion burden in the short term, with this effect observed only in female mice. Conversely, dietary modifications such as high-fibre and low-fibre, while enhancing gut integrity, did not exert any influence on CCM lesions. Additionally, no discernible impact on blood LPS levels was observed across all dietary interventions. This study findings indicate that the alteration of the gut microbiome through a high fat diet intervention can mitigate or regress CCM lesions, irrespective of circulating LPS levels. Given that surgical resection stands as the sole recourse for treating CCM patients afflicted with severe clinical symptoms, these findings serve as a foundational step toward studies to develop a non-surgical microbiome-targeted therapies. These therapies hold promise as safe and effective alternatives for the treatment of CCM, potentially circumventing the need for invasive surgical interventions, particularly in cases where severe clinical symptoms necessitate intervention. Furthermore, this study unveils that the influence of the gut microbiome on CCM disease extends beyond the LPS-TLR4 interaction, operating through distinct mechanisms.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/179555/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2023 Hamidreza Sadegh
dc.rights	au.edu.uts.lib/cph
dc.title	Defining the Role of Inflammation and Effective Therapies for the Commonest Cause of Stroke in Children: Cerebral Cavernous Malformation (CCM)	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Cerebral cavernous malformations (CCMs) are enlarged blood vessels that develop abnormally, posing a non-cancerous but potentially life-threatening condition that can result in a haemorrhagic stroke. Therefore, there is an urgent requirement for innovative, non-surgical treatment alternatives for CCM. Recent studies have identified the dysbiosis of gut microbiome and the innate immune response (TLR4-MEKK3-KLF signalling pathway) as a critical stimulant of CCM in mouse models. The gut barrier has since been identified as a major determinant of the disease course in CCM, whereby its disruption augments CCM formation in mouse models. These studies provide strong evidence that a novel and innovative strategy to treat CCM is to target the gut microbiome. In this study, we established a CCM1 knockout mouse model through the utilization of Cdh5CreERT2 (hereafter referred to as Ccm1iECKO) to assess the impact of diet-induced modifications to the microbiome on CCM development across two distinct temporal phases: short-term and long-term. Evaluation of brain lesion burden encompassed measurements of size and quantity through micro-CT imaging, while histological analysis was employed to examine gut morphology and integrity. Metagenomics and metabolomics sequencing were performed on collected faecal samples to track alterations in the gut microbiome and associated metabolites. Lastly, blood LPS levels were scrutinized following dietary interventions to elucidate the role of LPS in CCM. In summary, a diet rich in plant-based fats leads to a reduction in CCM lesion burden in the short term, with this effect observed only in female mice. Conversely, dietary modifications such as high-fibre and low-fibre, while enhancing gut integrity, did not exert any influence on CCM lesions. Additionally, no discernible impact on blood LPS levels was observed across all dietary interventions. This study findings indicate that the alteration of the gut microbiome through a high fat diet intervention can mitigate or regress CCM lesions, irrespective of circulating LPS levels. Given that surgical resection stands as the sole recourse for treating CCM patients afflicted with severe clinical symptoms, these findings serve as a foundational step toward studies to develop a non-surgical microbiome-targeted therapies. These therapies hold promise as safe and effective alternatives for the treatment of CCM, potentially circumventing the need for invasive surgical interventions, particularly in cases where severe clinical symptoms necessitate intervention. Furthermore, this study unveils that the influence of the gut microbiome on CCM disease extends beyond the LPS-TLR4 interaction, operating through distinct mechanisms.

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