Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation

• Published in: Science translational medicine 2019-11, Vol.11 (520)
• Main Authors: Tang, Alan T, Sullivan, Katie R, Hong, Courtney C, Goddard, Lauren M, Mahadevan, Aparna, Ren, Aileen, Pardo, Heidy, Peiper, Amy, Griffin, Erin, Tanes, Ceylan, Mattei, Lisa M, Yang, Jisheng, Li, Li, Mericko-Ishizuka, Patricia, Shen, Le, Hobson, Nicholas, Girard, Romuald, Lightle, Rhonda, Moore, Thomas, Shenkar, Robert, Polster, Sean P, Rödel, Claudia J, Li, Ning, Zhu, Qin, Whitehead, Kevin J, Zheng, Xiangjian, Akers, Amy, Morrison, Leslie, Kim, Helen, Bittinger, Kyle, Lengner, Christopher J, Schwaninger, Markus, Velcich, Anna, Augenlicht, Leonard, Abdelilah-Seyfried, Salim, Min, Wang, Marchuk, Douglas A, Awad, Issam A, Kahn, Mark L
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; Brain - metabolism; Brain - pathology; Carrier Proteins - metabolism; CCM2 protein; Cerebrovascular diseases; Colitis - complications; Dexamethasone; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Dextran; Dextran Sulfate; Emulsifiers; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Gastrointestinal Microbiome - drug effects; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - pathology; Hemangioma, Cavernous, Central Nervous System - drug therapy; Hemangioma, Cavernous, Central Nervous System - metabolism; Humans; Intestinal microflora; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; KRIT1 Protein - metabolism; Ligands; Lipopolysaccharides; MAP kinase; Membrane Proteins - metabolism; Mice; Microbiomes; Mucin; Mucosa; Mutation; Protein kinase; Proto-Oncogene Proteins - metabolism; Signal Transduction - drug effects; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aaw3521

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in , , or Disease onset is earlier and more severe in individuals with mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of , but not , in gut epithelial cells. Loss of gut epithelial results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.