TY  - JOUR
A1  - Tang, Alan T.
A1  - Sullivan, Katie Rose
A1  - Hong, Courtney C.
A1  - Goddard, Lauren M.
A1  - Mahadevan, Aparna
A1  - Ren, Aileen
A1  - Pardo, Heidy
A1  - Peiper, Amy
A1  - Griffin, Erin
A1  - Tanes, Ceylan
A1  - Mattei, Lisa M.
A1  - Yang, Jisheng
A1  - Li, Li
A1  - Mericko-Ishizuka, Patricia
A1  - Shen, Le
A1  - Hobson, Nicholas
A1  - Girard, Romuald
A1  - Lightle, Rhonda
A1  - Moore, Thomas
A1  - Shenkar, Robert
A1  - Polster, Sean P.
A1  - Roedel, Claudia Jasmin
A1  - Li, Ning
A1  - Zhu, Qin
A1  - Whitehead, Kevin J.
A1  - Zheng, Xiangjian
A1  - Akers, Amy
A1  - Morrison, Leslie
A1  - Kim, Helen
A1  - Bittinger, Kyle
A1  - Lengner, Christopher J.
A1  - Schwaninger, Markus
A1  - Velcich, Anna
A1  - Augenlicht, Leonard
A1  - Abdelilah-Seyfried, Salim
A1  - Min, Wang
A1  - Marchuk, Douglas A.
A1  - Awad, Issam A.
A1  - Kahn, Mark L.
T1  - Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation
JF  - Science Translational Medicine
N2  - Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10. Disease onset is earlier and more severe in individuals with PDCD10 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 PDCD10 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 Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 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 Pdcd10 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.
Y1  - 2019
U6  - https://doi.org/10.1126/scitranslmed.aaw3521
SN  - 1946-6234
SN  - 1946-6242
VL  - 11
IS  - 520
PB  - American Assoc. for the Advancement of Science
CY  - Washington
ER  -