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

Nov 29, 2019Science translational medicine

Different cell functions of PDCD10 shape the gut-brain connection in brain blood vessel malformations

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Abstract

Disruption of the gut barrier is associated with increased severity of cerebral cavernous malformation (CCM) in a mouse model.

Familial CCM is linked to genetic mutations, with earlier and more severe disease onset in individuals carrying these mutations.
Excess signaling from a specific protein pathway (MEKK3) following stimulation by gut-derived substances may be involved in lesion formation.
The gut barrier plays a critical role in the progression of CCM, regardless of the composition of the gut microbiome.
Chemical disruption of the gut barrier enhances CCM formation, while loss of a specific gene in gut cells also contributes to increased disease severity.
Exposure to certain dietary substances that weaken the gut's protective mucus layer is linked to a higher burden of CCM.
Treatment with dexamethasone has been shown to significantly reduce CCM formation by affecting both brain and gut cells.

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Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in,, orDisease onset is earlier and more severe in individuals withmutations. 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 withmutations. 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 epithelialresults 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 ofin 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. KRIT1CCM2PDCD10PDCD10PDCD10Pdcd10Krit1Pdcd10Pdcd10

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

Abstract

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