Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2 or PDCD10. Notably, 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 (LPS) 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 sodium sulfate 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 increase CCM burden analogous to loss of Pdcd10 in gut epithelium. Finally, we show that treatment with dexamethasone potently inhibits CCM formation in mice due to 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.

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D 3 , and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for 5 weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.

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Saint Francis Service Dogs (SFSD) trains dogs to aid people with multiple sclerosis, brain injury, and many other conditions. Organizations like SFSD must carefully consider when to neuter dogs to give them the best chance at successfully completing lengthy and expensive training. The objective of this retrospective cohort study was to assess differences in the incidence of health or behavior problems leading to dismissal between dogs neutered at different ages. Data on 245 dogs—including birth date, sex, neuter date, dismissal or successful completion of training, and (where applicable) reason for dismissal—were collected from SFSD records. Age-at-neuter was grouped (<7 months; 7–11 months; > 11 months) and compared for dogs who successfully completed training and dogs who were dismissed. Dogs neutered from 7 to 11 months of age were dismissed at a significantly lower overall rate than dogs neutered at an older or younger age. There were no differences between males and females. Labrador and golden retrievers were less likely to be dismissed than other breeds. This pattern was the same for dismissals for behavioral reasons. Dogs neutered at <7 months had more than twice the risk for health-related dismissals as dogs neutered at any older age and this pattern held for orthopedic dismissals. Labradors were at higher risk for orthopedic-related dismissal than golden retrievers and all other breeds. This study suggests that there is a relationship between dogs' age at neuter and the incidence of health and behavioral problems that can lead to dismissal from service dog training.