Causal relationship between gut microbiota and intracranial hemorrhage: A two-sample Mendelian randomization study.

Patients with intracranial hemorrhage (ICH) usually have an imbalance in the gut microbiota (GM); however, whether this is a causal correlation remains unclear. This study used summary data from an open genome-wide association study to conduct double-sample Mendelian randomization (MR) to test the causal correlation between GM and ICH. First, we used a cutoff value of P < 10E-5 to select single nucleotide polymorphisms critical for each GM. Inverse variance weighted, weighted median, and MR-PRESSO methods were used to evaluate the strength of this causal association. Finally, functional maps and annotations from genome-wide association studies were used to determine the biological functions of the genes. MR analysis revealed that Rikenellaceae RC9 gut group was significantly positively correlated with ICH risk. For every unit increase in Rikenellaceae RC9 gut group, the relative risk of ICH increased by 34.4%(P = 4.62E-04). Rhodospirillales, Terrisporobacter, Veillonellaceae, Coprococcus 3, unknown genus, Alphaproteobacteria, and Allisonella groups were negatively correlated with the risk of ICH, while Anaerofilum, Eubacteriumbrachy group, Clostridia, Howardella, and Romboutsia were negatively correlated with the risk of ICH. Nonetheless, the specific role of single nucleotide polymorphisms gene enrichment requires further investigation. This study suggests the causal effect on ICH. The discovery of >10 GMs associated with ICH could be used to prevent and treat ICH.

Pathologic features of brain hemorrhage after radiation treatment: case series with somatic mutation analysis.

BACKGROUND: Radiation treatment for diseases of the brain can result in hemorrhagic adverse radiation effects. The underlying pathologic substrate of brain bleeding after irradiation has not been elucidated, nor potential associations with induced somatic mutations. METHODS: We retrospectively reviewed our department's pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl's Prussian Blue, and Masson's Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies. RESULTS: One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes. CONCLUSIONS: Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.