A Chinese CADASIL Family with a Novel Mutation on Exon 10 of Notch3 Gene

Liu, Yuan; Huang, Saisai; Yu, Liqiang; Tan, Li; Diao, Shanshan; Chen, Zhi-Guo; Zhou, Guoqing; Sheng, Xihua; Xu, Yuan; Fang, Qi

doi:10.1016/j.jstrokecerebrovasdis.2021.105674

Cited by 2 publications

(1 citation statement)

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“…In addition to the genetic polymorphism, increasing evidence has highlighted the environmental effects on the progression of CADASIL. CADASIL patients carrying the same NOTCH3 variant have suffered with different onset ages and severity of clinical manifestations [11,12], even in monozygotic twins [13]. Moreover, CADASIL patients influenced by environmental factors such as smoking and alcohol consumption were more prone to stroke, a major symptom of CADASIL [14,15].…”

Section: Introductionmentioning

confidence: 99%

Gut microbes exacerbate systemic inflammation and behavior disorders in neurologic disease CADASIL

Liu,

Men,

Guo

et al. 2023

Microbiome

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Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3. The clinical manifestations are influenced by genetic and environmental factors that may include gut microbiome. Results We investigated the fecal metagenome, fecal metabolome, serum metabolome, neurotransmitters, and cytokines in a cohort of 24 CADASIL patients with 28 healthy household controls. The integrated-omics study showed CADASIL patients harbored an altered microbiota composition and functions. The abundance of bacterial coenzyme A, thiamin, and flavin-synthesizing pathways was depleted in patients. Neurotransmitter balance, represented by the glutamate/GABA (4-aminobutanoate) ratio, was disrupted in patients, which was consistent with the increased abundance of two major GABA-consuming bacteria, Megasphaera elsdenii and Eubacterium siraeum. Essential inflammatory cytokines were significantly elevated in patients, accompanied by an increased abundance of bacterial virulence gene homologs. The abundance of patient-enriched Fusobacterium varium positively correlated with the levels of IL-1β and IL-6. Random forest classification based on gut microbial species, serum cytokines, and neurotransmitters showed high predictivity for CADASIL with AUC = 0.89. Targeted culturomics and mechanisms study further showed that patient-derived F. varium infection caused systemic inflammation and behavior disorder in Notch3R170C/+ mice potentially via induction of caspase-8-dependent noncanonical inflammasome activation in macrophages. Conclusion These findings suggested the potential linkage among the brain-gut-microbe axis in CADASIL.

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