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

作者：Sheng Liu, Xuejiao Men, Yang Guo, Wei Cai, Ruizhen Wu, Rongsui Gao, Weicong Zhong, Huating Guo, Hengfang Ruan, Shuli Chou, Junrui Mai, Suning Ping, Chao Jiang, Hongwei Zhou, Xiangyu Mou, Wenjing Zhao, Zhengqi Lu · 发表于：Microbiome · 年份：2023 · DOI：10.1186/s40168-023-01638-3 · 被引用次数：38 · 研究领域：Cerebrovascular and genetic disorders、Neurological Disease Mechanisms and Treatments、Neurological diseases and metabolism

Abstract 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...