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

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 microbio...

Full description

Saved in:

Bibliographic Details
Published in:	Microbiome Vol. 11; no. 1; pp. 1 - 202
Main Authors:	Liu, Sheng, Men, Xuejiao, Guo, Yang, Cai, Wei, Wu, Ruizhen, Gao, Rongsui, Zhong, Weicong, Guo, Huating, Ruan, Hengfang, Chou, Shuli, Mai, Junrui, Ping, Suning, Jiang, Chao, Zhou, Hongwei, Mou, Xiangyu, Zhao, Wenjing, Lu, Zhengqi
Format:	Journal Article
Language:	English
Published:	London BioMed Central 08-09-2023 BMC
Subjects:	Abundance Alzheimer's disease Amyotrophic lateral sclerosis Behavior disorders CADASIL Caspase-8 Cell activation Coenzyme A Environmental factors Feces Flavin Fusobacterium varium Genetic testing Genomes Gut-brain axis Inflammasomes Inflammation Inflammatory cytokines Intestinal microflora Ischemia Leukoencephalopathy Macrophages Microbiome Microbiomes Microbiota Microorganisms Migraine Mutation Neurological diseases Neurotransmitters Pathogenesis Patients Proteins Vascular diseases Virulence γ-Aminobutyric acid
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 behavior disorder in Notch3 R170C/+ 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	2049-2618 2049-2618
DOI:	10.1186/s40168-023-01638-3