Gut microbiota is causally associated with poststroke cognitive impairment through lipopolysaccharide and butyrate

Abstract

Background Poststroke cognitive impairment (PSCI) is prevalent in stroke patients. The etiology of PSCI remains largely unknown. We previously found that stroke induces gut microbiota dysbiosis which affects brain injury. Hereby, we aimed to investigate whether the gut microbiota contributes to the pathogenesis of PSCI. Methods 83 stroke patients were recruited and their cognitive function were measured by Montreal Cognitive Assessment (MoCA) scores 3 months after stroke onset. The peripheral inflammatory factor levels and gut microbiota compositions of the patients were analyzed. Fecal microbiota transplantation from patients to stroke mice was performed to examine the causal relationship between the gut microbiota and PSCI. The cognitive function of mice was evaluated by Morris water maze test. Results 34 and 49 stroke patients were classified as PSCI and non-PSCI, respectively. Compared with non-PSCI patients, PSCI patients showed significantly higher levels of gut Enterobacteriaceae, lipopolysaccharide (LPS) and peripheral inflammation markers. Consistently, stroke mice that received microbiota from PSCI patients (PSCI mice) presented a higher level of Enterobacteriaceae, intestinal Toll-like receptor-4 (TLR4) expression, circulating LPS, LPS-binding protein (LBP) and inflammatory cytokines, and a lower level of fecal butyrate, severer intestine destruction and cognitive impairment than mice that received microbiota from nPSCI patients (nPSCI mice). In addition, we observed exacerbations in blood–brain barrier (BBB) integrity, microglial activation, neuronal apoptosis in the CA1 region of the hippocampus, and Aβ deposition in the thalamus of PSCI mice in comparison with nPSCI mice. Intraperitoneal injection of LPS after stroke caused similar pathology to those seen in PSCI mice. Supplementation with sodium butyrate (NaB) via drinking water rescued these detrimental changes in PSCI mice. Conclusions Our data indicate a cause–effect relationship between gut microbiota and PSCI for the first time, which is likely mediated by inflammation-regulating metabolites including LPS and butyrate.

Gut microbiota-derived metabolites mediate the neuroprotective effect of melatonin in cognitive impairment induced by sleep deprivation

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Multi-omics reveals specific host metabolism-microbiome associations in intracerebral hemorrhage

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“…found that Klebsiella, Escherichia-Shigella, and Bacteroides were positively correlated with systemic inflammatory markers in stroke patients ( Zheng et al., 2022 ). Mice received fecal bacteria transplantation from stroke patients or injection of Lipopolysaccharide exacerbated the neuroinflammatory response ( Wang et al., 2022 ). Our findings further explain the above phenomenon that active synthesis of pro-inflammatory molecules by gut microbiome in ICH patients promotes a systemic inflammatory response, ultimately lead to increased neuroinflammation.…”

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