Gut Microbiota Dysbiosis in Acute Ischemic Stroke Associated With 3-Month Unfavorable Outcome

 

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Gut Microbiota Dysbiosis in Acute Ischemic Stroke Associated With 3-Month Unfavorable Outcome

Huanhuan Sun^†, Mengmeng Gu^†, Zhongyuan Li, Xiangliang Chen^* and Junshan Zhou^*

• Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

Background: Alterations in the gut microbiota after ischemic stroke have been demonstrated, whereas the effect on stroke outcome remains to be established.

Methods: A total of 132 consecutive patients with acute ischemic stroke were prospectively enrolled. Their gut microbiomes within 24 h of admission were profiled using 16S ribosomal RNA (rRNA) gene (V3–V4 region) sequencing. Microbiota comparisons were made between groups with good outcome (n = 105) and poor outcome (n = 27) based on 3-month modified Rankin Scale scores of 0–2 and 3–6. Propensity score-matching (PSM) analysis was conducted to assess the robustness of our findings. The functional potential was predicted using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt).

Results: Patients in the poor outcome group were characterized by a significant reduction in the alpha diversity (Shannon index, p = 0.025; Simpson index, p = 0.010), an increase in the pathogenic bacteria (e.g., Enterococcaceae and Enterococcus), and a decrease in the short-chain fatty acids (SCFAs)-producing bacteria (e.g., Bacteroidaceae, Ruminococcaceae, and Faecalibacterium) to those with good outcome group (all p < 0.05). Similar results of microbial composition were obtained after PSM. The PICRUSt revealed that the pathway for membrane transport was relatively dominant in patients with poor outcome (p < 0.05).

Conclusion: This study demonstrated that stroke patients with 3-month poor outcome had baseline gut microbiota dysbiosis featured by increased pathogenic bacteria and decreased SCFAs-producing bacteria.

Introduction

Stroke is one of the leading causes of disability and death, especially in the population aged 50 years and older (1). For acute ischemic stroke, about one-third of patients die or become disabled within the first 3 months (2). Identifying prognostic factors in the acute phase of stroke is important and might provide a novel therapeutic target to improve the stroke outcome.

Evidence is emerging that the gut microbiota is intimately involved in the pathology of a wide range of neurological disorders, including acute ischemic stroke (3). This is supported by the observations that gut microbiota correlates closely with stroke risk factors, such as age, obesity, hypertension, diabetes, dyslipidemia, and atrial fibrillation (4–8). Moreover, recent studies described a consistent pattern of poststroke gut microbiota dysbiosis, which is characterized by an increase in opportunistic pathogens (e.g., Enterobacteriaceae) and a decrease in commensal bacteria (e.g., Fecalibacterium), yielding a pro-inflammatory effect (9–14). Besides, gut microbiota-derived metabolites such as trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs) might contribute to stroke pathology by modulating inflammation and atherosclerosis (11, 15–18). The SCFAs could regulate the expression of brain-derived neurotrophic factor (BDNF) (16); they could also modulate the effects of brain-invading lymphocytes, leading to an altered level of proinflammatory interleukin-17 (IL-17) and neuroprotective IL-10 (15). Interestingly, previous studies showed that the alterations of gut microbiota after stroke are correlated with the prognosis of stroke (10–13). The enrichment of Parabacteroides, Oscillospira, Enterobacteriaceae, etc., and depletion of Prevotella, Roseburia, Fecalibacterium, etc., were positively correlated with early unfavorable outcomes at discharge in patients with stroke (12). Whereas, the specific groups of bacteria and potential mediators associated with 3-month functional outcome in patients with acute ischemic stroke have not been fully revealed.

Here, we conducted this 16S ribosomal RNA (rRNA) gene sequencing-based study to characterize the gut microbiota in the acute phase of ischemic stroke and to compare the bacteria profiles of patients with different functional outcomes [3-month modified Rankin Scale (mRS) 0–2 vs. 3–6]. We aimed to: (1) reveal the taxonomic dysbiosis of gut microbiota related to unfavorable stroke outcome; (2) infer possible differences of functional composition associated with stroke outcome; (3) explore whether inflammatory cytokines (IL-17 and IL-10), BDNF, and TMAO are associated with gut microbiota and stroke outcome. An additional propensity score-matching (PSM) analysis was performed to correct for sample selection bias.