Stroke Dysbiosis Index (SDI) in Gut Microbiome Are Associated With Brain Injury and Prognosis of Stroke

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Stroke Dysbiosis Index (SDI) in Gut Microbiome Are Associated With Brain Injury and Prognosis of Stroke

Geng-Hong Xia^1†, Chao You^1,2†, Xu-Xuan Gao¹, Xiu-Li Zeng¹, Jia-Jia Zhu¹, Kai-Yu Xu³, Chu-Hong Tan¹, Ruo-Ting Xu¹, Qi-Heng Wu¹, Hong-Wei Zhou³, Yan He^4*‡ and Jia Yin^1*‡

• ¹Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
• ²Department of Neurology, The First People's Hospital of Zunyi, Zunyi, China
• ³State Key Laboratory of Organ Failure Research, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
• ⁴Microbiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China

Background: Significant dysbiosis occurs in the gut microbiome of stroke patients. Condensing these broad, complex changes into one index would greatly facilitate the clinical usage of gut microbiome data. Here, we formulated a gut microbiota index in patients with acute ischemic stroke based on their gut microbiota dysbiosis patterns and tested whether the index was correlated with brain injury and early outcome.

Methods: A total of 104 patients with acute ischemic stroke and 90 healthy individuals were recruited, and their gut microbiotas were compared and to model a Stroke Dysbiosis Index (SDI), which representing stroke-associated dysbiosis patterns overall. Another 83 patients and 70 controls were recruited for validation. The association of SDI with stroke severity (National Institutes of Health Stroke Scale [NIHSS] score) and outcome (modified Rankin scale [mRS] score: favorable, 0–2; unfavorable, >2) at discharge was also assessed. A middle cerebral artery occlusion (MCAO) model was used in human flora-associated (HFA) animals to explore the causal relationship between gut dysbiosis and stroke outcome.

Results: Eighteen genera were significantly different between stroke patients and healthy individuals. The SDI formula was devised based on these microbiome differences; SDI was significantly higher in stroke patients than in healthy controls. SDI alone discriminated stroke patients from controls with AUCs of 74.9% in the training cohort and 84.3% in the validation cohort. SDI was significantly and positively correlated with NIHSS score on admission and mRS score at discharge. Logistic regression analysis showed that SDI was an independent predictor of severe stroke (NIHSS ≥8) and early unfavorable outcome (mRS >2). Mice receiving fecal transplants from high-SDI patients developed severe brain injury with elevated IL-17⁺ γδ T cells in gut compared to mice receiving transplants from low-SDI patients (all P < 0.05).

Conclusions: We developed an index to measure gut microbiota dysbiosis in stroke patients; this index was significantly correlated with patients' outcome and was causally related to outcome in a mouse model of stroke. Our model facilitates the potential clinical application of gut microbiota data in stroke and adds quantitative evidence linking the gut microbiota to stroke.

Introduction

Ischemic stroke imposes a heavy burden on society, with 24.9 million cases worldwide (1). Although intravenous thrombolysis and endovascular treatment greatly improve some patients' prognosis, the prognosis for most patients with acute ischemic stroke is still poor. Therefore, identifying potential risk factors associated with stroke prognosis is important in clinical management.

In current clinical studies, stroke patients often display significant changes in microbial diversity and bacterial counts in fecal samples independent of certain comorbidities (hypertension, age and type 2 diabetes) (2–4). In a relatively large sample size, our previous study found that, compared to asymptomatic controls, patients with acute atherosclerosis stroke showed significant dysbiosis in the gut microbiota, with increases in opportunistic pathogens and decreases in beneficial genera, and such changes were especially pronounced in severe stroke patients (3). However, clinical studies remain limited in their ability to delineate the potential link between gut microbiome and stroke and characterize the underlying mechanisms of microbiota changes in these patients. The main challenges were the large number of microbes that differed between patients and healthy individuals and the heterogeneous nature of patient clinical pathology, diets and lifestyle, all of which have major influences on the composition of the gut microbiome.

Microbiota-based models may be an alternative method to facilitate the use of data on the gut microbiota in certain diseases. Disease-related models based on gut microbial alternation patterns or microbiota-targeted biomarkers specific to certain diseases were recently suggested as powerful tools for disease risk assessment, diagnosis, and even prognosis (5–8). A microbiota-based model of inflammatory bowel disease (IBD) showed high accuracy in disease diagnosis and, furthermore, reflected disease activity and treatment efficacy (6). Stool microbiota composition in cirrhosis patients was successfully used to predict the 90-day hospitalization rate, independent of clinical predictors (8).

Interaction between gut microbiota and stroke outcome was recently reported via animal experiments (9–12). Within animals, disturbance in the gut microbiota promoted an increase in the abundance of intestinal pro-inflammatory T cells and led to exacerbation of ischemic brain lesions along with worsened stroke outcomes (11, 13). A previous study has demonstrated the correlation between the gut microbiota dysbiosis and the severity of brain injury via two distinct stroke models (13), in which gut microbiota dysbiosis and stroke severity were influenced and interacted as both cause and effect. However, there may be some concerns about the little direct information regarding the role of the patients' intestinal flora on brain injury. Indeed, the role of human flora is somewhat differed from the role of the animal flora in convenient experimental animals (14). The human flora-associated (HFA) animals, established via the fecal microbiota transplantation (FMT) technology, is a stable model for studying the ecosystem and metabolism of the human intestinal flora (14–16). Studies using HFA animals will provide much needed information on the precise role of the intestinal flora in relation to humans (14).

Here, we applied microbiota-related analysis by sequencing 16S ribosomal RNA genes to contrast the gut microbiota of 104 patients with acute ischemic stroke with those of 90 healthy participants, and we developed a Stroke Dysbiosis Index (SDI), which was established based on the profound difference in microbial taxonomic features between patients and healthy individuals. An additional 153-member group was recruited to validate this microbial model. Furthermore, associations between SDI and patients' stroke severity and early outcome were assessed. Experimental stroke model was performed in HFA mice to explore the potential causality of patients' disturbed gut microbes on stroke brain injury.