Microbiome-gut-brain axis contributes to patients and Bama miniature pigs with acute large ischemic stroke

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Microbiome-gut-brain axis contributes to patients and Bama miniature pigs with acute large ischemic stroke

Dazhi Deng^1,2Hehua Lei^3,4Zheng Cao^3,4Cui Zhang^3,4Ruichen Du^3,4Xin Gao^3,4Junjie Wei⁵Yibo Lu⁶Xiangzhen Zhou⁷Limin Zhang^1,3,4*

• ¹Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China
• ²Department of Emergency, The People's Hospital of Guangxi Zhuang Autonomous Region and Guangxi Academy of Medical Sciences, Nanning, China
• ³State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan, China
• ⁴University of Chinese Academy of Sciences, Beijing, China
• ⁵Department of Neurology, The People's Hospital of Guangxi Zhuang Autonomous Region and Guangxi Academy of Medical Sciences, Nanning, China
• ⁶Department of Radiology, Nanning Fourth People's Hospital and Guangxi AIDS Clinical Treatment Center, Nanning, China
• ⁷Department of Pathology, The People's Hospital of Guangxi Zhuang Autonomous Region and Guangxi Academy of Medical Sciences, Nanning, China

Acute large hemispheric infarction (ALHI) is an overwhelming emergency with a great challenge of gastrointestinal dysfunction clinically. Here, we initially proposed delayed bowel movements as the clinical phenotype of strike to gut-brain axis (GBA) in ALHI patients by epidemiological analysis of 499 acute ischemic stroke (AIS) patients. ¹H NMR-based metabolomics revealed that AIS markedly altered plasma global metabolic profiling of patients compared with healthy controls. Risk factors of strike on GBA were the National Institutes of Health Stroke Scale (NIHSS) score ≥ 5 and stroke onset time ≤ 24 h. As a result, first defecating time after admission to the hospital ≥2 days could be considered as a potential risk factor for strike on GBA. Subsequently, the ALHI Bama miniature (BM) pig model with acute symptomatic seizure was successfully established by ligation of the left ascending pharyngeal artery combined with local air injection. Clinical phenotypes of brain necrosis such as hemiplegia were examined with brain diffusion-weighted imaging (DWI) and pathological diagnosis. In addition to global brain injury and inflammation, we also found that ALHI induced marked alterations of intestinal barrier integrity, the gut microbial community, and microbiota-derived metabolites including serotonin and neurotransmitters in both plasma and multiple brain tissues of BM pigs. These findings revealed that microbiota-gut-brain axis highly contributed to the occurrence and development of ALHI.

1 Introduction

Stroke is a leading cause of adult disability and mortality worldwide, especially in people aged 50 years and older (WHO, 2020; Ding et al., 2022). Epidemiological studies have shown that approximately 80% of stroke patients are diagnosed with ischemic stroke (Boursin et al., 2018; Barthels and Das, 2020; Wang et al., 2022), and anterior circulation ischemic infarctions (ACIs) account for 80% of ischemic strokes cases (Sparaco et al., 2019). Acute large hemispheric infarction (ALHI) caused by the interruption of blood supply in the middle cerebral artery is a severe form of ischemic stroke and accounts for 2–8% of acute ischemic stroke (AIS) (Zha et al., 2015). More than 50% of AHLI patients experience the development of malignant cerebral edema (MCE) accompanied by blood-brain barrier (BBB) breakdown and vasogenic edema formation, which lead to mortality of up to 80% (Liebeskind et al., 2019; Lehrieder et al., 2021). Meanwhile, invasive procedures including endobronchial electrocautery (He et al., 2021), central venous catheterization (Kugiyama et al., 2018), artificial pneumothorax (Gou et al., 2019), and transbronchial needle aspiration (Van Den Plas et al., 2020) that have been widely used in clinical management for patients can induce cerebral arterial air embolism. Both kinds of strokes induce neuronal cell death, systemic inflammation, and brain regional injury and subsequent metabolic disorders. However, the pathophysiologic pathways relating to outcomes of them are still largely unknown and worth conducting further research.

One typical consequence of ALHI is primary and secondary brain injury caused by focal and global brain inflammation. In ischemic stroke, the steep termination of blood supply in a vascular territory of the brain leads to the death of neural cells yielding an ischemic core and releasing damage-associated molecular patterns (DAMPs) such as adenosine and heat shock proteins, which trigger focal brain inflammation and immune response in the injured brain region (Schuhmann et al., 2021). Subsequently, a series of events including BBB damage, oxidative stress, and mitochondrial disruption result in secondary brain injury and global brain inflammation (Shi et al., 2019). Following an acute brain injury over stroke, peripheral leucocytes infiltrate the injured brain and release proinflammatory cytokines, thus further aggravating the BBB disruption and brain injury (Huang et al., 2022). The activated microglia by cytokines and chemokines distribute in the chronic stage of stroke forming global brain inflammation (Fifield and Vanderluit, 2020). Supportive evidence of global brain inflammation after stroke could also be found in the extensive distribution of a large number of cytokines (IL-1β, IL-6, and TNF-α) in the contralateral hemisphere of animal AIS models (Zaremba and Losy, 2001; Chen et al., 2019; Endres et al., 2022). Furthermore, previous studies also showed that global brain inflammation gradually induces global vascular inflammation in both intracerebral and subarachnoid hemorrhage mice models (Singh et al., 2018; Schuhmann et al., 2023).

In addition to brain injury and global brain inflammation, stroke results in systemic alterations including cardiovascular and gastrointestinal systems. Increasing evidence suggests that stroke can cause disruption of the gut microbiota homeostasis and intestinal epithelial barrier integrity, and vice versa (Agirman et al., 2021). The gut and its microbiota could also increase the risk of cerebrovascular events highly contributing to the onset of stroke (Agirman et al., 2021). Patients with ALHI, in particular, face a high risk of gastrointestinal dysfunction with a potential impact on the microbiome-gut-brain axis (Coggrave and Norton, 2013; Arunachala Murthy et al., 2022). In clinical stroke, previous studies with relatively limited sample size identified overall 62 upregulated (e.g., Enterobacteriaceae, Streptococcus, Lactobacillus, and Escherichia) and 29 downregulated microbial taxa (e.g., Eubacterium and Roseburia) in the fecal microbial community (Xu et al., 2021; Peh et al., 2022). In experimental stroke, specific gut microbiome composition and their metabolites such as short-chain fatty acids closely contribute to the severity of stroke. Although clinical stroke is limited due to ethical restrictions that prevent invasive sampling of AIS patients (Coggrave and Norton, 2013; Xu et al., 2021), these experimental data suggested that modulation of an interplay between the gut and brain could be a novel therapeutic strategy for stroke prevention.

In this study, we first conducted an epidemiological analysis of 499 AIS patients coupled with clinical magnetic resonance imaging (MRI) and computer tomography (CT) examinations. A phenomenon of delayed bowel movements was observed in LHI patients, which may be induced by a strike to the GBA. ¹H NMR-based metabolomics was also employed to reveal global metabolic profiling in the plasma of AIS patients. Subsequently, a Bama miniature (BM) pig model with ALHI was successfully established and employed to investigate the alterations of intestinal barrier integrity, the gut microbial community, and microbiota-derived metabolites. These findings highlight that microbiome-gut-brain axis contributes to both clinical AIS patients and ALHI BM pigs.

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