Interventional strategies for ischemic stroke based on the modulation of the gut microbiota

I'm sure there is something useful in here for your doctor to direct the nutritionist to create diet protocols. But nothing will occur. Your doctor and stroke hospital don't follow and implement research in any reasonable semblance of time. Our fucking failures of stroke associations do absolutely nothing to get survivors recovered, I have no fucking clue what they are for. They shouldn't have stroke in their name.

Interventional strategies for ischemic stroke based on the modulation of the gut microbiota

Jing Wang, Xiaofeng Liu^* and Qun Li^*

• Department of Gastroenterology, The 960th Hospital of the PLA, Jinan, Shandong, China

The microbiota-gut-brain axis connects the brain and the gut in a bidirectional manner. The organism’s homeostasis is disrupted during an ischemic stroke (IS). Cerebral ischemia affects the intestinal flora and microbiota metabolites. Microbiome dysbiosis, on the other hand, exacerbates the severity of IS outcomes by inducing systemic inflammation. Some studies have recently provided novel insights into the pathogenesis, efficacy, prognosis, and treatment-related adverse events of the gut microbiome in IS. In this review, we discussed the view that the gut microbiome is of clinical value in personalized therapeutic regimens for IS. Based on recent non-clinical and clinical studies on stroke, we discussed new therapeutic strategies that might be developed by modulating gut bacterial flora. These strategies include dietary intervention, fecal microbiota transplantation, probiotics, antibiotics, traditional Chinese medication, and gut-derived stem cell transplantation. Although the gut microbiota-targeted intervention is optimistic, some issues need to be addressed before clinical translation. These issues include a deeper understanding of the potential underlying mechanisms, conducting larger longitudinal cohort studies on the gut microbiome and host responses with multiple layers of data, developing standardized protocols for conducting and reporting clinical analyses, and performing a clinical assessment of multiple large-scale IS cohorts. In this review, we presented certain opportunities and challenges that might be considered for developing effective strategies by manipulating the gut microbiome to improve the treatment and prevention of ischemic stroke.

Introduction

Stroke is a devastating cerebrovascular disease characterized by high morbidity, disability, recurrence, and mortality. The data provided by the Global Burden of Disease (GBD) 2019 suggested that stroke is the second most common reason for death and the third leading reason for disability across the world. Also, the absolute number of first-ever stroke and stroke-related deaths has increased considerably over the last decade (GBD 2019 Stroke Collaborators, 2021). China has a greater burden of stroke, considering that the country has the highest prevalence of stroke in the world. Additionally, most of the years of life lost and disability-adjusted life years among Chinese adults are because of stroke (Wu et al., 2019; Ma et al., 2021; Wang Y. J. et al., 2022). Stroke can be broadly classified into ischemic and hemorrhagic stroke, with ischemic stroke (IS) contributing to more than 70% of total incidences of stroke worldwide (GBD 2016 Lifetime Risk of Stroke Collaborators et al., 2018; Tuo et al., 2022). It primarily occurs due to a cerebral arterial occlusion caused by a thrombus or embolus (Tian et al., 2019; Mistry and Dumont, 2020). Besides damaging the brain parenchyma surrounding the ischemic areas, IS also triggers complex neuropathophysiological and neuropathological events followed by neuroinflammation and immune response (Pluta et al., 2021; Zhang S. R. et al., 2021). Many recent studies have suggested that post-stroke immunosuppression and intestinal barrier damage can increase the risk of opportunistic infections after IS, which can seriously worsen the outcomes of IS (Ghelani et al., 2021). These findings indicate that effective treatment of IS and the extension of the therapeutic window are challenging, and new therapeutic strategies need to be developed.

Recanalization and neuroprotection are the main approaches for treating IS in the clinic. Performing intravenous/intra-arterial thrombolysis and mechanical thrombectomy for effective reperfusion following recanalization are necessary for a positive prognosis of IS patients (Prabhakaran et al., 2015; Wu et al., 2019). The Food and Drug Administration (FDA) has only approved intravenous recombinant tissue plasminogen activator (IV rtPA) for treating IS (National Institute of Neurological Disorders and Stroke rt-Pa Stroke Study Group, 1995). Endovascular reperfusion therapy can partially improve the overall likelihood of a good IS outcome (Prabhakaran et al., 2015; Wu et al., 2019; Saver and Adeoye, 2021). However, the overall safety and efficacy are limited by a narrow treatment window (Yeo et al., 2013) of 4.5 h from the onset of the symptoms, the challenges of cerebral ischemia-reperfusion injury (Eltzschig and Eckle, 2011; Sun et al., 2018), and the tendency of hemorrhagic transformation (Gauberti et al., 2018) during the treatment course. Therefore, many researchers are investigating novel approaches for treating IS. In the past two decades, more than 1,000 potential neuro-protectants have been found to attenuate ischemic brain injury by promoting neuronal survival, neural plasticity, neurogenesis, and synaptogenesis (Liberale et al., 2018; Shen et al., 2023). However, the studies were mainly conducted on experimental IS animal models, and only a few agents targeting these molecules could be administered in the clinic (Gauberti et al., 2018; Gan et al., 2020; Mani et al., 2023). Stem cell therapy and neural progenitor cell transplantation therapy provide a regenerative strategy for protecting neural tissue in the acute phase and the replacement of lost tissues in the sub-acute or chronic phase of IS (Wei et al., 2017; Yu et al., 2019). However, this technique has numerous challenges, including identifying suitable neural progenitors, low overall survival of the neurons, and insufficient neuronal differentiation (Wei et al., 2017; Wang S. N. et al., 2020; Mani et al., 2023). Thus, the technique needs to be further improved before clinical application.

Along with the typical neurological deficit in the acute phase (Powers, 2020), more than half of the patients with IS suffer from gastrointestinal complications, including gut motility and absorption dysfunction, intestinal bleeding, gut leakiness, and enteropathogenic sepsis (Wen and Wong, 2017). After the concept of the microbiota-gut-brain axis (MGBA) was proposed, many studies confirmed the presence of a bidirectional MGBA and the potential of microbiota-directed interventions to improve stroke outcomes (Zhao et al., 2018). Detailed studies on the underlying mechanisms might provide a theoretical basis for developing novel interventions and therapeutic strategies for IS based on microbes (Cryan et al., 2019). With the advancement of high-throughput and “-omics” technologies, especially the integration of metagenomics and metabolomics techniques, a strong correlation was found between the gut microbiota and potential risk factors for the onset, progression of pathological changes and the prognosis and recovery of IS patients (Benakis et al., 2016; Nam, 2019; Pluta et al., 2021). Several studies have shown that the gut microbiota and their metabolites might play a dual role in IS (Peh et al., 2022). As the gut microbiome is less diverse in IS patients, modulating the composition of the gut microbiome might improve the prognosis of IS patients. On the other hand, consuming foods rich in choline and L-carnitine increases the occurrence of IS due to the generation of trimethylamine-N-oxide. Meanwhile, consuming dietary fiber improves the outcomes in IS patients due to the action of short-chain fatty acid metabolites containing butyrate and propionate, derived from gut microbes (Chen et al., 2019b; Battaglini et al., 2020; Peh et al., 2022).

Several effective strategies have been proposed for treating disorders related to gut microbiota in IS patients. The gut microbiota can be modulated using two ways: (1) By identifying keystone taxa in the gut microbiome and performing interventions; (2) By altering the composition of the intestinal microbiota by single or combined use of dietary interventions, antibiotics, probiotics, fecal microbiota transplantation (FMT), or traditional Chinese medication (TCM). Several studies have also suggested that repairing the damaged intestinal mucosal barrier by gut-derived stem cell transplantation might be a new treatment strategy, which could prevent the occurrence of endotoxemia and secondary infections. Therefore, in this review, we discussed intestinal microbiota as an intervention technique for treating IS to gain further insights into the emerging field of IS therapy.

Dietary interventions in IS

Diet directly affects the composition of the gut microbial communities and the production of metabolites. Cellular stress caused by unhealthy diets, such as a high intake of high-fat foods, animal byproducts, and processed foods, may influence abnormal lipid metabolism and cerebral small vessel disease, which can trigger the neuroinflammatory process and, as a result, activate a neurodegenerative cascade (Nassir et al., 2021; Flaig et al., 2023). Foods high in choline and L-carnitine, such as red meat, can be metabolized by intestinal microbiota to produce trimethylamine N-oxide (TMAO), which has been shown in experimental and clinical studies to promote the occurrence of atherosclerosis and stroke (Koeth et al., 2013; Zhu et al., 2021). Reduced reverse cholesterol transport induced by TMAO via gut flora-related pathways is one possible mechanism (Zhu et al., 2021; Peh et al., 2022). Meanwhile, the presence of specific bacterial species in human feces has been linked to TMAO plasma concentration and diet pattern (Peh et al., 2022). TMAO may also promote platelet hyperreactivity and thrombosis by increasing Ca²⁺ release from intracellular stores during submaximal agonist stimulus-dependent platelet activation (Zhu et al., 2016). Clinical trials confirmed that plasma TMAO levels could independently predict the risk of thrombosis, including heart attack and stroke (Tang et al., 2013; Zhu et al., 2016; Wang M. et al., 2022). Furthermore, TMAO-mediated pathogenesis is associated with the activation of multiple inflammatory signaling pathways, which may result in oxidative stress, mitochondrial dysfunction, neuronal aging, synaptic compromise, and cognitive impairment (Praveenraj et al., 2022).

Consumption of dietary fiber and polyphenols, on the other hand, may improve stroke outcomes via gut flora-associated SCFAs such as butyrate and propionate (Fraga et al., 2019; Peh et al., 2022). Long-term consumption of short-term fermented soybeans (chungkookjang) containing specific Bacillus species in animal models of stroke could influence host metabolism, particularly inflammation and insulin resistance, through regulation of gut microbiota composition (increase in Lactobacillus, Bacillus, and Akkermansia) and metabolites (increase in propionate and butyrate), and further prevent neuronal cell death and memory dysfunction from the artery occlusion (Zhang T. et al., 2021). Nonetheless, the underlying mechanisms are unknown. In a recent study, sodium butyrate was shown to reduce neuronal apoptosis by activating PI3K/Akt via the G protein-coupled receptor GPR41/Gβγ in a rat model (Zhou et al., 2021).

Collectively, dietary intervention may be an appealing and valuable way to influence the course of IS.

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