Abstract

There has been a significant amount of interest in the past two decades in the study of the evolution of the gut microbiota, its internal and external impacts on the gut, and risk factors for cerebrovascular disorders such as cerebral ischemic stroke. The network of bidirectional communication between gut microorganisms and their host is known as the microbiota-gut-brain axis (MGBA). There is mounting evidence that maintaining gut microbiota homeostasis can frequently enhance the effectiveness of ischemic stroke treatment by modulating immune, metabolic, and inflammatory responses through MGBA. To effectively monitor and cure ischemic stroke, restoring a healthy microbial ecology in the gut may be a critical therapeutic focus. This review highlights mechanistic insights on the MGBA in disease pathophysiology. This review summarizes the role of MGBA signaling in the development of stroke risk factors such as aging, hypertension, obesity, diabetes, and atherosclerosis, as well as changes in the microbiota in experimental or clinical populations. In addition, this review also examines dietary changes, the administration of probiotics and prebiotics, and fecal microbiota transplantation as treatment options for ischemic stroke as potential health benefits. It will become more apparent how the MGBA affects human health and disease with continuing advancements in this emerging field of biomedical sciences.

1. Introduction

Stroke is the second leading cause of mortality and a significant contributor to disability globally [1]. Strokes come in two different varieties: ischemic and hemorrhagic. Ischemic stroke (IS) is caused by a thrombus or embolus blocking a cerebral artery, whereas hemorrhagic stroke is caused by a ruptured cerebral vessel [2]. The most prevalent type of stroke worldwide is IS, with 24.9 million cases annually, which imposes a considerable burden on society [1]. Due to its complicated pathogenesis, it exhibits refractory properties, particularly regarding the secondary damage caused by an early ischemia time window and reperfusion [3]. Therefore, the development of measures to lower the prevalence of IS and its detrimental consequences is highly warranted. Recent research has demonstrated that the gut microbiota regulates the pathogenesis of IS via the microbiota-gut-brain axis (MGBA) [4, 5].

The gut microbiota and gut microbiome refer to the collection of all the gastrointestinal (GI) microorganisms and their genetic material, respectively. These commensal microorganisms include eukaryotes (fungi and parasitic helminths), prokaryotes (bacteria and archaea), and viruses [6]. The community of microbes that resides in the GI tract is the largest and most diverse of all the communities of microorganisms and has received a great deal of attention [6]. Naturally, there is mounting evidence for a two-way exchange of information between the central nervous system (CNS) and the GI microbiota, also known as the MGBA, which has been demonstrated to be a significant contributor to the physiology of the brain. The gut microbiota can affect the cardio-cerebral-vascular system, immune system, gut function, and physiological activities through signaling molecules and bioactive metabolites. Additionally, the prevalence of IS are closely related to unchangeable factors (sex, age, and genetic predisposition or pathological alterations) and modifiable factors (hypertension, diet, lifestyle, obesity, hyperlipidemia, smoking, and abnormal blood glucose) [7, 8]. They all significantly impact the diversity and abundance of the gut microbiota.

Here, we concentrate on the gut microbiota’s current role in the pathogenesis of IS and how it affects its associated risk factors. We also discuss the potential of the gut microbiota as a novel therapeutic option for the prevention and treatment of IS.

2. Healthy Microbiome and Dysbiosis

The respiratory tract, skin surface, genitourinary systems, and GI tract all include commensal microorganisms. The gut contains commensal microbes, which comprise approximately 95% of the human microbiome. There are over 100 trillion bacteria, representing up to 5000 different species, and they weigh approximately 2 kg in the human gut, which contains ten times more microbial cells than the entire body [9]. More than 100 bacterial phyla constitute the human GI microbiota, with the majority of these species belonging to two phyla, namely, Firmicutes (Ruminococcus, Clostridium) and Bacteroidetes (Prevotella, Porphyromonas), with relatively small amounts of Actinobacteria (Bifidobacterium), Proteobacteria, and Verrucomicrobia [10]. It has been established that the ratio of the bacterial species of Bacteroidetes to Firmicutes significantly impacts health and disease [11]. In addition, it is crucial to emphasize that the gut microbiota is heterogeneous, with microbial density and diversity rising along the GI tract following immunological, chemical, and nutritional gradients [12]. As a result, each species is exceptionally well adapted to carry out particular functions in a specific digestive tract environment [12]. These microorganisms have developed a close, mutually advantageous symbiotic relationship with their hosts during the eons of coevolution rather than passively colonizing their hosts’ guts [12]. The host supplies shelter and nutrition for its microbial subtenants, and the microorganisms provide numerous health benefits in exchange [13]. Specifically, the digestion of food, production of metabolites, facilitation of nutrient absorption, and metabolism of xenobiotics and drugs are all positive functions of the intestinal microbiota in a healthy condition that supports host nutrition metabolism [14]. A well-balanced intestinal microbiota maintains a normal intestinal epithelial barrier by maintaining the structural integrity of tight-junction proteins, upregulating mucin genes, and limiting the adhesion of epithelial cells to pathogenic bacteria [15]. It also helps immunological initiation, modulation, and pathogen resistance [16].

Gut dysbiosis, also known as gut microbial dysbiosis, refers to pathological abnormalities in the composition, diversity, and abundance of intestinal flora that affect intestinal metabolism, the immune state, systemic inflammation, and other responses [17]. It is characterized by decreased microbial diversity, fewer beneficial bacteria, or a higher concentration of pathogenic microorganisms. The disruption of MGBA signaling caused by dysbiosis of the intestinal flora usually contributes to alterations in the intestinal structure and increased permeability of the mucosal epithelial barrier, resulting in pathophysiological effects [18]. Specifically, multiple factors inducing gut microbial dysbiosis can lead to leakiness of the intestinal wall, resulting in easier entry of endotoxins, microbial elements, and microbial metabolites into the systemic circulation, ultimately triggering an immune response and exacerbating systemic inflammation [19]. Gut dysbiosis causes T cells to polarize into proinflammatory Th17 (IL-17), Th1 (IFN-γ), or γδcells. These cells then migrate from the small intestine to the ischemic brain, where they cause infarct damage [20, 21]. Therefore, IS may develop when there is an imbalance in the bacterial species.

3. Alterations in the Gut Microbiota during Ischemic Stroke

Microbiome-associated molecular patterns (MAMPs) and metabolites secreted by the microbiome can interact with the mucosal epithelium and intestinal immune cells, stimulate the vagus nerve (VN), or enter the systemic circulation to communicate with the brain and potentially modify neuronal and immune responses [22]. In turn, the parasympathetic and sympathetic nerve fibers of the gut wall convey signals to the brain to influence immune cell and gut motility activity and alter the composition of the gut [23] (this is described in detail below). The commensal microbiota change such that opportunistic pathogens become dominant after IS. This change is most likely caused by the release of cytokines and chemokines produced in the brain, altered intestinal motility and permeability, and mucus production, all of which contribute to dysbiosis. The result of an IS is subsequently worsened by dysbiosis. Acute IS risk factors such as age, hypertension, diabetes, obesity, and vascular dysfunction have also been linked to gut flora dysbiosis [24].

Experimental and clinical research has demonstrated that the gut microbiota composition significantly influences the incidence and outcome of IS [20, 21]. Furthermore, the gut’s microbial composition substantially changes during the acute stage of IS [25]. Singh and colleagues showed that cerebral IS results in microbiota dysbiosis, with decreased bacterial diversity in mouse feces including a reduced abundance of Firmicutes and an excessive increase in Bacteroidetes. These changes are connected to decreased intestinal motility and increased intestinal wall permeability. Additionally, they discovered that microbiota transplantation might improve IS outcomes and impact immunity [21]. Yin and colleagues studied the gut microbes of patients with IS. They found that transient ischemic episodes were primarily associated with opportunistic pathogenic bacteria such as Enterobacter, Desulfovibrio, and Megasphaera, while beneficial bacteria such as Faecalibacterium and Prevotella were depleted [26]. Another study found that individuals with IS had higher levels of Atopobium and Lactobacillus ruminans, but Lactobacillus levels were decreased [27]. Chen and colleagues found an increased relative abundance of Bacteroidetes and decreased relative levels of Faecalibacterium, Oscillospira, Lactobacillus, and Streptococcus in a study of monkeys with focal cerebral ischemia, suggesting a correlation with the poststroke inflammatory response [28]. Additionally, they discovered a decline in plasma butyrate concentrations, which may be connected with a reduction in Oscillospira and Faecalibacterium levels. Monkeys with cerebral ischemia for 6-12 months had decreased plasma levels of short-chain fatty acids (SCFAs), suggesting that persistent gut flora dysbiosis may also influence the generation of SCFAs [28]. Li and colleagues’ findings imply that the intestinal flora is related to stroke severity. Lachnospiraceae, Pyramidobacter, and Enterobacter were increased in patients with mild stroke, but Ruminococcaceae and Christensenaceae were increased in patients with severe stroke [29]. Therefore, dysbiosis not only develops after stroke but also plays a role in its onset.

Benakis et al. [20] reported the relationship between the gut microbiome and the neuroinflammatory response to IS for the first time. They found that the symbiotic gut microbiota protects the brain by controlling immune cells in the small intestine; bacterial priming of dendritic cells leads to the growth of Treg cells, which suppress IL-17+γδ T cells. Additionally, they showed that T cells move from the intestines to the meninges, where they control the neuroinflammatory reaction [20]. Studies have indicated that lipopolysaccharides (LPS) may play a key role in chronic systemic inflammation after stroke [30], and elevated levels of plasma LPS or inflammatory cytokines are strongly connected with the overgrowth of Bacteroidetes [28]. The higher levels of proinflammatory tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interferon-gamma (IFN-γ) in the plasma of focal cerebral ischemia monkeys suggest both intestinal microecological dysregulation and chronic systemic inflammation following cerebral infarction [28]. As a result, chronic systemic inflammation and the poststroke gut microbiota may be potential stroke therapeutic targets.