Introduction

Ischemic stroke is a common cerebrovascular disease with high morbidity, lethality, and disability, and is becoming increasingly younger.1,2 Globally, approximately 15 million patients suffer from ischemic stroke every year, resulting in more than half a million deaths and 5 million permanent disabilities.3 The incidence of ischemic stroke has gradually increased owing to demographic changes and the prevalence of diabetes and obesity, which places a heavy economic burden on families and society.4 Currently, treatment strategies for improving the clinical symptoms of ischemic stroke include thrombolysis, thrombectomy, and drugs.5,6 Recombinant tissue plasminogen activator is the only drug approved by the US Food and Drug Administration for the treatment of ischemic stroke.7 However, a few drawbacks of intravenous thrombolysis include partial recanalization, hemorrhagic transformation, delayed reperfusion, and secondary damage.8 In addition, ischemic stroke is often accompanied by vascular recanalization and blood flow reperfusion, which further aggravates cellular metabolic disorders and organ damage, ultimately resulting in severe neurological function deficiencies known as cerebral ischemia-reperfusion injury (CIRI). Notably, CIRI can aggravate brain injury and lead to high rates of disability and death.9 Unfortunately, the pathogenesis of CIRI remains unclear. Therefore, elucidating the pathogenesis of CIRI and developing safe and effective therapeutic agents are major research challenges in the field of ischemic stroke.

Increasing evidence has shown that the functional role of the intestinal microbiome in cerebrovascular diseases has recently attracted considerable attention from scholars at home and abroad.10 The intestinal microbiome is a diverse community of microorganisms that lives in the gastrointestinal tract,11 including bacteria, fungi, parasites, and viruses. The intestinal microbiome consists of six phyla: Proteobacteria, Actinomycetes, Fusobacterium, Verrucomicrobia, Firmicutes, and Bacteroides. Among them, Firmicutes and Bacteroides are the most abundant, accounting for 70–75% of healthy bacteria.12 Of note, the intestinal microbiome is frequently referred to as a super “organ”13 and is sometimes known as the “second brain”14 because of its involvement in several immunological, neurological, and endocrine reactions. Moreover, the intestinal microbiome is of vital importance to the central and intestinal, this relationship is named as the “microbiome-gut-brain” axis.15 Previous studies have found that gut microbiota dysbiosis is closely related to CIRI and is a key risk factor for cerebrovascular disease.16 CIRI can alter in the composition of the gut microbiota and lead to change the secretion of gastrointestinal hormones, which are important factors with implications for the pathology and treatments of CIRI.17,18 Numerous studies have demonstrated that gut microbiota disorders cause structural and functional abnormalities during the progression.19 Wen et al20 reported that 50% of patients with ischemic stroke developed gastrointestinal complications in the clinical setting, including dysphagia, gastrointestinal bleeding, constipation, and bowel incontinence. Notably, some studies have found that gut microbiota dysbiosis may serve as a new biomarker for the prevention and treatment of ischemic stroke.21–23 Lou et al24 proved that gut microbiota is closely related to the occurrence of high on-treatment platelet reactivity in patients with ischemic stroke. Meanwhile, Bacteroidetes have been shown to be highly correlated with infract size and neuroinflammation.25,26 Through neuronal networks, the brain and gut communicate bidirectionally to form a complex “gut-brain” axis. On the one hand, the brain affects the function or permeability of the gut by transmitting nerve impulses to reduce intestinal motility and secretion.27 On the other hand, the gut microbiota reversely makes an effect on the brain function by sending signals back into the brain through the neuro-immune and endocrine pathways.28 Furthermore, other studies have shown that gut microbiota-derived metabolites such as phenylacetylglutamine and white matter hyperintensity.29 Other gut microbiota metabolites may serve as therapeutic and prognostic biomarkers for CIRI, including trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs).30,31 Intriguingly, an inverse correlation emerges between SCFA levels and the prognosis of reperfused stroke, particularly in elderly patients contending with pronounced stroke events. Lee et al32 reported that aged mice subjected to MCAO exhibited attenuated neuroinflammation and reduced neurological deficits when administered fecal transplants from young, SCFA-rich donors. Similarly, serum TMAO concentrations exhibit a positive correlation with the risk factors of stroke and the ensuing neurological deficits post-ischemic brain injuries.33 Lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, can enter the brain through compromised gut and BBB, and thereby accelerating CIRI progression.34 Fecal microbiota transplantation from healthy donors exhibited a therapeutic effect on CIRI and other neurological disorders.35,36 Therefore, the disordered “microbiome-gut-brain” axis plays an important regulatory role in the pathogenesis of cerebrovascular diseases, including CIRI.37

Recently, traditional Chinese medicine (TCM) has received increasing attention from international medical researchers because of its favorable therapeutic effects and low toxicity.38 Preclinical experiments and clinical trials have demonstrated that TCM exerts therapeutic effects on CIRI owing to its antioxidant, gut microbiota modulation, free radical scavenging, antithrombotic, and neuroprotective properties.39–41 Modern pharmacology has confirmed that TCM is a promising resource with great chemical diversity and multi-target and multi-pathway characteristics.42 Increasing evidence has shown that TCM exerts an anti-CIRI effect by regulating the composition and metabolism of the gut microbiota.43,44 Moreover, the theory of the “gut-brain” axis has been documented in Chinese medicine since ancient times, and TCM has improved gut microbiota dysbiosis and metabolic syndrome in the treatment of CIRI.45 These findings suggest that gut microbiota may serve as a new therapeutic target for TCM in the prevention and treatment of CIRI.

This review summarizes the functional role of gut microbiota in the occurrence and progression of CIRI. In addition, the present review comprehensively summarizes the latest progress in TCM in curing CIRI through the “microbiome-gut-brain” axis, aiming to provide a theoretical basis for the development of new drugs against CIRI.

Functional Role of the “Microbiota-Gut-Brain” Axis in CIRI

Gut microbiota plays an important role in human health and diseases.46 The “microbiota-gut-brain” axis is a bidirectional communication network between gut microbiota and their host.47 Dysbiosis of the gut microbiota is related to the development of common stroke risk factors, such as obesity, diabetes, hypertension, and atherosclerosis, which increase the risk of CIRI.48 Acute stress in ischemic stroke also changes the composition and abundance of the gut microbiota, which may affect the prognosis of CIRI.49 Moreover, numerous studies have shown that the gut microbiota can improve ischemic stroke prognosis by regulating neuroactive molecules and immune cell functions, enhancing neural network plasticity, and reducing neuroinflammation.18,50 These findings indicate that the pathogenesis of CIRI is closely related to an imbalance in gut microbiota. Herein, we summarize the functional role of the microbiota–gut–brain axis in the development and progression of CIRI (Figure 1) as well as the underlying mechanism.

Figure 1 Schematic representation illustrating bidirectional interaction between CIRI and the gut microbiota via the gut-brain axis.

Abbreviations: CIRI, cerebral ischemia-reperfusion injury; ANS, autonomic nervous system; ENS, enteric nervous system; HPA, hypothalamic-pituitary-adrenal; BBB, blood-brain barrier; TMAO, trimethylamine N-oxide; SCFAs, short-chain fatty acids; BAs, bile acids; LPS, lipopolysaccharide.

Note: Created in BioRender. Ren, (Y) (2024) https://BioRender.com/v74a311.

Gut Microbiota Dysbiosis

Normal gut microbiota and the host are in a dynamic balance of mutual benefit and symbiosis. The “microbiome-gut-brain” axis consists of bidirectional communication between the brain and intestines, linking neural function, cognition, and emotion of the brain with peripheral intestinal functions.51 Unfortunately, the “gut-brain” axis is disrupted in CIRI,37 which contributes to alterations in the composition and abundance of gut microbiota. Wang et al52 reported that the ratio of Firmicutes to Bacteroidetes in CIRI mice was lower than that in normal mice, which usually serves as a sign of gut disturbance. Recent studies have reported that Enterobacteriaceae, Bifidobacterium, Lactobacillus, Desulfovibrio, Alloprevotella, Ruminococcus, and Escherichia are enriched in high-risk ischemic stroke patients.53,54 Another study found that patients with CIRI presented with an increased abundance of pathogenic bacteria in the intestinal tract, such as Enterobacter and Megasphaera, and a decreased abundance of commensal or beneficial genera, such as Bacteroides and Prevotella, and these gut microbiota dysbiosis was positively associated with the pathological progression of CIRI.55 Tan et al56 reported that dysbiosis of the gut microbiota in patients with acute ischemic stroke enhances the subsequent risk of poor functional outcomes. Moreover, systemic exposure to Porphyromonas gingivalis may increase the risk of ischemic stroke.57 Kawato et al58 found that continual gram-negative bacteria induced accelerated stroke onset in stroke-prone spontaneously hypertensive rats. Other studies have reported that the compositional and functional imbalance of the gut microbiota is an independent predictor of poor prognosis in ischemic stroke.18,59 A recent study has reported that Enterobacteriaceae may serve as a biomarker of cognitive impairment in CIRI.21 Dysbiosis of the gut microbiota has a positive effect on neural function of the brain, which in turn exacerbates brain infarction.50,60 Notably, prebiotic administration and fecal microbiota transplantation from healthy donors have been shown to inhibit CIRI progression and reduce brain infarct volume.61,62 In summary, gut microbiota plays a vital role in the occurrence and development of CIRI.

Intestinal Mucosal Barrier

Integrity of the intestinal mucosal barrier is the foundation of multiple functions of the intestinal tract to keep normal.63 Disruption of the intestinal mucosal barrier is an important pathophysiological process in ischemic stroke64 and CIRI,65 resulting in intestinal injury, secondary infection, and even death. A clinical study showed that dysbiosis of the gut microbiota is an independent risk factor for acute ischemic stroke-associated pneumonia.66 Another study showed that stroke increased intestinal barrier permeability and dysfunction, which enhanced the translocation and dissemination of bacteria originating from the gut microbiota.67 Chen et al68 found that cerebral ischemic stroke not only caused intestinal barrier disruption but also aggravated gut microbiota translocation. Notably, probiotics have been found to modulate host intestinal barrier function through their surface components and metabolites. For example, S-layer protein 2 of vaginal Lactobacillus crispatus 2029 promoted the growth of immature Caco-2 cells, production of vascular endothelial growth factor, decreased paracellular permeability, and enhanced the intestinal barrier function of Caco-2 monolayer cells.69 Hagihara et al70 proved that Clostridium butyricum MIYAIRI588 increased the abundance of beneficial genera, protected intestinal barrier function, and enhanced anti-inflammatory lipid metabolites. Another study showed that administration of Clostridium butyricum ameliorated CIRI progression via antioxidant and anti-apoptotic mechanisms.71 These results suggest that improving the function and integrity of the intestinal mucosal barrier is important in the treatment of CIRI.

Gut Microbiota Metabolism Disorder

Accumulating evidence has demonstrated that active metabolites produced by the gut microbiota play a crucial role in the maintenance of homeostasis, immune maturation, mucosal integrity, and energy metabolism.72,73 Intestinal microbiota-derived metabolites, such as SCFAs, TMAO, LPS, and bile acids (BAs), can exert beneficial or deleterious effects on CIRI and various extraintestinal organs.16 Among them, SCFAs are the main metabolites produced in the colon by bacterial fermentation of dietary fiber and resistant starch, including butyrate, acetate, and propionate,74 which may affect cerebral ischemic stroke outcomes by modulation of the “gut-brain” axis.75,76 For example, SCFAs produced by beneficial bacteria can promote motor function recovery after ischemic stroke by affecting the immune cells throughout the body.77 Chen et al62 reported that the intestinal levels of SCFAs in cerebral ischemic stroke model rats were lower than those in healthy rats, and that butyric acid showed the highest negative correlation with ischemic stroke. Lee et al32 proved that fecal microbiota transplantation promotes post-stroke recovery by modulating the gut microbiota and reducing inflammation and neurological deficits. TMAO is a key indicator for evaluating the prognosis of patients with cerebral ischemic stroke.78,79 A cross-sectional study showed that higher plasma TMAO level at admission was an independent predictor of stroke severity, infarct volume, and pro-inflammatory monocyte levels in patients with acute cerebral ischemia.80,81 Liu et al82 reported that trimethylamine produced by gut microbiota metabolism is converted to TMAO through hepatic endoflavin monooxygenase, which contributes to platelet hyperreactivity and thrombosis risk by augmenting Ca2+ release.83 Other studies have reported that circulating LPS can worsen clinical outcomes after cerebral ischemic stroke by increasing brain inflammation and blood-brain barrier (BBB) permeability.84–86 A recent study showed that elevated serum BAs levels contribute to improving poor functional outcomes after ischemic stroke.87 Functionally, gut microbiota-derived metabolites are involved in the physiological regulation of CIRI by regulating oxidative stress, inflammation, mitochondrial damage, apoptosis, ferroptosis, and neurological damage.43,88,89 Taken together, gut microbiota and their metabolites may serve as promising therapeutic targets for the diagnosis and treatment of CIRI.

Gut Microbiota and Host Immunity

Based on current knowledge, the gut microbiota is not only essential for immune homeostasis but also influences the host’s response to immune-mediated diseases and the function of the gastrointestinal immune system.90 The gastrointestinal tract is considered to be the largest immune organ in the human body and contains more than 70% of the entire immune system in terms of the number of immune cells.17 Previous studies have found that patients with cerebral ischemic stroke are susceptible to immunocompromised.91,92 Notably, CIRI-induced gut microbiota dysbiosis can trigger immune responses via T cell activation.93 Benakis et al94 showed that dysbiosis of the gut microbiota weakened intestinal immune homeostasis and altered dendritic cell activity in a cerebral ischemic stroke mouse model, as evidenced by increased regulatory T cells and reduced interleukin (IL)-17-positive γδ T cells. Hu et al89 summarized that gut microbiota dysbiosis activates the intestinal immune system and promoted pro-inflammatory cytokine levels, which in turn leads to CIRI. Other studies proved that CIRI causes persistent host gut microbiota dysbiosis and promoted pro-inflammatory cytokine secretion.95,96 Moreover, intestinal dysbiosis facilitates ischemic stroke pathology and prognosis by regulating immunological pathways, such as the NF-κB pathway,97 the type I interferon pathway,98 and the inflammasome pathway.99 Increasing evidence has demonstrated that gut dysbiosis reduces Treg cells and systemic anti-inflammatory cytokines100,101 such as IL-10 and transforming growth factor-beta. Gut microbiota metabolites (such as SCFAs) promote Treg cell proliferation and serve as ligands for G-protein-coupled receptors.102 SCFAs exhibit protective effects against CIRI progression by regulating host immune homeostasis and inhibiting inflammation.103,104 Collectively, gut microbiota affects CIRI prognosis by regulating immune and inflammatory responses via the “gut-brain” axis.

Effect of TCM on Gut Microbiota in CIRI

CIRI belongs to the category of “stroke disease” in Chinese medicine, and its pathogenesis is rooted in the deficiency of the liver and kidney.105 Currently, TCMs serves as a promising resource for the treatment of CIRI by activating blood circulation and removing blood stasis, modulating gut microbiota, clearing heat and removing toxins, benefiting qi and tonifying blood, nourishing yin, and activating blood.40,106,107 Numerous studies have shown that TCM exerts anti-CIRI prevention and therapeutic effects by regulating the gut microbiota.108,109 On the one hand, TCMs improved intestinal disorders caused by CIRI, as well as modulated the composition and abundance of gut microbiota.110 In contrast, TCMs alleviate the organ dysfunction syndrome caused by pathogenic bacterial translocation and harmful gut microbiota metabolites in cerebral ischemic stroke.111,112 In addition, TCM treatment improved the intestinal mucosal barrier and maintained intestinal homeostasis by regulating the composition of the intestinal microbiome.113 The functional role of TCM in CIRI by regulating the gut microbiota is summarized in Figure 2 and Table 1.

Table 1 Summary of Traditional Chinese Medicine in Treating CIRI by Regulating Gut Microbiota

Figure 2 Traditional Chinese medicine in the treatment of CIRI via the “gut-brain” axis.

Abbreviations: TCM, traditional Chinese medicine; GM, gut microbiota.

Note: Created in BioRender. Ren, (Y) (2024) https://BioRender.com/s71m955.

Effect of TCM on Gut Microbiota Dysbiosis

Currently, TCM is used both as the main therapeutic agent and an adjuvant therapy for the prevention and treatment of several neurological diseases, including CIRI.139 Numerous studies using TCM have found that the gut microbiota serves as a key regulatory mechanism in the treatment of cerebrovascular diseases.140,141 For example, Shengmai San,142 NaoMaiTong,143 Angong Niuhuang pill,43 San Hua Tang,120 Dan-deng-tong-nao capsule,115 and other TCM formulas have been used to treat CIRI by modulating gut microbiota. Chen et al68 reported that the Gegen and Chuanxiong combination treatment increased the abundance of beneficial bacteria and relieved the complications of CIRI, which was similar to the results of Wang et al.44 Moreover, several Chinese herbs exhibited potent anti-CIRI therapeutic efficacy by modulating intestinal homeostasis, including Gastrodia elata Blume,110 rhubarb,144 and Dioscorea polystachya.109 Furthermore, the active ingredients of TCM, including hydroxycinnamic acids,145 rhubarb anthraquinone glycosides,146 escin,136 and notoginsenoside R1.133 Xu et al138 found that Astragaloside IV reduces autophagy and oxidative stress induced by gut microbiota dysbiosis in mouse models of acute ischemic stroke. Collectively, TCM can prevent the development and progression of CIRI by improving the dysbiosis of the gut microbiota.

Effect of TCM on Intestinal Mucosal Barrier and Host Immunity

TCMs have been reported to improve the integrity and permeability of the intestinal mucosal barrier by regulating the composition and abundance of gut microbiota and, in turn, reducing the immune-inflammatory response triggered by the migration of harmful bacteria and toxic metabolites of gut microbiota to other organs and the circulatory system.45,147 For example, Qishiwei Zhenzhu pill treatment ameliorated CIRI progression by improving intestinal integrity and gut microbiota disorder and inhibiting inflammation.129 Zhang et al130 demonstrated that Tong-Qiao-Huo-Xue decoction had a protective effect against CIRI by improving intestinal mucosal barrier destruction and reducing the activation and migration of intestinal γδT cells. Treatment with Panax notoginsenoside extract exerts a neuroprotective effect on CIRI by upregulating brain-derived neurotrophic factor levels and inflammation by enhancing the abundance of beneficial bacteria (such as Bifidobacterium longum).148 Moreover, Chinese herbal monomers exert a therapeutic effect on CIRI by improving the intestinal mucosal barrier and suppressing inflammation. For example, Dou et al149 showed that resveratrol alleviates CIRI by inhibiting intestinal pro-inflammatory immunity, neuroinflammation, and inflammation-induced BBB disruption by modulating gut microbiota-mediated Th17/Tregs and Th1/Th2 polarity shifts. Similarly, cornuside restricts CIRI progression by inactivating the IL-17F/TRAF6/NF-κB pathway via maintaining intestinal barrier function, and reducing intestinal inflammation and neuroinflammation.135 Collectively, TCM alleviated CIRI by inhibiting inflammation and promoting intestinal mucosal barrier repair induced by dysbiosis of the gut microbiota.

Effect of TCM on Intestinal Metabolism

Recent studies have found that the gut microbiota can participate in the progression of CIRI by releasing endotoxins and their harmful metabolites to mediate systemic and neuroinflammation.86,150 Many gut microbiota metabolites have been identified,151,152 such as SCFAs, BA, TMAO, LPS, indole-3-propionic acid, choline and its metabolites, ethanol, imidazole propionate, and endotoxins have been etc. TCM has been shown to alleviate CIRI progression by regulating the gut microbiota metabolites. For example, Tanhuo decoction mitigated acute ischemic stroke by reducing the levels of LPS and TMAO by modulating the “gut-brain” axis.153 The Ang Niuhuang pill ameliorated CIRI by modulating microbial metabolites related to inflammation and neuroprotection,43 such as uridine, guanosine, and inosine. Administration of San Hua Tang enhanced SCFA levels and inhibited inflammation in rats with CIRI.120 Moreover, other TCMs ameliorated CIRI progression by regulating enteric metabolism. Huangqi-Honghua combination treatment reduced neurological deficits, cerebral infarct volume, and necrotic neuron rate in the CIRI rat model by maintaining gut homeostasis and affecting BA metabolism,44 which is similar to the protective effect of rhubarb on CIRI.154 NaoMaiTong treatment not only improved gut microbiota disturbances but also adjusted plasma metabolic disorders.127 Liu et al131 showed that Dahuang prevents CIRI progression by improving gut microbiota disorders and regulating amino acid and energy metabolism. Several studies have shown that gastrointestinal hormones play an important role in CIRI progression by maintaining intestinal and immune homeostasis,155 which have become a therapeutic target for the treatment of CIRI with TCM.156,157 Collectively, TCM treatment attenuated CIRI by regulating microbiota metabolites.

Clinical Trials of TCM for CIRI Management

Preclinical studies have confirmed that TCM has a wide range of pharmacological effects on CIRI, and clinical trials are being conducted. For example, Guo et al153 showed that acute ischemic stroke patients treated with Tanhuo decoction had increased abundance of beneficial bacteria (such as Bifidobacteria, Streptococci, and Ruminococci), decreased abundance of pathogenic bacteria (such as Bacteroidetes, Anaerobacter, and Enterococci faecalis), and reduced levels of aseptic inflammation and microbial metabolites (LPS and TMAO). Guo et al140 showed that TCM treatment increased the microbial diversity and abundance of beneficial bacteria in patients with CIRI and the effect of approaching healthy people’s gut microbiota. Other studies have shown that TCM therapy improves neurological function and limb motor impairment, and enhances the quality of life of patients with CIRI.158,159 Moreover, ongoing clinical studies are exploring the safety and efficacy of TCM for the treatment of CIRI (Table 2). For example, a Singaporean substudy reported that Neuroaid (MLC601) was a safe TCM for ischemic stroke patients receiving a 3-month treatment.160,161 Recently, a multicenter, randomized, and placebo-controlled trial found that Naoxintong capsule was a safe drug for treating cerebral ischemic stroke and reduced the 2-year stroke recurrence rate.162 Another clinical study pointed out that the efficacy and safety of TCM for the treatment of CIRI are superior to those of Western medicine.163 However, the specific active components of TCM against CIRI and their mechanisms remain unknown, and the combination of molecular docking studies, molecular dynamics simulations, network pharmacology, and genomics/transcriptomics analyses may deepen our understanding of the multi-targeted effects and potential efficacy of TCM in treating CIRI. Based on these findings, TCM is a promising alternative for clinical treatment of CIRI. Importantly, there is an urgent need to establish screening models of compatibility and screening targets for TCM in various diseases, including CIRI.

Table 2 Clinical Trials of Traditional Chinese Medicine in Cerebral Ischemic Stroke

Discussion and Perspective

Gut microbiota has become a research hotspot and is emerging as an important new therapeutic target for the treatment of CIRI. The symptoms of CIRI are characterized by gut microbiota imbalance, intestinal and BBB dysfunction, and peripheral and central inflammations. Meanwhile, the imbalance in intestinal homeostasis facilitated the development and progression of CIRI, and probiotics or fecal microbial transplantation from healthy donors contributed to improving CIRI by modulating the composition and abundance of the gut microbiota. Moreover, gut microbiota dysbiosis may lead to the production of harmful metabolites and the disruption of gastrointestinal hormone secretion. Currently, both clinical and animal studies have shown that TCM has a corrective effect on disordered gut microbiota, such as increasing the abundance of beneficial bacteria, decreasing the abundance of pathogenic bacteria, and maintaining intestinal homeostasis. Increasing evidence has shown that TCM is effective in the prevention and treatment of CIRI by improving gut microbiota dysbiosis and intestinal barrier dysfunction, and altering gut microbiota metabolism. Therefore, elucidating the functional role and mechanisms of TCM in regulating gut microbiota by the “gut-brain” axis may provide a theoretical basis for new treatment strategy for CIRI.

However, the treatment of CIRI using TCM still faces challenges that must be addressed. (1) The metabolism, toxicity, and pharmacokinetic profile of TCM in clinical trials of CIRI should be further explored. (2) Research on the active ingredients of TCM is limited by its unstable chemical structure, low bioavailability, and susceptibility to oxidation. The quality, safety and effectiveness of TCM can be controlled by the use of well-defined compounds. (3) The greatest challenge in TCM drug delivery into the brain is bypassing the BBB, which prevents the entry of many potential therapeutic agents. Currently, there exist primarily three approaches for achieving drug delivery to the brain through BBB targeting, such as receptor-mediated transcytosis, carrier-mediated transcytosis, and absorptive-mediated transcytosis.164 (4) Nearly 25,000 Chinese herbals will become extinct, severely limiting the clinical use of TCM for the treatment of CIRI. (5) There is a lack of sufficient clinical data on the efficacy of TCM against CIRI. (6) The detailed molecular mechanisms of TCM anti-CIRI by regulating the “gut-brain” axis are not clear.

Conclusion

TCMs have excellent anti-CIRI effects and are important agents for the treatment of cerebrovascular diseases. This review analyzed the functional role of gut microbiota in the pathogenesis of CIRI and systematically summarized recent advancements in research on TCM for the prevention and treatment of CIRI, along with clinical evidence, which provides a scientific and comprehensive reference for the use of TCM in the treatment of CIRI and promotes the utilization and development of TCM resources.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

There is no funding to report.

Disclosure

The authors declare no conflicts of interest in this work.

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