Abstract

Introduction

   Xingnao Jiutan tablets (XNJT), a compound Chinese medicine, have been
   applied to the treatment of the sequelae of cerebral thrombosis or
   cerebral hemorrhage, transient cerebral ischemia, and central retinal
   vein obstruction, etc., but the underlying mechanisms are not yet
   clear. This research focused on examining the impact of XNJT for
   cerebral ischemia/reperfusion (MCAO/R) injury, utilizing gut microbiota
   and metabolomic studies.

Methods

   The primary components of XNJT were identified through the application
   of the HPLC technique. We established a MCAO/ R model in mice and
   conducted behavioral evaluations, cerebral blood flow measurements, and
   TTC staining. We used ELISA, high-throughput 16S rDNA gene sequencing,
   and metabolomics techniques to detect inflammatory factors, microbial
   populations, and metabolites, respectively. Finally, we performed
   Spearman correlation analysis to investigate the relationships among
   gut microbiota and metabolites, comprehensively exploring the
   mechanisms of XNJT to alleviate cerebral ischemia-reperfusion injury.

Results

   We discovered that XNJT effectively enhanced neurological performance,
   alleviated cerebral infarction, diminished neuronal cell death, and
   increased cerebral blood flow. Moreover, XNJT downregulated the
   secretion of pro-inflammatory cytokines like TNF, IL-6, and IL-1b.
   Additionally, XNJT improved gut microbiota levels in MCAO/R mice,
   particularly Bacteroides, Firmicutes, Escherichia-Shigella, and
   Ligilactobacillus. Furthermore, XNJT primarily modulated differential
   metabolites in the gut through Glycerophospholipid, Linoleic acid, and
   Sphingolipid metabolism pathways. Spearman correlation analysis
   revealed significant associations among intestinal microbiota and
   various metabolites.

Discussion

   In summary, our findings suggest that XNJT can improve cerebral
   ischemia/reperfusion injury outcomes, reduce inflammatory responses,
   and regulate gut microbiota and differential metabolites. It’s possible
   that the potential mechanisms are connected to controlling gut
   microbiota and metabolism.

   Keywords: Xingnao Jiutan tablets, cerebral ischemia/reperfusion, gut
   microbiota, metabolism, brain-gut axis

1. Introduction

   Stroke, a disorder of the central nervous system, is marked by high
   morbidity, mortality, disability, and economic burden due to brain
   tissue damage from blocked or burst blood vessels in the brain
   ([39]Grysiewicz et al., 2008). Research indicates that worldwide,
   stroke ranks as the second most common cause of mortality, representing
   11.6% of total deaths, and is the third leading reason for disability
   ([40]Demsie and Lorkowski, 2020; [41]Feigin et al., 2022).
   Additionally, China has the highest stroke prevalence worldwide, with a
   trend toward younger patients ([42]Zhou et al., 2019; [43]Xian et al.,
   2022). Stroke types include ischemic stroke and cerebral hemorrhagic
   stroke, where ischemic stroke occurs more frequently, constituting 60%
   to 80% of all stroke cases ([44]Herpich and Rincon, 2020; [45]Liu
   et al., 2020). The primary cause of ischemic stroke is the blockage of
   the intracranial artery, leading to intricate brain neuropathological
   alterations such as excitotoxicity, oxidative stress,
   neuroinflammation, and breakdown of the blood-brain barrier,
   culminating in brain tissue death and neurological impairments
   ([46]Maida et al., 2020; [47]Candelario-Jalil et al., 2022; [48]Huang
   et al., 2022; [49]Rajeev et al., 2022; [50]Zong et al., 2022). Clinical
   manifestations of neurological deficits include hemiparesis, speech
   difficulties, facial asymmetry, and impaired consciousness. Presently,
   thrombolysis and interventional treatment stand as the most efficacious
   therapies, yet they come with high costs and constraints like a limited
   time frame and related risks. Therefore, it’s critically important to
   develop efficient and economical treatment methods to reduce the burden
   of strokes on both society and families. In conclusion, studying the
   pathophysiologic process of ischemic stroke and establishing a
   comprehensive system for its prevention, diagnosis, treatment, and
   prognosis is of great significance.

   A growing collection of studies suggests that ischemic stroke affects
   gut microbiota and that regulating gut flora could be an innovative
   approach to preventing and treating strokes ([51]Pluta et al., 2021;
   [52]Yamashiro et al., 2021; [53]Zhang et al., 2021). Dysbiosis of the
   gut microbiota can disrupt brain function and result in neurological
   disorders ([54]Durgan et al., 2019). Furthermore, gut
   microbiota-related metabolites, including short-chain fatty acids and
   lipopolysaccharides, show a significant correlation with the
   development and outcomes of stroke ([55]Chen et al., 2019b; [56]Cheng
   et al., 2022). This suggests a role for the brain-microbe-gut axis in
   the pathology of strokes. Gut microbiota serves as a “two-way”
   communication system between the gastrointestinal system and the brain.

   Recently, the healing impact of Chinese medicine on a range of
   illnesses has gained broad acknowledgment, along with its recognized