Systematic Insights into the Relationship between the Microbiota–Gut–Brain Axis and Stroke with the Focus on Tryptophan Metabolism

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Systematic Insights into the Relationship between the Microbiota–Gut–Brain Axis and Stroke with the Focus on Tryptophan Metabolism

by Xinyu Shen ^1,2 and

¹

Genomics Research Center, Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, College of Pharmacy, Harbin Medical University, Harbin 150081, China

²

Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China

^*

Author to whom correspondence should be addressed.

Metabolites 2024, 14(8), 399; https://doi.org/10.3390/metabo14080399

Submission received: 18 June 2024 / Revised: 15 July 2024 / Accepted: 15 July 2024 / Published: 24 July 2024

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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Abstract

Stroke, as a serious cerebral vascular disease with high incidence and high rates of disability and mortality, has limited therapeutic options due to the narrow time window. Compelling evidence has highlighted the significance of the gut microbiota and gut–brain axis as critical regulatory factors affecting stroke. Along the microbiota–gut–brain axis, tryptophan metabolism further acquires increasing attention for its intimate association with central nervous system diseases. For the purpose of exploring the potential role of tryptophan metabolism in stroke and providing systematic insights into the intricate connection of the microbiota–gut–brain axis with the pathological procedure of stroke, this review first summarized the practical relationship between microbiota and stroke by compiling the latest case-control research. Then, the microbiota–gut–brain axis, as well as its interaction with stroke, were comprehensively elucidated on the basis of the basic anatomical structure and physiological function. Based on the crosstalk of microbiota–gut–brain, we further focused on the tryptophan metabolism from the three major metabolic pathways, namely, the kynurenine pathway, serotonin pathway, and microbial pathway, within the axis. Moreover, the effects of tryptophan metabolism on stroke were appreciated and elaborated here, which is scarcely found in other reviews. Hopefully, the systematic illustration of the mechanisms and pathways along the microbiota–gut–brain axis will inspire more translational research from metabolic perspectives, along with more attention paid to tryptophan metabolism as a promising pharmaceutical target in order to reduce the risk of stroke, mitigate the stroke progression, and ameliorate the stroke prognosis.

Keywords:

stroke; gut microbiota; gut–brain axis; tryptophan metabolism

1. Introduction

As an acute cerebrovascular condition, stroke is one of the most important contributors to long-term disability and mortality, affecting millions of people each year worldwide. Ischemic stroke (IS) and hemorrhage stroke (HS) are the two main types of strokes, among which 87% are ischemic, 10% are intracerebral hemorrhage (ICH), and 3% are subarachnoid hemorrhage (SAH) according to the 2024 American Heart Association statistical update [1,2], implying the structural or functional damage to brain tissue caused by the blockage or rupture of cerebral blood vessels. Recent years have witnessed alarming growth as well as the youthful trend of stroke incidence with the prevalence of unhealthy lifestyle and eating habits. In the US, there is a projection that an additional 3.4 million adults over 18 will suffer a stroke by 2030 [1]. Although the therapy of stroke has improved during the past few decades, including intravenous thrombolysis, intra-arterial thrombectomy, recombinant tissue plasminogen activator therapy, and so on, it is limited due to the narrow therapeutic window, individual differences, as well as the potential risk [3]. In addition, dementia, cognitive impairment [4], anxiety, depression [5], and communication disorder [6] can be observed in a large amount of post-stroke cases. Thus, early prevention and intervention of stroke and understanding potential therapeutic targets are particularly essential.

Numerous studies suggested that intestinal disorders accompanied by gut microbial alteration, such as inflammatory bowel disease, irritable bowel syndrome, and constipation, have complex interactions with stroke [7,8,9,10]. Gastrointestinal disorders or gut dysbiosis, on the one hand, often appear as complications in stroke patients; on the other hand, they may increase the risk of stroke [11] or worsen cerebral infarction [12]. The gut environment influences brain function in many ways, involving the central nervous system (CNS), enteric nervous system (ENS), autonomic nervous system (ANS), neuroendocrine system (hypothalamic–pituitary–adrenal axis), and immune system [13]. Likewise, the brain fine-tunes gut activities. The intricate bidirectional communication system between the gastrointestinal tract (GIT) and the brain is called the gut–brain axis (GBA). Since gut microbiota act as an integral regulator in the GBA, the GBA was further extended to the microbiota–gut–brain axis (MGBA) [14].

A key component of the MGBA is tryptophan, an essential amino acid whose metabolism is directly or indirectly regulated by the gut microbiota [15]. Products of tryptophan metabolism, including 5-hydroxytryptamine (serotonin, 5-HT), kynurenines, indole derivatives, etc., exert profound impacts on the pathways related to MGBA [16]. Mounting evidence supports a clear correlation between stroke and Trp metabolism in the MGBA with regard to enzyme activities, metabolite level changes, and related genes [17,18,19]. Promisingly, tryptophan and its metabolites serve as potential biomarkers as well as therapeutic targets of neurological disorders, including stroke, endorsing high precision of diagnosis and alternative treatments.

In this review, we systematically summarize the mechanism of MGBA and comprehensively discuss the role of MGBA in stroke, with a focus on the correlation between tryptophan metabolism and the pathogenesis and progression of stroke, combining the latest knowledge so as to provide a reference for further exploration of the prevention, treatment, and rehabilitation of stroke.

 

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