Traditional Chinese medicine treatment of insomnia based on microbial-gut-brain axis theory

Abstract

In recent years, insomnia has gradually become a common disease in society, which seriously affects people's quality of life. At present, with the deepening of research on intestinal microbiota-gut-brain axis in Western medicine, many studies suggest that regulating the gastrointestinal tract can treat brain-related diseases. It is found that brain-gut-bacteria axis plays an important role in the prevention and treatment of primary insomnia. At present, although the clinical treatment of insomnia with Western medicine can improve the insomnia symptoms of patients to a certain extent, there are still obvious adverse reactions, such as anxiety and depression, drug addiction, etc., so long-term oral drug therapy cannot be carried out. Traditional Chinese medicine (TCM) and acupuncture techniques have certain therapeutic effects on insomnia. TCM believes that the brain and gastrointestinal system are connected through the meridian, and the pathophysiology is closely related. This paper will discuss the theory and feasibility of TCM for the treatment of insomnia from the pathological relationship between brain-gut axis, intestinal flora and insomnia.

Core Tip: In recent years, insomnia has gradually become a common disease in society, which seriously affects people's quality of life. At present, with the deepening of research on intestinal microbiota-gut-brain axis in Western medicine, many studies suggest that regulating the gastrointestinal tract can treat brain-related diseases.

INTRODUCTION

Insomnia is a condition in which the patient is dissatisfied with the duration and/or quality of sleep, thereby affecting daytime social functioning[1]. Cognitive decline, fatigue, or mood disorders associated with impaired daytime function occur[1]. Lack of sleep is the main cause of decreased daytime activity and cognitive ability. Chronic insomnia can lead to depression, anxiety, substance abuse, suicide, auto accidents, and immune disorders[2-4]. In today's increasingly competitive society, insomnia has become a common health problem. Studies have shown that brain activity is greatly affected by intestinal flora, and the mechanism may be related to neurotransmitters, immune factors and neuropeptides in the brain-gut axis[5].

BACKGROUND OF GUT MICROBIOTA-GUT-BRAIN AXIS

In the 1980s, the concept of "brain-gut axis" was first proposed, which refers to the bidirectional regulatory axis connecting the gastrointestinal tract and the central nervous system (CNS). The brain-gut axis consists of two pathways: (1) The descending pathway from the brain to the gut; and (2) The ascending pathway from the gut to the brain. Gut flora affects the brain primarily by secreting small molecules, but also by regulating immune, neuroendocrine, and vagal pathways. The gut microbiota-gut-brain axis (GBA) is a key regulatory pathway between the brain and the gastrointestinal tract[6,7].

BRAIN-GUT AXIS AND PRIMARY INSOMNIA

The GBA is a dynamic bidirectional neuroendocrine system. This bidirectional communication network consists of the CNS, autonomic nervous system, enteric nervous system (ENS), and hypothalamic-pituitary-adrenal (HPA) axis system. The outer branches of the glycemic index (GI) tract are connected to the enterobrain axis via the spinal cord and vagus nerve fibers, while the brain transmits outgoing parasympathetic and sympathetic nerves to the GI tract. According to recent studies on the pathophysiology of insomnia, one is that insomnia is related to the secretion disorder of cortisol and adrenalin releasing hormone caused by the dysfunction of HPA axis[8]. Secondly, insomnia is highly correlated with central neurotransmitters and inflammatory response factors, among which 5-HT, gamma-aminobutyric acid, tumor necrosis factor-α and interleukin-6 are dominant[9-11].

INTESTINAL FLORA AND PRIMARY INSOMNIA

The intestinal microbial community is composed of more than 1000 types of bacteria, most of which belong to firmicutes, bacteroides, Proteus and actinomyces[12]. Numerous studies have identified the microbial-GBA[13]. In this axis, the gut microbiota affects brain function and generates two-way information flow through three main pathways[14,15]. The first is the immunomodulatory pathway, in which the microbiota interacts with immune cells to influence the levels of cytokines, cytokinetic response factors, and prostaglandin E2[16]. The second is that insomnia is related to autonomic nervous dysfunction, autonomic nervous function is innervated by the pineal gland, in which the sympathetic god regulates the secretion of melatonin by the pineal gland, further affecting the quality of sleep. The third is the vagus nerve pathway, where the ENS plays a large role.

The ENS forms synaptic connections with the vagus nerve, which connects the gut to the brain, forming an information transmission pathway known as the enteric microbial-ENS-vago-brain pathway[17].

The CNS also affects intestinal flora. The HPA axis can regulate intestinal peristalsis, epithelial cell function and intestinal permeability, thus affecting the environment of intestinal microbiota and further changing the composition of intestinal microbiota[18-20].

DAMAGE OF INTESTINAL FLORA TO INSOMNIA

Chronic disturbance of host circadian rhythm and sleep loss will affect the metabolism of intestinal flora and trigger changes in its composition, usually reducing the total number of Lactobacillaceae organisms, but increasing the population of bacteroides polyformis and so on, resulting in microbial ecological imbalance[21-23].

Changes in the gut microbiome may mediate the harmful effects of insomnia, which are closely linked to inflammation. Modern studies have found that inflammation is a key mediator in the pathogenesis of metabolic and neurodegenerative diseases related to sleep deprivation[24,25]. Insomnia can cause elevated lipopolysaccharide (LPS), which in turn activates the Toll-like receptor 4/nuclear transcription factor-kappa B (TLR4/NF-κB) signaling pathway, thus promoting the production of inflammatory factors[26]. In addition, insomnia can also cause the imbalance of intestinal microflora, destroy the intestinal barrier, and increase the toxin content in peripheral blood, which indicates that microbial metabolites may participate in the inflammatory response induced by insomnia after entering the circulation[27,28]. Studies have suggested that insomnia can lead to the imbalance of intestinal microbial ecosystem, the destruction of intestinal barrier, and the influx of bacterial metabolites (LPS) into peripheral blood, thus activating the TLR4/NF-κB signaling pathway and ultimately promoting the development of inflammatory response[29].

TRADITIONAL CHINESE MEDICINE AND GBA

Sleep is an active process occurring in the CNS, which is regulated by the nervous, endocrine and immune systems, and there are various complex connections among these systems, which participate in the regulation of sleep-wake mechanism. Recent studies have shown that acupuncture can regulate the level of disturbed neurotransmitters, cytokines and hormones, promote the expression of biological clock genes, and maintain sleep-wake cycle. The types of studies include clinical studies and animal experiments, which have laid a foundation for revealing the specific mechanism of acupuncture in the treatment of insomnia and promoting clinical application[30].

CONCLUSION

At present, the mechanism of TCM treatment of insomnia is not clear, and the specific role of gut microbiota-GBA in it needs to be further studied. In future studies, it is necessary to further elucidate the mechanism and pathway of action of TCM in treating insomnia, so as to bring new breakthroughs for TCM to explore the nature of syndrome from the perspective of intestinal microecology.