Research Progress on the Relationship between Intestinal Flora and Mental and Psychological Diseases

The effects of microorganisms on the central nervous system are manifested in both health and disease states. The symbiotic microorganisms in the human gut have certain effects on the brain development before and after birth. Chronic inflammation in patients with irritable bowel syndrome (IBS), psychiatric disorders such as PTSD, anxiety disorders, etc., is likely to be associated with an imbalance in gut flora. Intestinal flora regulates the central nervous system mainly through nerve, endocrine, metabolic and immune pathways. The mechanisms involved in the influence of intestinal flora on the central nervous system are diverse, so it is necessary to explore the role of intestinal flora in mental and psychological diseases.


Introduction
The direct link between the brain and gut flora may seem implausible, but the use of antibiotics and probiotics in the clinic has shown that gut flora can influence brain function. In decompensated cirrhosis, the use of antibiotics and probiotics can alleviate or reverse hepatic encephalopathy [1] [2]; in addition, in patients with gastrointestinal diseases associated with psychological disorders, such as irritable bowel syndrome, the imbalance of intestinal flora is common, and the use of probiotics can improve gastrointestinal symptoms and their accompanying depressive and anxiety symptoms [3]. At the same time, animal experi-DOI: 10.4236/aim.2020.106021 296 Advances in Microbiology ments have also proved that intestinal flora is involved in the occurrence and development of neurological diseases caused by immune disorders, and can regulate brain development in rats with multiple sclerosis model [4]. Therefore, this emerging field of research not only gives us a better understanding of this range of diseases, but also provides us with new ideas to find treatments for these diseases. Based on the existing animal experiments, this paper mainly discusses how the intestinal flora regulates the brain activity and leads to the occurrence and development of mental and psychological diseases. At the same time, the limited relevant clinical research is also reviewed, so as to provide new ideas for the research and treatment of mental and psychological diseases.
There is a complex ecosystem of microorganisms in the human gut, including bacteria, fungi, archaea and viruses. These microorganisms are collectively called intestinal microbiota [5].  [24]. Recent research has revealed that gut flora interacts with the brain through the gut. Evidence suggests that gut flora plays an important role in regulating mood and brain activity. Whether it is the downstream regulation of the brain or the upstream regulation of the intestinal flora, it mainly plays a role through immunity, HPA axis and neurotransmitter [25]. Exactly how the gut flora is related to the brain is still being explored and it is speculated that increased permeability of the intestinal wall caused by stress may play an important role. The colonized intestinal flora and its products enter the circulatory system through the intestinal wall, thus activating the immune system and HPA axis in rats.
Taking probiotics prevents translocation. Researchers have found evidence of intestinal bacterial translocation in the serum of people with mental illness, such as depression, which may be linked to abnormally activated immune systems and the HPA axis [26]. The findings suggest that gut flora may be a potential target for the treatment of mental illness. In particular, animal studies in recent years have shown that depression can cause changes in gut flora [27]. Meanwhile, the composition of intestinal flora of rats exposed to long-term stress was significantly different from that of the control group. In addition, Bailey [28] et al.

Intestinal Bacteria and Post-Traumatic Stress Disorder
Post traumatic stress disorder (PTSD) is a type of stress related disorder in which sudden, threatening or catastrophic life events lead to delayed appearance and long-term persistence of individual clinical symptoms that are severe and greatly impair mental health. Studies have shown that the average incidence of PTSD due to different types of trauma is about 12% and can be as high as 80% [29]; epidemiological studies show that more than half of people with PTSD have comorbidities such as depression, other anxiety disorders, and substance abuse. In recent decades, with the rapid development of society and the accelerated pace of life, the frequent occurrence of various traumatic events, such as natural disasters, wars, terrorist incidents, traffic accidents, public safety incidents and so on, people are under increasing psychological stress, and the incidence of PTSD is on the rise. PTSD has become a serious public health and social problem. PTSD has attracted more and more attention and is one of the current research hotspots. Research on the pathogenesis of PTSD has focused on its association with genetic susceptibility, neuroendocrinology, neuroimmunology, biochemistry, and psychosocial environment [30] [31] [32] [33]. As an indicator of the activity of the hypothalamic-pituitary-adrenal axis (HPA), cortisol secretion regulates and reflects the physiological response of the body to fear and stress, which has become a consensus among experts. Recent studies have found that the development and maintenance of PTSD is closely related to functional changes in the HPA axis [34] [35]. Typically, exposure to stress triggers an emotional response, which activates the hypothalamus through a connection to the limbic system of the brain, triggering activity in the HPA axis. Corticotropin releasing hormone (CRH) followed by paraventral hypothalamus neurons ACTS on the anterior pituitary and releases Adrenocorticotropin (ACTH) hormone. ACTH is transported to the adrenal cortex through peripheral blood circulation, which promotes the production and release of cortisol. This whole process is called forward feedback function of the HPA axis, while the process in which elevated cortisol levels inhibit the pituitary, hypothalamus, and hippocampus through a negative feedback mechanism is called negative feedback function of the HPA axis. The HPA axis should play an important role in pressure response and homeostasis maintenance. Other studies have found that urine and plasma dopamine (DA) levels are noted to be positively correlated with PTSD [36] [37], DA is a neurotransmitter closely associated with memory, and PTSD is at least partly a mental disorder associated with emotional memory, so the association between the DA system and PTSD symptoms is understandable. The researchers found that the different stages of conditioned fear memory formation are regulated by the DA system. Although these studies, along with related genetic studies and phenotypic polymorphism studies, provide some compelling evidence for the complexity of the pathogenesis of PTSD. However, a full, comprehensive and systematic understanding of the etiology and pathogenesis of PTSD is not yet available, and new related factors, especially important common links, need to be actively explored in order to obtain key measures to intervene in the development of PTSD. The brain-gut axis is the bidirectional regulating axis of the interaction between the brain and the gastrointestinal tract, including central nervous system (CNS), autonomic nervous system (ANS), enteric nervous system (ENS), HPA axis and other structures. The functions of each part are coordinated. The gastrointestinal tract is the only organ controlled jointly by CNS, ANS and ENS in the body, which has both sensory function and motor function. It is called "emotional reactor". Gastrointestinal discomfort is often accompanied by emotional response, which, in turn, activates the neural activity of CNS related parts, transmits regulatory information down the brain-gut axis to the gastrointestinal tract, changes its dynamic and secretory functions, activates intestinal mucosal immunity, and affects intestinal mucosal barrier function. Irritable bowel syndrome patients are often accompanied by physical discomfort, anxiety, depression, fatigue and other symptoms, and some animal models of irritable bowel syndrome are also based on the brain-gut axis theory [38] [39] [40]. Some pa- tients with inflammatory bowel disease are associated with anxiety and depression, and the severity of anxiety and depression parallels the activity of the disease [41]. Most functional gastrointestinal patients were associated with HPA axis abnormality and ANS dysfunction. In patients with gastroesophageal reflux, there is a strong correlation between anxiety, depression and gastrointestinal symptoms such as heartburn, and psychological or antidepressant treatment is effective in some patients [42]. In psychiatric patients, depression and generalized anxiety disorders are often accompanied by gastrointestinal discomfort. These studies suggest that disorders of the brain-gut axis may play a role in the development of mental illness.

Intestinal Bacteria and Autism and Depression
Autism spectrum disorder (ASD) is a neurobehavioral developmental disorder associated with impaired social and verbal communication. Autism is a classic autism spectrum disorder. Studies have shown a link between gut flora and autism. The imbalance of intestinal flora may lead to the overproliferation of neurotoxin-producing bacteria and induce autism symptoms. Many patients with GENERALIZED anxiety disorder often see the gastroenterology department for gastrointestinal symptoms for the first time [43]; especially in children with autism, gastrointestinal symptoms such as nausea, vomiting, constipation, diarrhea and other common [44]. It has been reported that oral vancomycin has a certain effect on aggressive children with autism in the short term [45]. Changes in intestinal flora and specific intestinal symbiotic strains play a role in autism spectrum disorders [46]. Clostridium difficile is presumed to cause autism. In fact, two studies have found that in addition to C. difficile, autistic people have imbalances in other intestinal flora [47] [48] [49] [50] [51]. Autism patients have an imbalance between firmicutes and bacteroidetes [48]. It was found that bacteroidetes dominated the autistic patients and firmicutes dominated the healthy controls [49]. In addition, intestinal flora composition changes, such as bifidobacteria, lactobacillus. However, studies have cast doubt on the link between gut flora and autism. This difference may be due to sampling and detection techniques, while differences in the metabolic components of urine and faeces in autistic and healthy people may also lead to differences in the bacterial flora. Depression is a common mood disorder caused by neuropsychological or immune imbalance [52]. Probiotics can relieve depressive symptoms in animal models of depression. Lactic acid bacteria are also thought to have antidepressant properties. Lactobacillus rhamnosus and Lactobacillus helveticus can relieve depressive symptoms caused by mother and child separation by restoring cortisol levels [53]. Similarly, Lactobacillus rhamnosus has been shown to regulate cortisol and GABA receptors through the vagal pathway, thereby reducing depressur-related behavior [54]. Bifidobacterium also has potential antidepressant effects. Infant bifidobacteria can reduce depressive symptoms in rats that were forced to swim or separated from their mothers. These mechanisms may be associated with lo-  [55]. In rat models of myocardial infarction accompanied by depression, the probiotics Lactobacillus and Bifidobacterium have been shown to act as antidepressants by reducing inflammatory factors and rebuilding the intestinal wall membrane barrier [55]. In addition, intestinal microbial metabolites such as butyrate have been found to have antidepressant effects in animal experiments. In addition, the mixture of unsaturated fatty acid N. 3, Lactobacillus rhamnosus and Lactobacillus helveticus can also reverse the depressive symptoms in rats after myocardial infarction [55].  [61]. However, probiotics can relieve anxiety symptoms. In animal studies, both bifidobacteria and lactobacillus were found to correct symptoms in anxious rat models. Intestinal flora can also affect the function of the HPA axis. The hyperactivity of HPA axis in sterile rats was accompanied by an increase in peripheral neurotransmitters and a decrease in brain-derived neurotrophic factors [62]. In addition, external stress can affect the composition of gut flora [63]. It was found that mother-child isolation resulted in decreased bacteroides and increased clostridium in the intestinal flora of rhesus monkeys, accompanied by an increase in peripheral inflammatory factors. Lactobacillus helveticus and Lactobacillus rhamnosus were administered to rats to relieve the psychological stress caused by water restriction and to reshape the integrity of the intestinal mucosal wall [64]. Lactobacillus farciminis also prevents an increase in intestinal permeability caused by stress and reduces serum cortisol levels [65]. Bifidobacterium longum can correct anxious behavior and restore BDNF level in the central nervous system of rats with infectious colitis through vagal nerve pathway [66]. Lactobacillus helveticus and Bifidobacterium longum have anti-anxiety effects in both animals and healthy people.

Conclusion and Prospect
More and more animal and human studies show the brain, the bowel, and the