A Deep Insight into the Correlation Between Gut Dysbiosis and Alzheimer’s Amyloidopathy

Recent research has shown a strong correlation between gut dysbiosis and Alzheimer’s disease (AD). The purpose of this review is to investigate the relationship between gut dysbiosis, immune system activation, and the onset of AD and to examine current breakthroughs in microbiota-targeted AD therapeutics. A review of scientific literature was conducted to assess the correlation between gut dysbiosis and AD and the various factors associated. Gut dysbiosis produces an increase in harmful substances, such as bacterial amyloids, which makes the gut barrier and blood-brain barrier more permeable. This leads to the stimulation of immunological responses and an increase in cytokines such as interleukin-1? (IL-1?). As a result, gut dysbiosis accelerates the progression of AD. The review highlights the connection between gut dysbiosis and AD and the potential for microbiota-targeted therapies in AD treatment.

Acupuncture point selection for prevention and treatment of generalized anxiety disorder from the perspective of Microbiota-Gut-Brain Axis / 国际中医中药杂志

Disorders of the gut flora (GF) affect the level of 5-hydroxytryptamine (5-HT) in the brain of patients with generalized anxiety disorder (GAD) and influence the development of the disease. Most of the acupuncture points selected for GAD are based on the principles of local acupuncture points and acupuncture points following the distant channels of the meridians, regarding Baihui (DU 20), Fengchi (GB 20), and Yintang (GV 29) as the main acupuncture points, and the acupuncture points selected for the regulation of GF are Zhongwan (CV 12), Tianshu (ST 25), and Guanyuan (RN 4) and Zusanli (ST 36). Recently, many studies have been conducted on the mechanism of action of acupuncture in the treatment of GAD from the perspective of GF, but few have investigated the theoretical of acupuncture points used to prevent and treat GAD. This paper discusses the theoretical basis of acupuncture to regulate the "microbiota-gut-brain axis" (MGBA) for the prevention and treatment of GAD, and proposes the method of "regulating the internal organs and calming the mind and relieving anxiety" through analyzing the researches on the regulation of GF and GAD.

Advances in intestinal flora and attention deficit hyperactivity disorder / 国际儿科学杂志

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, which can be characterized by hyperactivity and(or)impulsivity, inattention, or a combination.The etiology and pathophysiological mechanism of ADHD have not been clarified yet.More and more studies have shown ADHD has intestinal flora disorder, which may affect the occurrence and development of ADHD through microbiome-gut-brain axis (MGBA). Treatment strategies targeting gut microbiota, including probiotics and dietary therapies, are considered to be a novel and effective method for the prevention or treatment of ADHD.This article reviews the changes of intestinal flora and the progress of diet and probiotics in ADHD children, in order to provide new ideas for treatment of ADHD children.

Role of gut microbiota in perioperative neurocognitive disorders after cardiopulmonary bypass surgery in rats with humanized gut flora / 南方医科大学学报

OBJECTIVE@#To investigate whether gut microbiota disturbance after cardiopulmonary bypass (CPB) contributes to the development of perioperative neurocognitive disorders (PND).@*METHODS@#Fecal samples were collected from healthy individuals and patients with PND after CPB to prepare suspensions of fecal bacteria, which were transplanted into the colorectum of two groups of pseudo-germ-free adult male SD rats (group NP and group P, respectively), with the rats without transplantation as the control group (n=10). The feces of the rats were collected for macrogenomic sequencing analysis, and serum levels of IL-1β, IL-6 and TNF-α were measured with ELISA. The expression levels of GFAP and p-Tau protein in the hippocampus of the rats were detected using Western blotting, and the cognitive function changes of the rats were assessed with Morris water maze test.@*RESULTS@#In all the 3 groups, macrogenomic sequencing analysis showed clustering and clear partitions of the gut microbiota after the transplantation. The relative abundances of Klebsiella in the control group (P < 0.005), Akkermansia in group P (P < 0.005) and Bacteroides in group NP (P < 0.005) were significantly increased after the transplantation. Compared with those in the control group, the rats in group NP and group P showed significantly decreased serum levels of IL-1β, IL-6 and TNF-α and lowered expression levels of GFAP and p-Tau proteins (all P < 0.05). Escape platform crossings and swimming duration in the interest quadrant increased significantly in group NP (P < 0.05), but the increase was not statistically significant in group N. Compared with those in group P, the rats in group NP had significantly lower serum levels of IL-1β, IL-6 and TNF-α and protein expressions of GFAP and p-Tau (all P < 0.05) with better performance in water maze test (P < 0.05).@*CONCLUSION@#In patients receiving CPB, disturbances in gut mirobiota contributes to the development of PND possibly in relation with inflammatory response.

Review of traditional Chinese medicines in ameliorating neuropsychiatric diseases by improving the levels of monoamine neurotransmitters via gut microbiota regulation / 中国中药杂志

The degeneration of monoaminergic system and the reduction of monoamine neurotransmitters(MNTs) are associated with the occurrence of a variety of neuropsychiatric diseases, becoming the key indicators for clinical diagnosis and treatment. Recent studies suggested gut microbiota could influence the occurrence, development, and treatment of neuropsychiatric diseases by directly or indirectly regulating the synthesis and metabolism of MNTs. Rich clinical experience has been accumulated in the amelioration and treatment of neuropsychiatric diseases by traditional Chinese medicines. The traditional oral administration method demonstrates obvious advantages in regulating gut microbiota. It provides a new idea for explaining the pharmacodynamic material basis and mechanism of traditional Chinese medicines in ameliorating neuropsychiatric disease by improving the levels of MNTs via gut microbiota regulation. Focusing on three common neuropsychiatric diseases including Alzheimer's disease, Parkinson's disease, and major depression, we summarized the pathways of gut microbiota in regulating the levels of MNTs and the paradigms of traditional Chinese medicines in ameliorating neuropsychiatric diseases via the "bacteria-gut-brain axis", aiming to provide ideas for the development of drugs and treatment schemes.

A New Study From Ivan de Araujo Lab Reported GLP-1 Mediated Gut-Brain Neural Circuit Controls Appetite Suppression / 中山大学学报(医学科学版)

A new study in Cell from Ivan de Araujo and colleagues reported that intestinal GLP-1 acts on an inter-organ sympathetic neural circuit that induces appetite suppression. This study revealed that GLP-1， secreted by ileal L cells， sensing by intestinal myenteric layer intestinofugal neurons activated a sympatho-gastro-spinal-reticular-hypothalamic pathway involved in appetite suppression， linking stomach distention to craniofacial programs for food rejection. These molecularly indentified， delimited enteric circuits may be targeted to ameliorate the abdominal bloating and loss of appetite typical of gastric motility disorders.

Effects of neuropathic pain induced by selective nerve injury model on intestinal microflora diversity in mice / 西安交通大学学报(医学版)

【Objective】 To investigate the effects of neuropathic pain induced by selective nerve injury (SNI) on intestinal microflora diversity in C57 mice. 【Methods】 36 C57 mice were randomly divided into SNI model group (n=18), sham-operation group (n=8), and control group (n=10). At day 0,1, 3, 7, and 14 after modeling, mechanical pain threshold and thermal pain sensitivity tests were carried out. At day 14 after modeling, colon content (fresh feces) from all the mice were collected for intestinal microflora diversity analysis. 【Results】 One day after modeling, the mechanical pain threshold in SNI group decreased significantly (more than 70%) due to nerve injury, and the thermal pain threshold decreased by 40%, while sham group and control group had no significant decrease. SNI group showed foot hyperalgesia, and the difference was statistically significant compared with sham group and control group (P<0.001). Compared with control group, sham-operation group had a transient decrease in thermal pain threshold on the first day after modeling (P=0.006), but there was no difference in pain threshold between the two groups on the third day after modeling. The α-diversity analysis showed that the abundance of Observed, Chao1, ACE and Simpson in SNI group was significantly lower than that in control group (P<0.05). That is, SNI group had flora disorder due to pain stimulation. Observed, Chao1, ACE, and Simpson were less abundant in sham group than in control group (P<0.05) and the change was between SNI group and control group. 【Conclusion】 Neuropathic pain induced by SNI model resulted in the decrease of mechanical pain threshold and thermal pain threshold, which leads to the reduction of intestinal flora diversity in C57 mice.

Relationship between gut microbiota and substance addiction and its research progress / 西安交通大学学报(医学版)

Microbiota is the entire collection of microorganisms in a specific niche, such as the human gut. It impacts almost all organ systems and is related to disease resistance and susceptibility of the host. The microbiome refers to all of the genetic material within a microbiota. Microbiota is studied by means of sequencing specific genes or metagenomes; analyzing the species and their abundance and function; and determining the structure, diversity, evolutionary relationships, biological and medical significance, and their interactions with the environment of the microbiota. Human gut microbiota refers to that living in the human intestinal tract, including bacteria, fungi and viruses (bacteriophages). Current studies show that gut microbiota is closely related to human health, and its influence scope is far beyond the digestive system, but also involves the immune system, cardiovascular system, nervous system and other aspects. Substance addiction, a chronic recurrent brain disease, is characterized by persistent craving for addictive substances and forced drug use, which can cause changes in gut microbiota. We intend to discuss the relationship of gut microbiota with alcohol, cocaine, opioids, methamphetamine and other addictive substances, indicating that intervention in gut microbiota, which affects the structure and function of the brain, may become a new way to treat substance addiction.

Research progress on the relationship between intestinal flora and mild cognitive impairment / 中国综合临床

Changes in the composition and ratio of the gut microbes may be associated with many diseases, including mild cognitive impairment (MCI). MCI includes amnestic mild cognitive impairment (aMCI) and non-amnestic mild cognitive impairment (non-aMCI). AMCI translates into Alzheimer's disease (AD) risk is higher, so aMCI may be the best stage for the prevention of AD in the future. Studies have shown that modulating the gut microbiota in patients with aMCI can improve their cognitive function.

Progress of microbiota-gut-brain axis in the pathogenesis of white matter injury in preterm infants / 国际儿科学杂志

White matter injury in preterm infants is a unique form of brain injury.It is one of the most common cause of chronic neurological diseases such as cerebral palsy and various neurobehavioral disorders.Perinatal infection, inflammation and hypoxic ischemia are related to the pathophysiology of white matter injury in preterm infants.Signals released by the gut microbiota, such as microbial metabolites, can modulate inflammatory and immune responses characterized by microglial activation, and ultimately it affects the differentiation of premyelin oligodendrocytes and causes white matter injury in preterm infants.Recently more attention has been paid to the role of gut microbiota in the pathogenesis of white matter injury in preterm infants.This article reviews the progress of "microbiota-gut-brain axis" involved in the pathogenesis of white matter injury in preterm infants, so as to provide reference for further prevention and treatment of white matter injury.

Research progress of gut microbiota in the antidepressant effect of traditional Chinese medicine / 药学学报

Depression is a common emotional mental disorder. Patients not only continuously showed depression, pessimism and apathy in mood, but also have gastrointestinal symptoms such as anorexia and constipation in body. Widely attention has been also received in the potential biological role of gut microbiota in the pathogenesis of depression. It plays an important role in the interaction between the intestine and the brain, not only affecting the intestinal barrier function, but also maintaining the homeostasis of host through the microbiota-gut-brain axis. In recent years, the traditional Chinese medicine (TCM) has the advantages of obvious therapeutic effects and few side effects when treating neuropsychiatric diseases, such as depression. The pharmacological mechanism of TCM exerting antidepressant effects by regulating the structure of gut microbiota, reducing displacement, and maintaining the normal function of gut microbiota has been also widely concerned. By investigating the relevant literature in recent years, this paper summarizes the antidepressant effect of TCM in different directions such as Chinese medicine monomer, single medicine and compound medicine. And this paper reviews the antidepressant effects and mechanisms of TCM at different levels, such as the correction of gut microbiota structure, the regulation of immunity, the transplantation of gut microbiota and the regulation of its metabolites. This paper will provide a basis for further explaining the mechanism of gut microbiota in depression and the mechanism of antidepressant effect of TCM.

The postoperative cognitive dysfunction induced by central inflammation with possible involvement of the gut-brain axis

Abstract Background: Postoperative cognitive dysfunction is widely recognized as severe postoperative central nervous dysfunction and has a significant impact on the 'patient's physical and mental health. Methods: Postoperative models of tibial fracture in aged rats were established, including the control group, model group, CCL11 protein injection group, and saline injection group. Morris water maze test was used to detect the behavioral characteristics of rats. Enzyme-Linked Immunosorbent Assay was used or determine the content of CCL11 and CXCL10. Immunofluorescence staining was used to detect the distribution of CD14+CD163+macro-phages in colon tissues and CD11b+CCR3+microglia cells in hippocampal tissues. Western blot analyzed NOX1 and STAT3 expression in hippocampus tissues. Results: Water maze test results confirmed severe cognitive impairment in CCL11 rats. The content of CCL11 and CXCL10 in the CCL11 group was much higher than that of the model group. The distribution of macrophage and microglia cells in the CCL11 model group was greater than that in the model group and the saline group. The expression of NOX1 and STAT3 in the CCL11 group was higher compared with the model group. Conclusion: Abnormal macrophage function and excessive CCL11 secretion were observed in the rats with lower limb fractures after surgery. Postoperative central inflammation in rats with lower limb fracture induced postoperative cognitive dysfunction through the gut-brain axis molecular mechanism.

Kombucha como alimento potencialmente psicobiótico / Kombucha as a potential psychobiotic food

Os casos de transtorno de ansiedade têm apresentado crescimento considerável desde o início do século XX, onde a terapia medicamentosa oferecida, geralmente apresenta efeito sedativo, portanto, a busca por tratamentos adjuvantes para tratar quadros de ansiedade se fazem necessários. Estudos indicam que a modulação da microbiota intestinal pode estar relacionada à regulação neural dos indivíduos através de diversas vias, incluindo a aplicação de cepas probióticas e consumo de alimentos fermentados tradicionais como iogurte e kombucha, colaborando para a melhoria da qualidade de vida destes pacientes. Este projeto teve como objetivo buscar os metabólitos e neurotransmissores presentes no kombucha a fim de verificar seu potencial psicobióticos e comparar as aplicações e metabólitos produzidos por cepas probióticas existentes no mercado e em alimentos fermentados tradicionais que atuem no eixo intestino-cérebro. Foram realizadas pesquisas em bases de dados online, como Pubmed, Web of Science, Scielo, Scopus e Google Scholar no período entre 2002 e 2022 relacionados aos possíveis efeitos dos probióticos em condições de ansiedade, bem como como os mecanismos que envolvem o eixo cérebro-intestino, seja por meio de testes em humanos e em modelos animais. As espécies mais testadas quanto ao seu potencial probiótico e ação nos transtornos de ansiedade encontradas foram Lactobacillus paracasei, L. casei, L. rhamnosus, Bifidobacterium infanti e B. longum. Cada gênero demonstra um grau diferente na redução da ansiedade dos indivíduos. Os alimentos potencialmente probióticos, incluindo alimentos fermentados tradicionais, além de atuar como complemento à terapia em quadros de ansiedade, tem relevância no setor socioeconômico

Anxiety disorder cases have shown considerable growth since the beginning of the 20th century, where the drug therapy offered usually has a sedative effect. Therefore, the search for adjuvant treatments to treat anxiety disorders is necessary. Studies indicate that the modulation of the intestinal microbiota may be related to the neural regulation of individuals in several ways, including the application of probiotic strains and consumption of traditional fermented foods such as yogurt and kombucha, contributing to the improvement of the quality of life of these patients. This project aimed to identify and compare the psychobiotic effect in the gut-brain axis of the metabolites and neurotransmitters produced by kombucha and commercial probiotic strains. The research was carried out in online databases, such as Pubmed, Web of Science, Scielo, Scopus, and Google Scholar in the period between 2002 and 2022 related to the possible effects of probiotics in anxiety conditions as the mechanisms that involve the brain-gut axis either through tests in humans or animal models. The species most tested for their probiotic potential and action on anxiety disorders were Lactobacillus paracasei, L. casei, L. rhamnosus, Bifidobacterium infanti, and B. longum. Each genus demonstrates a different degree of reducing individuals' anxiety. Potentially probiotic foods, including traditional fermented foods, acting as a complement to therapy in cases of anxiety, have relevance in the socioeconomic sector

Effects of Nardostachys jatamansi on gut microbiota of rats with Parkinson's disease / 中国中药杂志

Under the guidance of the traditional Chinese medicine(TCM) theory of "Zangfu-organs of spleen and stomach" and the modern theory of "microbiota-gut-brain axis", this study explored the effects of Nardostachys jatamansi on the gut microbiota of rats with Parkinson's disease(PD). The 40 SD rats were randomly divided into the control group, PD model group, levodopa group, and Nardostachys jatamansi ethanol extract group. The PD model was established by subcutaneous injection of rotenone in the neck and back area. After 14 days of intragastric administration, the PD rats' behaviors were analyzed through open field test, inclined plane test, and pole test. After the behavioral tests, the striatum, colon, and colon contents of rats in each group were collected. Western blot was employed to detect the protein expression of tyrosine hydroxylase(TH) and α-synuclein(α-syn) in striatum and that of α-syn in colon. Enzyme linked immunosorbent assay(ELISA) was used to detect the levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and nuclear factor-kappa B(NF-κB) in striatum and colon. High-throughput sequencing of 16 S rRNA gene was conducted to detect the differences in microbial diversity, abundance, differential phyla, and dominant bacteria of rats between groups. The results indicated that Nar. ethanol extract could relieve dyskinesia, reverse the increased levels of α-syn, TNF-α, IL-1β, and NF-κB in striatum, and improve the protein expression of TH in striatum of PD rats. The α diversity analysis indicated a significant decrease in diversity and abundance of gut microbiota in the PD model. The results of linear discriminant analysis effect size(LEfSe) of dominant bacteria indicated that Nardostachys jatamansi ethanol extract increased the relative abundance of Clotridiaceae, Lachnospiraceae, and Anaerostipes, and reversed the increased relative abundance of Proteobacteria, Gammaproteobacteria, Enterobacteriaceae, and Escherichia-Shigella in PD model group to exhibit the neuroprotective effect. In summary, the results indicated that Nar. ethanol extract exert the therapeutic effect on PD rats. Specifically, the extract may regulate gut microbiota, decrease the levels of proinflammatory cytokines, and reduce the protein aggregation of α-syn in the colon and striatum to alleviate intestinal inflammation and neuroinflammation. This study provides a basis for combining the theory of "Zangfu-organs of spleen and stomach" with the theory of "microbiota-gut-brain axis" to treat PD.

Revisão sistemática sobre os efeitos dos probióticos na depressão e ansiedade: terapêutica alternativa? / A systematic review of the effects of probiotics on depression and anxiety: an alternative therapy?

Resumo Esta revisão visa a conhecer e analisar os efeitos dos probióticos na depressão, ansiedade e estresse psicológico. Esses distúrbios estão entre as principais causas de incapacidades no mundo. As farmacoterapias convencionais costumam apresentar fraca resposta ou efeitos colaterais adversos. Estudos mais recentes têm demonstrado uma densa comunicação bidirecional chamada de eixo cérebro-intestino. Pesquisas estão evidenciando as relações entre alterações no microbioma entérico e distúrbios psiquiátricos, abrindo caminho para o surgimento de terapêuticas alternativas. Fez-se uma busca sistemática por ensaios clínicos randomizados duplo/triplo cego controlados por placebo no PubMed, Scopus e Lilacs. Para seleção dos estudos usaram-se as recomendações dos principais itens para relatar revisões sistemáticas e meta-análises (PRISMA). Nove artigos preencheram os critérios e foram analisados quanto aos efeitos na depressão, ansiedade, estresse psicológico e em biomarcadores. Sete encontraram resultados positivos em ao menos um dos itens. Conclui-se que o uso de probióticos para aliviar sintomas desses distúrbios é promissor, principalmente, por seu potencial efeito anti-inflamatório, mas são necessários ensaios clínicos randomizados duplo-cegos mais amplos e rigorosos para balizar tais conclusões.

Abstract This review aims to understand and analyse the effects of probiotics on depression, anxiety and psychological stress. These disorders are among the leading causes of disability worldwide. Conventional pharmacotherapies usually have a poor response or adverse side effects. In this context, recent studies have demonstrated a dense bi-directional communication named gut-brain axis. Evidences are demonstrating the relationship between disturbance in the enteric microbiome and psychiatric disorders, paving the way for the emergence of alternative therapies. A systematic search for randomized double/triple blind placebo-controlled clinical trials was performed in PubMed, Scopus and Lilacs. The studies selection followed the recommendations of the main items for report systematic reviews and meta-analyses (PRISMA). Nine articles met the criteria and were analysed for effects on depression, anxiety, psychological stress and biomarkers. Seven found positive results in at least one of the items. We concluded that the use of probiotics to alleviate depressive symptoms and anxiety is promising, mainly due to its potential anti-inflammatory effect, but additional and more rigorous double blind randomized clinical trials are necessary to endorse such conclusions.

The role of the microbiota-gut-brain axis in neuropsychiatric disorders

The microbiota-gut-brain axis is a bidirectional signaling mechanism between the gastrointestinal tract and the central nervous system. The complexity of the intestinal ecosystem is extraordinary; it comprises more than 100 trillion microbial cells that inhabit the small and large intestine, and this interaction between microbiota and intestinal epithelium can cause physiological changes in the brain and influence mood and behavior. Currently, there has been an emphasis on how such interactions affect mental health. Evidence indicates that intestinal microbiota are involved in neurological and psychiatric disorders. This review covers evidence for the influence of gut microbiota on the brain and behavior in Alzheimer disease, dementia, anxiety, autism spectrum disorder, bipolar disorder, major depressive disorder, Parkinson's disease, and schizophrenia. The primary focus is on the pathways involved in intestinal metabolites of microbial origin, including short-chain fatty acids, tryptophan metabolites, and bacterial components that can activate the host's immune system. We also list clinical evidence regarding prebiotics, probiotics, and fecal microbiota transplantation as adjuvant therapies for neuropsychiatric disorders.

Hot Topics in Recent Parkinson’s Disease Research: Where We are and Where We Should Go / 神经科学通报·英文版

Parkinson’s disease (PD), the second most common neurodegenerative disease, is clinically characterized by both motor and non-motor symptoms. Although overall great achievements have been made in elucidating the etiology and pathogenesis of PD, the exact mechanisms of this complicated systemic disease are still far from being clearly understood. Consequently, most of the currently-used diagnostic tools and therapeutic options for PD are symptomatic. In this perspective review, we highlight the hot topics in recent PD research for both clinicians and researchers. Some of these hot topics, such as sleep disorders and gut symptoms, have been neglected but are currently emphasized due to their close association with PD. Following these research directions in future PD research may help understand the nature of the disease and facilitate the discovery of new strategies for the diagnosis and therapy of PD.

Research progress on the association between Parkinson′s disease and inflammatory bowel disease in genetics and gut microbiota / 中华神经科杂志

Parkinson′s disease (PD) is a common degenerative disease of central nervous system. PD is closely related to gastrointestinal diseases in comorbidity studies, and the “gut brain axis” disorder may be involved in their relationship. In recent years, relevant studies have suggested that there are genetic and epidemiological evidences to link PD with inflammatory bowel disease (IBD). This article reviews the relationship between PD and IBD from the genetic evidence and the relevant concept of “gut brain axis”.

Research advances on relationship between gut microbiota and anorexia nervosa / 中华全科医师杂志

Anorexia nervosa is a mental disorder characterized by an intense fear of gaining weight, a distortion of body image, longstanding dietary restriction and low body weight, which has an impact on the cognition, behavior and emotion of patients to varying degrees. Recently, thanks to the advances of microbiota-gut-brain axis research, the role of gut microbiota in the mechanisms of anorexia nervosa has been elucidated. The application of probiotics has been proved to alleviate anxiety, depression and improve appetite, which is expected to be an important measure for the treatment of anorexia nervosa in the future.

Research progress in function and related mechanism of gut-brain axis in traumatic brain injury / 中华创伤杂志

Traumatic brain injury（TBI）in combination with its sequelae is currently a public health problem that seriously endangers human health. Accumulating studies have deeply investigated the pathological processes of TBI to find possible therapeutic targets. In recent years，the relationship between TBI pathogenesis and gut-brain axis changes in aspects of microflora，metabolites，inflammatory factors and neurohumoral changes has drawn widespread attention，which not only provides a better understanding how TBI affects gut-brain axis，but also provides new therapeutic targets in improving cure rate and recovery level after TBI. However，due to the existence of complicated gut-brain axis self-regulation as well as the individual differences of TBI patients，the recognition and transformation for the latest experimental research are largely limited. In this review，the authors summarize how TBI event influences gut-brain axis balance，as well as how gut-brain axis regulates TBI pathogenesis mutually，so as to provide a better understanding of the interaction between gut-brain axis and TBI.