Intestinal Nerve Research Articles

A Comprehensive Review and Update on Cannabis Hyperemesis Syndrome.

Cannabis, derived from Cannabis sativa plants, is a prevalent illicit substance in the United States, containing over 400 chemicals, including 100 cannabinoids, each affecting the body's organs differently upon ingestion. Cannabis hyperemesis syndrome (CHS) is a gut-brain axis disorder characterized by recurring nausea and vomiting intensified by excessive cannabis consumption. CHS often goes undiagnosed due to inconsistent criteria, subjective symptoms, and similarity to cyclical vomiting syndrome (CVS). Understanding the endocannabinoid system (ECS) and its dual response (pro-emetic at higher doses and anti-emetic at lower doses) is crucial in the pathophysiology of CHS. Recent research noted that type 1 cannabinoid receptors in the intestinal nerve plexus exhibit an inhibitory effect on gastrointestinal motility. At the same time, the thermoregulatory function of endocannabinoids might explain compulsive hot bathing in CHS patients. The prevalence of cannabis CHS is expected to rise as legal restrictions on its recreational use decrease in several states. Education and awareness are vital in diagnosing and treating CHS as its prevalence increases. This comprehensive review explores the ECS's involvement, CHS management approaches, and knowledge gaps to enhance understanding of this syndrome.

Hypothalamic SLC7A14 accounts for aging-reduced lipolysis in white adipose tissue of male mice

The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. However, the underlying mechanisms remain unclear. Here, we show the expression of SLC7A14 is reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviates the aging-reduced lipolysis, whereas SLC7A14 deletion mimics the age-induced lipolysis impairment. Metabolomics analysis reveals that POMC SLC7A14 increased taurochenodeoxycholic acid (TCDCA) content, which mediates the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulates the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain–gut–adipose tissue crosstalk in age-induced lipolysis impairment.

Moniezia benedeni drives the SNAP-25 expression of the enteric nerves in sheep's small intestine

BackgroundThe neuroimmune network plays a crucial role in regulating mucosal immune homeostasis within the digestive tract. Synaptosome-associated protein 25 (SNAP-25) is a presynaptic membrane-binding protein that activates ILC2s, initiating the host's anti-parasitic immune response.MethodsTo investigate the effect of Moniezia benedeni (M. benedeni) infection on the distribution of SNAP-25 in the sheep's small intestine, the recombinant plasmid pET-28a-SNAP-25 was constructed and expressed in BL21, yielding the recombinant protein. Then, the rabbit anti-sheep SNAP-25 polyclonal antibody was prepared and immunofluorescence staining was performed with it. The expression levels of SNAP-25 in the intestines of normal and M. benedeni-infected sheep were detected by ELISA.ResultsThe results showed that the SNAP-25 recombinant protein was 29.3 KDa, the titer of the prepared immune serum reached 1:128,000. It was demonstrated that the rabbit anti-sheep SNAP-25 polyclonal antibody could bind to the natural protein of sheep SNAP-25 specifically. The expression levels of SNAP-25 in the sheep's small intestine revealed its primary presence in the muscular layer and lamina propria, particularly around nerve fibers surrounding the intestinal glands. Average expression levels in the duodenum, jejunum, and ileum were 130.32 pg/mg, 185.71 pg/mg, and 172.68 pg/mg, respectively. Under conditions of M. benedeni infection, the spatial distribution of SNAP-25-expressing nerve fibers remained consistent, but its expression level in each intestine segment was increased significantly (P < 0.05), up to 262.02 pg/mg, 276.84 pg/mg, and 326.65 pg/mg in the duodenum, jejunum, and ileum, and it was increased by 101.06%, 49.07%, and 89.16% respectively.ConclusionsThese findings suggest that M. benedeni could induce the SNAP-25 expression levels in sheep's intestinal nerves significantly. The results lay a foundation for further exploration of the molecular mechanism by which the gastrointestinal nerve-mucosal immune network perceives parasites in sheep.

The effect of nerve cells on the intestinal barrier function and the influence of human milk oligosaccharides (hMOs) on the intestinal neuro-epithelial crosstalk

The intestinal epithelium is an important gatekeeper of the human body by forming a barrier for the luminal content of the intestine. The barrier function is regulated by a complex crosstalk between different cell types, including cells from the enteric nervous system (ENS). ENS is considered to influence gastrointestinal processes and functions, but its direct effect on epithelial barrier function remains to be confirmed. To investigate the effect of nerve cells on the gut barrier function, an in vitro co-culture system was established in which T84 intestinal epithelial cells and SH-SY5Y nerve cells were seeded in ratios of 29:1 and 14:1. When the epithelial barrier was disrupted with the calcium ionophores A23187, we found that nerve cells exert a protective effect on A23187-induced disruption and that this protective effect is nerve cell concentration-dependent. This was demonstrated by rescuing effects on transepithelial electrical resistance (TEER) and upregulation of tight junction (TJ) protein expression. Furthermore, we studied whether similar rescuing effects could be achieved with the human milk oligosaccharides (hMOs) 2′-fucosyllactose (2′-FL) and 3-fucosyllactose (3-FL). Our results illustrate that in the presence of nerve cells 2′-FL and 3-FL do not have any additional rescuing effects, but that these hMOs can substitute the rescuing effects of nerve cells in the absence of nerve cells. Meanwhile, 2′-FL and 3-FL show different regulation effects on TJ expression. These findings provide valuable insights into potential therapeutic strategies for maintaining intestinal barrier integrity.

Intrinsic factors behind long COVID: III. Persistence of SARS‐CoV‐2 and its components

AbstractConsiderable research has been done in investigating SARS‐CoV‐2 infection, its characteristics, and host immune response. However, debate is still ongoing over the emergence of post‐acute sequelae of SARS‐CoV‐2 infection (PASC). A multitude of long‐lasting symptoms have been reported several weeks after the primary acute SARS‐CoV‐2 infection that resemble several other viral infections. Thousands of research articles have described various post‐COVID‐19 conditions. Yet, the evidence around these ongoing health problems, the reasons behind them, and their molecular underpinnings are scarce. These persistent symptoms are also known as long COVID‐19. The persistence of SARS‐CoV‐2 and/or its components in host tissues can lead to long COVID. For example, the presence of viral nucleocapsid protein and RNA was detected in the skin, appendix, and breast tissues of some long COVID patients. The persistence of viral RNA was reported in multiple anatomic sites, including non‐respiratory tissues such as the adrenal gland, ocular tissue, small intestine, lymph nodes, myocardium, and sciatic nerve. Distinctive viral spike sequence variants were also found in non‐respiratory tissues. Interestingly, prolonged detection of viral subgenomic RNA was observed across all tissues, sometimes in multiple tissues of the same patient, which likely reflects recent but defective viral replication. Moreover, the persistence of SARS‐CoV‐2 RNA was noticed throughout the brain at autopsy, as late as 230 days following symptom onset among unvaccinated patients who died of severe infection. Here, we review the persistence of SARS‐CoV‐2 and its components as an intrinsic factor behind long COVID. We also highlight the immunological consequences of this viral persistence.

Potential therapeutic application of probiotics in the treatment of neuropathic pain: A mechanistic aspects of brain-gut axis

The “gut-brain axis” or “brain-gut axis” communication mechanism has a bidirectional approach because it depends on showing top-down or bottom-up channels to function. It is one of the few systems in the body that combines neuronal routes with humoral pathways, which include cytokines, hormones, and neuropeptides as chemical messages. It was also discovered to be diverse because it contains spinal, vagus, sympathetic, and intestinal nerves. The role of microbes as signaling agents in the gut-brain axis has been proven by the most recent research, which is primarily based on animal models. Probiotics are living bacteria that improve one’s health when ingested in large enough doses. Gut microbes are suspected to play a role in a variety of psychiatric disorders, making them a potential therapeutic target. The stomach and the brain are linked via a two-way communication pathway called the microbiota-gut-brain axis. Current interventional research on probiotics and the gut-brain axis has been evaluated for its findings in the treatment of depression, anxiety, and schizophrenia. Neuropathic pain is brought on by a lesion or injury to the nerve system, which is further demonstrated by a malfunction of the somatosensory system. Such a developed form of pain affects both peripheral and central nervous system neurons. According to research, probiotics can enhance the gut’s dynamic environment and are good for both the gut and the brain. Therefore, the focus of this review is on how probiotics, the microbiota-gut-brain axis, and the gut-brain axis relate to neuropathic pain.

Zuojin pill improves chronic unpredictable stress-induced depression-like behavior and gastrointestinal dysfunction in mice via the theTPH2/5-HT pathway.

The complex bidirectional communication between the gastrointestinal tract and the brain is associated with mental disorders such as depression; serotonin, as a crucial neurotransmitter in the communication system between the central nervous system and the gastrointestinal tract, has effects on regulating gastrointestinal motility and sensation and improving psychosomatic status. Zuojin pill is used as a traditional Chinese medicine formula for the treatment of gastrointestinal disorders. This study explored the effects of Zuojin pill on the improvement of depression and gastrointestinal function in CUMS mice via TPH2 and its mechanism. The aim of this study was to investigate whether Zuojin pill could improve depression and concomitant gastrointestinal dysfunction, and to reveal whether Zuojin pill could work through the regulation of the tryptophan hydroxylase 2 (TPH2) pathway. The CUMS model was established to observe the effects of Zuojin pill on depression-like behavior and gastrointestinal function in mice. Nissler staining and HE staining were used to observe the structure of hippocampal neurons and intestinal mucosa respectively. 5-HT levels in serum, hippocampus, and intestinal tissues were measured by ELISA, and TPH2 expression in hippocampus and intestinal nerves was observed by WB and immunofluorescence. In order to investigate the protective effect and mechanism of Zuojin pill on PC12 cells, CORT used an in vitro model to produce PC12 cell damage. Our study showed that Zuojin pill ameliorated depression-like behavior and gastrointestinal dysfunction in CUMS mice, elevated BDNF, 5-HT, and TPH2 expression in the hippocampus, and restored the ratio of dopaminergic and GABAergic neurons between intestinal muscles. In vitro experiments showed that Zuojin pill exerted a protective effect on neurons by regulating TPH2 ubiquitination and thus inhibiting CORT-induced apoptosis of PC12 cells. Zuojin pill improves chronic unpredictable stress-induced depression-like behavior and gastrointestinal dysfunction in mice via the TPH2/5-HT pathway. Therefore, TPH2 may be a potential therapeutic target for depression with gastrointestinal dysfunction.

Association of Gut Flora and Short-Chain Fatty Acid Metabolite in Functional Constipation and Regulation of High-Fibre Diet on Them

Constipation is one of the most prevalent diseases in the world, and it has a significant impact on the quality of life of people. There are several critical factors associated with constipation, including short-chain fatty acid content and the composition of the gut microbiota. A disorder in any of these factors can cause an abnormal bowel movement and the symptoms of constipation. Diet regulates the gut microbiota and influences the immune system. Recent research suggests that high fibre foods promote the growth and stabilization of the intestinal nerves, as well as an increase in the number of useful bacteria found in the intestines. Fibre deficiency increases the risk of GI distress and contributes to poor gastrointestinal motility. Long-term treatment of constipation is dependent on developing a diet that provides sufficient fibre. A high fibre diet is probably not just essential to manage constipation, but also to lower the risk of developing other chronic illnesses associated with diet. In this paper, the relationship between high fibre diet and microbiota and short chain fatty acids in constipation patients is analyzed.

To study the importance of pyrroloquinoline quinone in pet nutrition and health care

Pyrroloquinoline quinone (PQQ) is a highly functional oxidoreductase coenzyme, which has a variety of physiological functions such as regulating the level of free radicals in the body, antioxidant and promoting nerve growth factor regeneration. PQQ playes a significant role in disease prevention and treatment, which has attracted wide attention in recent years. PQQ can protect the brain nerve and intestinal nerve of pets, reduce stress and anti-aging, and also promote nutrient absorption and improve immunity. Mammals can only take PQQ through external supplements and cannot synthesize it themselves. Therefore, the application of PQQ supplements in pet breeding can play a significant positive effect. Based on the studies supplementing PQQ in weaned rats and pigs, this paper will explain the necessity of PQQ for mammals, and discuss the feasibility of strengthening the use of PQQ supplement in pet nutrition and health care, and advocate further research on this by pet-related enterprises, which may open up new markets.

Association between jejunal remodeling in fasting rats and hypersensitivity of intestinal afferent nerves to mechanical stimulation.

Remodeling of Intestinal properties and hypersensitivity of intestinal afferents to mechanical stimulation were previously demonstrated in a fasting rat model. Other studies investigated the association between mechanical and histological remodeling during fasting. This study aimed to further explore the relationship between the jejunal remodeling and intestinal afferent hypersensitivity by combining afferent nerve recordings with histological and mechanical data. Eight male Sprague Dawley rats had no access to food for 7days (Fasting group). Seven male rats served as controls (Control group). Jejunal segments were studied in vitro in an organ bath for analysis of afferent signaling and for analysis of mechanical and histomorphological parameters. Correlation analyses were done to analyze association between nerve activity (spike rate increase ratio, SRIR) at distension levels of 20, 40 and 80 cmH2O and mechanical stress and histomorphological changes of the jejunal segments. Compared with the Control group, the main findings in jejunal segments in the Fasting group were (1) Most histomorphometry parameters were reduced (P < 0.05-P < 0.001), (2) SRIR values were higher (P < 0.001), (3) The relative numbers of intermuscular and submucosal neurons were increased (P < 0.05-P < 0.01), and (4) SRIR was negatively correlated with intestinal wall thickness, circumferential muscle layer thickness and positively correlated with the inner residual strain, the number of neurons, and the mechanical stress. In conclusion, the fasting-induced histomorphological remodeling (reduced wall thickness and increased relative number of neurons) and biomechanical remodeling (residual strain changes and high stress level) of the intestine in fasting rats were associated with hypersensitivity of intestinal afferents. Afferent hypersensitivity appears to be dependent on stress rather than on strain.

Schwannoma: A Rare Case of Submucosal Gastric Tumor.

Schwannoma is a tumor that originates from the Schwann cells that surround a neuron's axon. This tumor is very rare in the gastrointestinal tract and develops submucosally from intestinal nerve plexuses. The most common location for gastrointestinal schwannomas is the stomach, where they account for only 0.2% of gastric tumors. We present the case of a 56-year-old asymptomatic patient who was diagnosed, following a routine ultrasound examination, with an abdominal tumor. An abdominal MRI confirmed the gastric origin of the tumor. Although a subsequent upper-digestive endoscopic ultrasound was performed, a definitive diagnosis could not be established. Thus, a laparoscopic wedge resection of the stomach was performed. The immunohistochemical examination of the tumor established the diagnosis of benign schwannoma. Despite the availability of advanced endoscopy and imaging techniques, the diagnosis of gastric schwannoma is very rarely preoperative. The immunohistochemical identification of S-100 on the surgical specimen confirmed the diagnosis.

The microbiota-gut-brain axis regulates motivation for exercise.

The microbiota-gut-brain axis regulates motivation for exercise.

Enteric nervous system damage caused by abnormal intestinal butyrate metabolism may lead to functional constipation.

Functional constipation (FC) is a high morbidity gastrointestinal disease for which dysfunction in the enteric nervous system is a major pathogenesis mechanism. To enhance our understanding of the involvement of intestinal microbiota and its metabolites in the pathogenesis of FC, we conducted a shotgun metagenomic sequencing analysis of gut microbiota and serum short-chain fatty acids (SCFAs) analysis in 460 Chinese women with different defecation frequencies. We observed that the abundance ofFusobacterium_varium, a butyric acid-producing bacterium, was positively correlated (P = 0.0096) with the frequency of defecation; however, the concentrations of serum butyric acid was negatively correlated (P = 3.51E-05) with defecation frequency. These results were verified in an independent cohort (6 patients with FC and 6 controls). To further study the effects of butyric acid on intestinal nerve cells, we treated mouse intestinal neurons in vitro with various concentrations of butyrate (0.1, 0.5, 1, and 2.5 mM). We found that intestinal neurons treated with 0.5 mM butyrate proliferated better than those in the other treatment groups, with significant differences in cell cycle and oxidative phosphorylation signal pathways. We suggest that the decreased butyrate production resulting from the reduced abundance of Fusobacterium in gut microbiota affects the proliferation of intestinal neurons and the energy supply of intestinal cells. However, with FC disease advancing, the consumption and excretion of butyric acid reduce, leading to its accumulation in the intestine. Moreover, the accumulation of an excessively high amount of butyric acid inhibits the proliferation of nerve cells and subsequently exacerbates the disease.

Neuroimmune regulation in Hirschsprung's disease associated enterocolitis.

Neuroimmune pathways are important part of the regulation of inflammatory response. Nerve cells regulate the functions of various immune cells through neurotransmitters, and then participate in the inflammatory immune response. Hirschsprung's disease (HD) is a congenital abnormal development of intestinal neurons, and Hirschsprung-associated enterocolitis (HAEC) is a common complication, which seriously affects the quality of life and even endangers the lives of children. Neuroimmune regulation mediates the occurrence and development of enteritis, which is an important mechanism. However, there is a lack of review on the role of Neuroimmune regulation in enterocolitis associated with Hirschsprung's disease. Therefore, this paper summarizes the characteristics of the interaction between intestinal nerve cells and immune cells, reviews the neuroimmune regulation mechanism of Hirschsprung's disease associated enterocolitis (HAEC), and looks forward to the potential clinical application value.

Intrastriatal injection of Parkinson’s disease intestine and vagus lysates initiates α-synucleinopathy in rat brain

Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain and the pathological accumulation of misfolded α-synuclein (α-syn) in the brain. A growing body of evidence suggests that the formation of misfolded α-syn and aggregation may begin in the peripheral nervous system, specifically the enteric nervous system, and then propagate to the central nervous system via the vagus nerve. However, the PD-like neuropathology induced by the intestine and vagus nerve extracts is rarely investigated. In this work, we injected lysates of the intestine and vagus obtained from a diagnosed PD patient, which contained abnormal α-syn aggregates, into the rat striatum unilaterally. Strikingly, such an injection induced dopaminergic neurodegeneration and α-syn depositions in the striatum, substantia nigra, and other brain regions, including the frontal cortex, somatosensory cortex, hypothalamus, brain stem, and cerebellum. Moreover, significant activation of microglia and the development of astrogliosis were observed in the substantia nigra pars compacta of the injected rats. These findings provide essential information for our understanding of PD pathogenesis, as we established for the first time that the α-syn aggregates in the intestine and vagus of a PD patient were sufficient to induce prion-like propagation of endogenous α-syn pathology in wild-type rats.

Luteolin ameliorates loperamide-induced functional constipation in mice.

Functional constipation (FC) is one of the most common gastrointestinal disorders characterized by hard stools and infrequent bowel movements, which is associated with dysfunction of the enteric nervous system and intestinal motility. Luteolin, a naturally occurring flavone, was reported to possess potential pharmacological activities on intestinal inflammation and nerve injury. This study aimed to explore the role of luteolin and its functional mechanism in loperamide-induced FC mice. Our results showed that luteolin treatment reversed the reduction in defecation frequency, fecal water content, and intestinal transit ratio, and the elevation in transit time of FC models. Consistently, luteolin increased the thickness of the muscular layer and lessened colonic histopathological injury induced by loperamide. Furthermore, we revealed that luteolin treatment increased the expression of neuronal protein HuC/D and the levels of intestinal motility-related biomarkers, including substance P (SP), vasoactive intestinal polypeptide (VIP), and acetylcholine (ACh), as well as interstitial cells of Cajal (ICC) biomarker KIT proto-oncogene, receptor tyrosine kinase (C-Kit), and anoctamin-1 (ANO1), implying that luteolin mediated enhancement of colonic function and contributed to the anti-intestinal dysmotility against loperamide-induced FC. Additionally, luteolin decreased the upregulation of aquaporin (AQP)-3, AQP-4, and AQP-8 in the colon of FC mice. In summary, our data showed that luteolin might be an attractive option for developing FC-relieving medications.

Peptidergic modulation of a multi-functional central pattern generator in the pulmonate snail

Egg laying in pulmonate snails is a well-orchestrated process that involves a period of reduced locomotion, followed by substrate cleaning with rhythmic rasping of the surface to make tiny grooves, into which eggs are deposited. Although the neurohormonal control of initiating egg laying has been well established, the signals that modulate the buccal central pattern generator to substrate cleaning during egg laying are not known. Neuropeptides of the invertebrate gonadotropin-releasing hormone/corazonin family (invGnRH/CRZ) have been shown to be involved in reproduction and allied behaviors in many vertebrates and invertebrates. Here, we show that the buccal motor pattern underlying substrate cleaning during egg laying is altered by a vertebrate GnRH agonist. Signals from the intestinal nerve innervating reproductive structures, previously shown to be both necessary and sufficient for egg-laying behaviors, are blocked by a vertebrate GnRH antagonist. Further, the vertebrate GnRH-triggered response elicits rhythmic, phase 2 and non-phase 2 activity in the buccal motor pattern, with a shutdown of phase 3, indicative of repetitive rasping without accompanied swallowing behavior. Using immunohistochemistry, intracellular electrophysiology and extracellular nerve stimulation, we show that a member of the invGnRH/CRZ family of neuropeptides could be the signal that contextually switches the multifunctional buccal CPG to a biphasic rasping rhythm that underlies substrate cleaning behavior during egg laying in the pulmonate snail Planorbella (Helisoma) trivolvis.

The interaction between obesity and visceral hypersensitivity.

Obesity has been a worldwide problem associated with numerous chronic diseases such as cardiovascular disease, type 2 diabetes, and metabolic disorders. It may also play a role in visceral hypersensitivity, contributing to irritable bowel syndrome. (i) Adipose tissue secretes various inflammatory mediators, causing intestinal hyperpermeability and nerve endings activation. (ii) Obesity and gastrointestinal microbiota could affect each other, and microbial metabolites can increase sensitivity of the colon. (iii) Vitamin D deficiency contributes to both fat accumulation and disruption of the intestinal mucosal barrier. (iv) Brain-gut axis may be another bridge from obesity to visceral hypersensitivity.

Transepithelial Effect of Probiotics in a Novel Model of Gut Lumen to Nerve Signaling.

Recent studies have shown that the gut microbiome changes brain function, behavior, and psychiatric and neurological disorders. The Gut-Brain Axis (GBA) provides a neuronal pathway to explain this. But exactly how do commensal bacteria signal through the epithelial layer of the large intestine to activate GBA nerve afferents? An in vitro model is described. We differentiated two human cell lines: Caco2Bbe1 into mature epithelium on 0.4-micron filters and then SH-SY5Y into mature neurons in 24-well plates. These were co-cultured by placing the epithelium-laden filters 1 mm above the neurons. Twenty-four hours later they were tri-cultured by apical addition of 107Lactobacillus rhamnosus or Lactobacillus fermentum which settled on the epithelium. Alone, the Caco2bbe1 cells stimulated neurite outgrowth in underlying SH-SY5Y. Beyond this, the lactobacilli were well tolerated and stimulated further neurite outgrowth by 24 h post-treatment, though not passing through the filters. The results provide face validity for a first-of-kind model of transepithelial intestinal lumen-to nerve signaling. The model displays the tight junctional barrier characteristics found in the large intestine while at the same time translating stimulatory signals from the bacteria through epithelial cells to attracted neurons. The model is easy to set-up with components widely available.

Study on the toxic-mechanism of triclosan chronic exposure to zebrafish (Danio rerio) based on gut-brain axis

Triclosan (TCS), as a broad-spectrum bactericide, is extensively used in the fine chemical and textile industries. It is recognized as a new type of environmental endocrine disruptor with frequent detection and environmental pollution. However, the toxicity mechanism regarding neurodevelopment and neurobehavior remains unclear. This study is intended to explore the underlying toxic mechanism of TCS based on gut-brain axis. TCS-chronic exposure affected the development of zebrafish, induced feminization, obesity physical signs and abnormal organ index and caused neurobehavioral abnormalities by inhibiting both neurotransmitter acetylcholinesterase and dopamine activity, promoting brain neuron apoptosis and accelerating diencephalic lesions. Meanwhile, TCS-chronic exposure led to gut microbiota dysbiosis and decreased diversity, such as increased pathogenic bacteria and decreased probiotics in adult zebrafish gut, which caused many pathological damages, including partial shedding and ablation of intestinal villi, inflammatory infiltration, thinning of intestinal wall, and increased goblet cell in villus. Based on the communication between intestinal peripheral nerves and CNS, the above histopathological injuries and disorders were well underpinned and illustrated by the changes of biomarkers and the expression of related marker genes in the gut-brain axis. Additionally, short-chain fatty acids (SCFA), as the regulators of intestinal sympathetic nerve activation, are also secreting products of intestinal microflora and play a crucial role in regulating the balance of intestinal flora and protecting intestinal homeostasis. SCFA in low doses can effectively alleviate and rescue the toxic effects under TCS exposure, which evidenced that TCS exerted systemic toxic effects on the gut-brain axis by influencing the composition and diversity of gut flora in zebrafish, and fully demonstrated the interaction effect between intestine and brain. Hence, these findings contribute to the understanding, prevention, and diagnosis of endocrine disrupting diseases caused by environmental pollutants from the perspective of the gut-brain axis, and strengthening the early warning, management and control of TCS pollution.