• Gastrointestinal hormones
• dysbiosis
• gut microbiota
• interkingdom signaling
• metabolic disease

• Gastrointestinal Microbiome/physiology
• Humans
• Animals
• Gastrointestinal Hormones/metabolism
• Dysbiosis/microbiology
• Dysbiosis/metabolism
• Bacteria/metabolism
• Bacteria/classification
• Bacteria/genetics
• Fecal Microbiota Transplantation
• Signal Transduction
• Inflammatory Bowel Diseases/microbiology
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/therapy
• Gastrointestinal Tract/microbiology
• Gastrointestinal Tract/metabolism

• dipeptidyl peptidase-4
• gastrointestinal symptoms
• neuropeptide Y
• obesity
• pancreatic polypeptide
• peptide YY
• type 2 diabetes

• Humans
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/physiopathology
• Male
• Female
• Middle Aged
• Neuropeptide Y/analysis
• Neuropeptide Y/blood
• Cross-Sectional Studies
• Dipeptidyl Peptidase 4/analysis
• Dipeptidyl Peptidase 4/blood
• Obesity/complications
• Obesity/physiopathology
• Adult
• Peptide YY/analysis
• Gastrointestinal Diseases/etiology
• Gastrointestinal Diseases/physiopathology
• Pancreatic Polypeptide/analysis
• Surveys and Questionnaires
• Jejunum
• Aged

• Inflammation
• Neuroregulation
• Skin
• Wound healing

• Postdoctoral Research Start-Up Fund of Lishui People’s Hospital
• Traditional Chinese Medicine Science and Technology Planning Project of Zhejiang Province
• Medical and Health Science and Technology Planning Project of Zhejiang Province
• Key Research & Development Plan of Zhejiang Province
• National Natural Science Foundation of China
• Zhejiang Provincial Natural Science Foundation of China

• enteric glia
• enteric nervous system
• gut epithelial barrier
• inflammatory bowel disease
• intrinsic primary afferent neurons

• Deutsche Forschungsgemeinschaft
• German Research Foundation

• DP2 AT012345 NCCIH NIH HHS

• NGF
• NPY
• VIP
• acetylcholine
• angiogenesis
• diabetes mellitus
• keratinocytes
• norepinephrine
• sympathetic system
• wound healing

Peptide YY (PYY) 3–36, the main circulatory form of PYY, plays important roles in gastrointestinal motility, secretion, and absorption. However, it is unknown whether PYY 3–36 has underlying functions in colitis. The Crohn’s disease (CD)-like mouse model in which CD is induced by trinitrobenzene sulfonic acid (TNBS) was established and utilized to investigate this potential role for PYY 3–36. The results showed that the expression of colonic mucosal PYY and PYY receptors Y1, Y2, Y4 were significantly increased in mice with TNBS-induced colitis. In vitro, PYY 3–36 remarkably inhibited the production of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) from lipopolysaccharide (LPS)-induced macrophages. In vivo, a high concentration of PYY 3–36 robustly decreased the weight loss and death rate and attenuated the pathological colon tissue damage observed in mice with TNBS-induced colitis. Further studies uncovered that PYY 3–36 treatment reduced the levels of colon myeloperoxidase (MPO) and both colonic and systemic TNF-α and IL-6 observed in murine colitis. Furthermore, flow cytometric analysis showed PYY 3–36 altered the proportion of Th1/Th2 splenocytes in the disease model of colitis. Collectively, these results suggest that PYY 3–36 may be a promising candidate for the improvement of colitis, reflected by the attenuation of colon inflammatory responses observed in experimental murine colitis.

• PYY 3–36
• Th1/Th2 cells
• colitis
• inflammation
• trinitrobenzene sulfonic acid

• Crohn’s disease
• Ileal margin
• Neuropeptides
• Plexitis
• Postoperative recurrence

• Crohn Disease/complications
• Crohn Disease/surgery
• Humans
• Ileum/surgery
• Margins of Excision
• Neoplasm Recurrence, Local/complications
• Neuropeptides
• Prognosis
• Recurrence
• Retrospective Studies

• Crohn’s disease
• NPY
• TNF
• mucosal explants
• neuroimmune
• ulcerative colitis

The prescription of Tong Xie Yao Fang (TXYF) was derived from the Yuan dynasty “Dan Brook Heart Law,” which was a representative formula for treating liver-spleen disharmony, diarrhea, and abdominal pain. The prescription is composed of four herbs for soothing the liver and strengthening the spleen. TXYF is reportedly capable of eliminating discomfort in ulcerative colitis (UC). This classic formula has been widely used for regulating gastrointestinal motor dysfunction and repairing colon mucosa. This review aims to provide current information on the pharmacology and clinical research of TXYF in the treatment of UC, and to critically appraise that information, in order to guide the future clinical use and experimental study of TXYF in the treatment of UC. We searched online databases including PubMed, CNKI, and Google Scholar for research published between 2010 and 2020 on TXYF and its efficacy in the treatment of UC. The findings indicated that TXYF has anti-inflammatory and immunomodulatory effects, regulates cell signal transduction, brain-gut axis, and intestinal flora in UC, and may promote targeting of bone mesenchymal stem cells (BMSCs) to the colonic mucosa and accelerate healing of the colonic mucosal barrier. In addition, the results of clinical studies showed that TXYF has good efficacy and few adverse reactions in the treatment of UC. Although it has achieved some success, the research is limited by deficiencies; there is a lack of unified standards for the construction of UC animal models and for administration regimen. In addition, the dosage of TXYF is not consistent and lacks pharmacological verification, and clinical trial data are not detailed or sufficiently rigorous. Therefore, a more rigorous, comprehensive, and in-depth study of TXYF in the treatment of UC is needed.

Microbes colonize the gastrointestinal tract are considered as highest complex ecosystem because of having diverse bacterial species and 150 times more genes as compared to the human genome. Imbalance or dysbiosis in gut bacteria can cause dysregulation in gut homeostasis that subsequently activates the immune system, which leads to the development of inflammatory bowel disease (IBD). Neuromediators, including both neurotransmitters and neuropeptides, may contribute to the development of aberrant immune response. They are emerging as a regulator of inflammatory processes and play a key role in various autoimmune and inflammatory diseases. Neuromediators may influence immune cell’s function via the receptors present on these cells. The cytokines secreted by the immune cells, in turn, regulate the neuronal functions by binding with their receptors present on sensory neurons. This bidirectional communication of the enteric nervous system and the enteric immune system is involved in regulating the magnitude of inflammatory pathways. Alterations in gut bacteria influence the level of neuromediators in the colon, which may affect the gastrointestinal inflammation in a disease condition. Changed neuromediators concentration via dysbiosis in gut microbiota is one of the novel approaches to understand the pathogenesis of IBD. In this article, we reviewed the existing knowledge on the role of neuromediators governing the pathogenesis of IBD, focusing on the reciprocal relationship among the gut microbiota, neuromediators, and host immunity. Understanding the neuromediators and host-microbiota interactions would give a better insight in to the disease pathophysiology and help in developing the new therapeutic approaches for the disease.

• Inflammation
• Gut microbiota
• Inflammatory bowel disease
• Enteric nervous system
• Neuroimmunomodulation
• Neuromediator

Neuropeptide Y (NPY) is found throughout the central nervous system where it appears to be involved in the regulation of a wide range of physiological effects. The Mongolian gerbil, a member of the rodent family Muridae, is a diurnal animal and has been widely used in various aspects of biomedical research. This study was conducted to investigate the organization of NPY-immunoreactive (IR) neurons in the gerbil visual cortex using NPY immunocytochemistry. The highest density of NPY-IR neurons was located in layer V (50.58%). The major type of NPY-IR neuron was a multipolar round/oval cell type (44.57%). Double-color immunofluorescence revealed that 89.55% and 89.95% of NPY-IR neurons contained gamma-aminobutyric acid (GABA) or somatostatin, respectively. Several processes of the NPY-IR neurons surrounded GABAergic interneurons. Although 30.81% of the NPY-IR neurons contained calretinin, NPY and calbindin-D28K-IR neurons were co-expressed rarely (3.75%) and NPY did not co-express parvalbumin. Triple-color immunofluorescence with anti-GluR2 or CaMKII antibodies suggested that some non-GABAergic NPY-IR neurons may make excitatory synaptic contacts. This study indicates that NPY-IR neurons have a notable architecture and are unique subpopulations of the interneurons of the gerbil visual cortex, which could provide additional valuable data for elucidating the role of NPY in the visual process in diurnal animals.

• Mongolian gerbil
• calcium-binding protein
• immunocytochemistry
• neuropeptide Y
• visual cortex

• Animals
• Gerbillinae
• Immunohistochemistry
• Neuropeptide Y/metabolism
• Visual Cortex/physiology

• Autonomic nervous system
• Enteric ganglia
• Immunohistochemistry
• Neuropeptide Y
• Postnatal development
• Receptors
• Western blot analysis

• Age Factors
• Animals
• Animals, Newborn
• Immunohistochemistry/methods
• Neurons/metabolism
• Neuropeptide Y/metabolism
• Rats
• Receptors, Neuropeptide Y/metabolism
• Tyrosine 3-Monooxygenase/metabolism

• enteroendocrine cells
• gut dysfunction
• gut microbiota
• immune system
• inflammatory bowel disease

• Animals
• Dysbiosis/immunology
• Dysbiosis/microbiology
• Enteroendocrine Cells/immunology
• Enteroendocrine Cells/microbiology
• Gastrointestinal Diseases/immunology
• Gastrointestinal Diseases/microbiology
• Gastrointestinal Microbiome/immunology
• Gastrointestinal Tract/immunology
• Gastrointestinal Tract/microbiology
• Homeostasis/immunology
• Humans
• Immunity, Mucosal
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/microbiology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/microbiology

• R01 DK098370 NIDDK NIH HHS
• R01 DK105585 NIDDK NIH HHS
• R01 DK112436 NIDDK NIH HHS
• National Natural Science Foundation of China
• Fundamental Research Fund of Shandong University
• National Institutes of Health

• Fatty acids
• Free Fatty Acids Receptors
• G protein-coupled receptors
• Inflammatory bowel disease

• Animals
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/metabolism
• Ligands
• Receptors, G-Protein-Coupled/metabolism
• Signal Transduction

• Animals
• Arginine/analogs & derivatives
• Arginine/pharmacology
• Benzazepines/pharmacology
• Body Weight
• Colitis/chemically induced
• Colitis/drug therapy
• Colitis/metabolism
• Colitis/pathology
• Dextran Sulfate/toxicity
• Disease Models, Animal
• Female
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Neuropeptide Y/antagonists & inhibitors

• Regeneron Pharmaceutical

The gut barrier plays an important role in human health. When barrier function is impaired, altered permeability and barrier dysfunction can occur, leading to inflammatory bowel diseases, irritable bowel syndrome or obesity. Several bacteria, including pathogens and commensals, have been found to directly or indirectly modulate intestinal barrier function. The use of probiotic strains could be an important landmark in the management of gut dysfunction with a clear impact on the general population. Previously, we found that Lactobacillus rhamnosus CNCM I-3690 can protect intestinal barrier functions in mice inflammation model. Here, we investigated its mechanism of action. Our results show that CNCM I-3690 can (i) physically maintain modulated goblet cells and the mucus layer and (ii) counteract changes in local and systemic lymphocytes. Furthermore, mice colonic transcriptome analysis revealed that CNCM I-3690 enhances the expression of genes related to healthy gut permeability: motility and absorption, cell proliferation; and protective functions by inhibiting endogenous proteases. Finally, SpaFED pili are clearly important effectors since an L. rhamnosus ΔspaF mutant failed to provide the same benefits as the wild type strain. Taken together, our data suggest that CNCM I-3690 restores impaired intestinal barrier functions via anti-inflammatory and cytoprotective responses.

• Oesophagus
• extrinsic innervation
• neuropeptide Y
• retrograde tracing

• G protein-coupled receptors
• Heterodimerization
• Homodimerization
• Neuropeptide Y
• Proliferation

• Animals
• CHO Cells
• Cell Proliferation/physiology
• Cricetulus
• Neuropeptide Y/metabolism
• Protein Multimerization/physiology
• Receptors, Neuropeptide Y/metabolism

• R21 CA198698 NCI NIH HHS
• R01 CA197964 NCI NIH HHS
• P30 CA051008 NCI NIH HHS
• R03 CA178809 NCI NIH HHS
• R01 CA123211 NCI NIH HHS

Apathy is observed across several neurological and psychiatric conditions; however, its pathogenesis remains unclear. We clarified the involvement of brain–gut signaling in the disruption of goal-directed behavior. Male C57BL/6J mice were exposed to water immersion (WI) stress for 3 days. Food intake and nesting behavior were measured as indexes of motivation. Repeated WI caused decrease in food intake and nesting behavior. Plasma levels of peptide YY (PYY), IL-6, and ratio of dopamine metabolites in the striatum were significantly elevated after WI. PYY and IL-6 administration significantly decreased nesting behavior. The reductions in feeding and nesting behavior were blocked by PYY receptor (Y2R) antagonist or dopamine agonist. The ameliorative effect of the Y2R antagonist was diminished by the dopamine D2 receptor (D2R) antagonist. The reduction in goal-directed behavior is associated with dysfunction of D2R signaling via increased peripheral PYY, suggesting that PYY antagonism is a novel candidate for decline of motivation in several depressive diseases.

• Anorexia
• Dopamine
• Goal-directed behavior
• Nest building
• PYY

• Anxiety
• Depression
• Gut microbiota
• Gut peptides
• Gut–brain axis

• Anxiety/metabolism
• Anxiety/microbiology
• Brain/metabolism
• Brain/microbiology
• Cholecystokinin/metabolism
• Corticotropin-Releasing Hormone/metabolism
• Depression/metabolism
• Depression/microbiology
• Endocrine System/metabolism
• Endocrine System/microbiology
• Gastrointestinal Microbiome
• Ghrelin/metabolism
• Glucagon-Like Peptide 1/metabolism
• Humans
• Neuropeptide Y/metabolism
• Oxytocin/metabolism
• Peptide Hormones/metabolism

• Anorexia Nervosa
• Bulimia Nervosa
• Crohn's Disease
• Eating Disorders
• Inflammatory Bowel Disease
• Ulcerative Colitis

• Chromogranin A
• colon
• endocrine cells
• immunohistochemistry
• morphometry
• rectum

Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn’s disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients’ quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease.

• Enteric nervous system
• Enteroendocrine cells
• Immune cells
• Inflammatory bowel disease
• Musashi-1
• Neurogenin 3
• Stem cells

• Amines/immunology
• Animals
• Chromogranins/immunology
• Chromogranins/metabolism
• Disease Models, Animal
• Gastrointestinal Microbiome
• Gastrointestinal Tract/immunology
• Gastrointestinal Tract/metabolism
• Ghrelin/immunology
• Ghrelin/metabolism
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/epidemiology
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/therapy
• Neuroendocrine Cells/immunology
• Neuroendocrine Cells/metabolism
• Neuropeptide Y/antagonists & inhibitors
• Neuropeptide Y/immunology
• Neuropeptide Y/metabolism
• Neurosecretory Systems/cytology
• Neurosecretory Systems/immunology
• Prevalence
• Quality of Life
• Recurrence
• Serotonin/immunology
• Serotonin/metabolism
• Serotonin Antagonists/therapeutic use
• Somatostatin/immunology
• Somatostatin/metabolism
• Substance P/antagonists & inhibitors
• Substance P/immunology
• Substance P/metabolism
• Vasoactive Intestinal Peptide/immunology
• Vasoactive Intestinal Peptide/metabolism

The present study aimed to determine whether there is an association between abnormalities in enteroendocrine cells in dextran sulfate sodium (DSS)-induced colitis and the clonogenic and/or proliferative activities of stem cells. A total of 48 male Wistar rats were divided into four groups. Animals in the control group were provided with normal drinking water, whereas DSS colitis was induced in the remaining three groups. The rats with DSS-induced colitis were randomized into the following three groups: i) DSS group, which received 0.5 ml 0.5% carboxymethyl cellulose (CMC; vehicle); ii) DSS-G group, which was treated with 3-[(dodecylthiocarbonyl)-methyl]-glutarimide at 20 mg/kg body weight in 0.5% CMC; and iii) DSS-Q group, which was treated with dehydroxymethylepoxyquinomicin at 15 mg/kg body weight in 0.5% CMC. Treatments were administered intraperitoneally twice daily for 5 days in all groups. Subsequently, tissue samples from the colon were stained with hematoxylin-eosin, or immunostained for chromogranin A (CgA), Musashi 1 (Msi1), Math-1, neurogenin 3 (Neurog3) and neurogenic differentiation D1 (NeuroD1). The densities of CgA, Msi1-, Math-1-, Neurog3- and NeuroD1-immunoreactive cells were determined. DTCM-G, and DHMEQ ameliorated the inflammation in DSS-induced colitis. The density of CgA-, Neurog3- and NeuroD1-immunoreactive cells was significantly higher in the DSS group compared with in the control group, and the density of CgA cells was correlated with the densities of Neurog3- and NeuroD1-immunoreactive cells. There were no significant differences in the densities of Msi1- and Math-1-immunoreactive cells among the four experimental groups. The elevated densities of enteroendocrine cells detected in DSS-induced colitis may be due to the increased differentiation of early enteroendocrine progenitors during secretory lineage. It is probable that the DSS-induced inflammatory processes trigger certain signaling pathways, which control differentiation of the stem-cell secretory lineage into mature enteroendocrine cells.

Approximately 3.6 million individuals suffer from inflammatory bowel disease (IBD) in the western world, with an annual global incidence rate of 3–20 cases/100,000 individuals. The etiology of IBD is unknown, and the currently available treatment options are not satifactory for long-term treatment. Patients with inflammatory bowel disease present with abnormalities in multiple intestinal endocrine cell types, and a number of studies have suggested that interactions between gut hormones and immune cells may serve a pivotal role in the pathophysiology of IBD. The aim of the present study was to investigate alterations in colonic endocrine cells in a rat model of IBD. A total of 30 male Wistar rats were divided into control and trinitrobenzene sulfonic acid (TNBS)-induced colitis groups. Colonoscopies were performed in the control and TNBS groups at day 3 following the induction of colitis, and colonic tissues were collected from all animals. Colonic endocrine and immune cells in the obtained tissue samples were immunostained and their densities were quantified. The densities of chromogranin A, peptide YY, and pancreatic polypeptide-producing cells were significantly lower in the TNBS group compared with the control group, whereas the densities of serotonin, oxyntomodulin, and somatostatin-producing cells were significantly higher in the TNBS group. The densities of mucosal leukocytes, B/T-lymphocytes, T-lymphocytes, B-lymphocytes, macrophages/monocytes and mast cells were significantly higher in the TNBS group compared with the controls, and these differences were strongly correlated with alterations in all endocrine cell types. In conclusion, the results suggest the presence of interactions between intestinal hormones and immune cells.

Patients with inflammatory bowel disease (IBD), as well as animal models of human IBD have abnormal enteroendocrine cells. The present study aimed to identify the possible mechanisms underlying these abnormalities. For this purpose, 40 male Wistar rats were divided into 4 groups as follows: the control group, the group with trinitrobenzene sulfonic acid (TNBS)-induced colitis with no treatment (TNBS group), the group with TNBS-induced colitis treated with 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G; an activator protein-1 inhibitor) (DTCM-G group), and the group with TNBS-induced colitis treated with dehydroxymethylepoxyquinomicin (DHMEQ; a nuclear factor-κB inhibitor) treatment (DHMEQ group). Three days following the administration of TNBS, the rats were treated as follows: those in the control and TNBS groups received 0.5 ml of the vehicle [0.5% carboxymethyl cellulose (CMC)], those in the DTCM-G group received DTCM-G at 20 mg/kg body weight in 0.5% CMC, and those in the DHMEQ group received DHMEQ at 15 mg/kg body weight in 0.5% CMC. All injections were administered intraperitoneally twice daily for 5 days. The rats were then sacrificed, and tissue samples were taken from the colon. The tissue sections were stained with hemotoxylin-eosin and immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP), somatostatin, Musashi1 (Msi1), Math1, Neurogenin3 (Neurog3) and NeuroD1. The staining was quantified using image analysis software. The densities of CgA-, PYY-, PP-, Msi1-, Neurog3- and NeuroD1-positive cells were significantly lower in the TNBS group than those in the control group, while those of serotonin-, oxyntomodulin- and somatostatin-positive cells were significantly higher in the TNBS group than those in the control group. Treatment with either DTCM-G or DHMEQ restored the densities of enteroendocrine cells, stem cells and their progenitors to normal levels. It was thus concluded that the abnormalities in enteroendocrine cells and stem cells and their differentiation progenitors may be caused by certain signaling substances produced under inflammatory processes, resulting in changes in hormone expression in enteroendocrine cells. These substances may also interfere with the colonogenic activity and the differentiation of the stem-cell secretory lineage into mature enteroendocrine cells.