Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2

2007 ◽  
Vol 293 (1) ◽  
pp. G211-G221 ◽  
Author(s):  
David L. Sigalet ◽  
Laurie E. Wallace ◽  
Jens J. Holst ◽  
Gary R. Martin ◽  
Tatsuru Kaji ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Concomitant Administration ◽  
Mucosal Inflammation ◽  
Trinitrobenzene Sulfonic Acid ◽  
Neural Pathways ◽  
Submucosal Plexus ◽  
Dss Colitis ◽  
Glucagon Like Peptide ◽  
Anti Inflammatory ◽  
Oxide Synthase

Glucagon-like peptide-2 (GLP-2) is an important regulator of nutritional absorptive capacity with anti-inflammatory actions. We hypothesized that GLP-2 reduces intestinal mucosal inflammation by activation of vasoactive intestinal polypeptide (VIP) neurons of the submucosal plexus. Ileitis or colitis was induced in rats by injection of trinitrobenzene sulfonic acid (TNBS), or colitis was induced by administration of dextran sodium sulfate (DSS) in drinking water. Subsets of animals received (1–33)-GLP-2 (50 μg/kg sc bid) either immediately or 2 days after the establishment of inflammation and were followed for 3–5 days. The involvement of VIP neurons was assessed by concomitant administration of GLP-2 and the VIP antagonist [Lys1-Pro2,5-Arg3,4-Tyr6]VIP and by immunohistochemical labeling of GLP-2-activated neurons. In all models, GLP-2 treatment, whether given immediately or delayed until inflammation was established, resulted in significant improvements in animal weights, mucosal inflammation indices (myeloperoxidase levels, histological mucosal scores), and reduced levels of inflammatory cytokines (IFN-γ, TNF-α, IL-1β) and inducible nitric oxide synthase, with increased levels of IL-10 in TNBS ileitis and DSS colitis. Reduced rates of crypt cell proliferation and of apoptosis within crypts in inflamed tissues were also noted with GLP-2 treatment. These effects were abolished with coadministration of GLP-2 and the VIP antagonist. GLP-2 was shown to activate neurons and to increase the number of cells expressing VIP in the submucosal plexus of the ileum. These findings suggest that GLP-2 acts as an anti-inflammatory agent through activation of enteric VIP neurons, independent of proliferative effects. They support further studies to examine the role of neural signaling in the regulation of intestinal inflammation.

Synbindin restrains proinflammatory macrophage activation against microbiota and mucosal inflammation during colitis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-321094
Author(s):  
Luoyan Ai ◽  
Yimeng Ren ◽  
Mingming Zhu ◽  
Shiyuan Lu ◽  
Yun Qian ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Intestinal Inflammation ◽  
Fusobacterium Nucleatum ◽  
Degradation Pathway ◽  
Mucosal Inflammation ◽  
Intestinal Epithelial ◽  
Heterozygous Deletion ◽  
Macrophage Response ◽  
Dss Colitis ◽  
Membrane Tethering

ObjectiveAs a canonical membrane tethering factor, the function of synbindin has been expanding and indicated in immune response. Here, we investigated the role of synbindin in the regulation of toll-like receptor 4 (TLR4) signalling and macrophage response to microbiota during colitis.DesignThree distinct mouse models allowing global, myeloid-specific or intestinal epithelial cell-specific synbindin heterozygous deletion were constructed and applied to reveal the function of synbindin during dextran sodium sulfate (DSS) colitis. Effects of synbindin on TLR4 signalling and macrophage activation in response to bacterial lipopolysaccharide (LPS) or Fusobacterium nucleatum were evaluated. The colocalisation and interaction between synbindin and Rab7b were determined by immunofluorescence and coimmunoprecipitation. Synbindin expression in circulating monocytes and intestinal mucosal macrophages of patients with active IBD was detected.ResultsGlobal synbindin haploinsufficiency greatly exacerbated DSS-induced intestinal inflammation. The increased susceptibility to DSS was abolished by gut microbiota depletion, while phenocopied by specific synbindin heterozygous deletion in myeloid cells rather than intestinal epithelial cells. Profoundly aberrant proinflammatory gene signatures and excessive TLR4 signalling were observed in macrophages with synbindin interference in response to bacterial LPS or Fusobacterium nucleatum. Synbindin was significantly increased in intestinal mucosal macrophages and circulating monocytes from both mice with DSS colitis and patients with active IBD. Interleukin 23 and granulocyte-macrophage colony-stimulating factor were identified to induce synbindin expression. Mechanistic characterisation indicated that synbindin colocalised and directly interacted with Rab7b, which coordinated the endosomal degradation pathway of TLR4 for signalling termination.ConclusionSynbindin was a key regulator of TLR4 signalling and restrained the proinflammatory macrophage activation against microbiota during colitis.

scholarly journals Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

2020 ◽  
Author(s):  
Elliot Yi-Hsin Lin ◽  
Hsuan-Ju Lai ◽  
Yuan-Kai Cheng ◽  
Kai-Quan Leong ◽  
Li-Chieh Cheng ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Experimental Colitis ◽  
Neutrophil Extracellular Trap ◽  
Mucosal Barrier ◽  
Mucosal Inflammation ◽  
Intestinal Barrier Function ◽  
Trinitrobenzene Sulfonic Acid ◽  
Barrier Integrity

Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria, and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.

scholarly journals Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology

2020 ◽  
Author(s):  
Stefan Grathwohl ◽  
Emmanuel Quansah ◽  
Nazia Maroof ◽  
Jennifer A Steiner ◽  
Liz Spycher ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Immune Modulation ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Alpha Synuclein ◽  
Submucosal Plexus ◽  
Wild Type ◽  
Genetic Ablation ◽  
Dss Colitis

Abstract Background : Intraneuronal accumulation of a-synuclein (αSyn) is key in Parkinson’s disease (PD) pathogenesis. The pathogenic process is suggested to begin in the enteric nervous system decades before diagnosis of PD and then propagate into the brain. The triggers for these events are unclear but, in some patients, colitis might play a critical role. Methods : We administered lipopolysaccharide (LPS) or dextran sulfate sodium (DSS) to assess the effect of different types of experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice and quantified local gene expression by RT-PCR and level of αSyn accumulation by immunofluorescence imaging. Immune modulation during the DSS colitis paradigm in the αSyn transgenic mice included genetic ablation of Cx3cr1 or treatment with recombinant IL-10. To determine long-term effects of experimental colitis, we induced DSS colitis in young αSyn transgenic mice and aged them under normal conditions up to nine or 21 months before analyzing their brains by immunohistochemistry. In vivo experiments were performed in randomized cohorts. Blinded experimenters performed image analysis and statistical analysis depended on data type (i.e., Student’s t-test, ANOVA, mixed-effects model). Results : We demonstrate that mild sustained or one strong insult of experimental DSS colitis triggers αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS experimental colitis or inflammation induced by LPS does not have such an effect. Lack of macrophage-related Cx3cr1-signalling during DSS colitis increases accumulation of αSyn in the colonic submucosal plexus of αSyn transgenic mice while systemic treatment with immune-dampening IL-10 ameliorates this phenomenon. Additionally, DSS colitis-induced αSyn accumulation in young αSyn transgenic mice persists for months and is exacerbated by lack of Cx3cr1-signaling. Remarkably, experimental colitis at three months of age exacerbates the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons. Conclusions : Our data suggest that specific types of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.

scholarly journals Deciphering the combinatorial influence of diet and the microbiota on experimental colitis

2017 ◽  
Author(s):  
Sean R. Llewellyn ◽  
Graham J. Britton ◽  
Eduardo J. Contijoch ◽  
Arthur Mortha ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Dietary Protein ◽  
Intestinal Inflammation ◽  
High Protein Diet ◽  
Experimental Colitis ◽  
Mucosal Inflammation ◽  
Germ Free ◽  
Dss Colitis ◽  
Microbial Density ◽  
Specific Pathogen ◽  
Host Physiology

AbstractBackground & AimsThe complex interactions between diet and the microbiota that influence mucosal inflammation and inflammatory bowel disease are poorly understood. Experimental colitis models provide the opportunity to control and systematically perturb diet and the microbiota in parallel to quantify the contributions between multiple dietary ingredients and the microbiota on host physiology and colitis.MethodsTo examine the interplay of diet and the gut microbiota on host health and colitis, we fed over 40 different diets with varied macronutrient sources and concentrations to specific pathogen free or germ free mice either in the context of healthy, unchallenged animals or colitis models (dextran sodium sulfate (DSS) and T cell transfer).ResultsDiet influenced physiology in both health and colitis across all models, with the concentration of protein and psyllium fiber having the most profound effects. Increasing dietary protein elevated gut microbial density and worsened DSS colitis severity. Depleting gut microbial density by using germ-free animals or antibiotics negated the effect of a high protein diet. Psyllium fiber influenced host physiology and attenuated colitis severity through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary protein and psyllium fiber in parallel explain most variation in gut microbial density, intestinal permeability, and DSS colitis severity, and changes in one ingredient can be offset by changes in the other.ConclusionsOur results demonstrate the importance of examining complex mixtures of nutrients to understand the role of diet in intestinal inflammation.

scholarly journals Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 275
Author(s):  
Elliot Yi-Hsin Lin ◽  
Hsuan-Ju Lai ◽  
Yuan-Kai Cheng ◽  
Kai-Quan Leong ◽  
Li-Chieh Cheng ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Experimental Colitis ◽  
Neutrophil Extracellular Trap ◽  
Mucosal Barrier ◽  
Mucosal Inflammation ◽  
Intestinal Barrier Function ◽  
Trinitrobenzene Sulfonic Acid ◽  
Barrier Integrity

Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.

scholarly journals Contribution of the Gut Microbiota in P28GST-Mediated Anti-Inflammatory Effects: Experimental and Clinical Insights

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 577 ◽  
Author(s):  
Benoît Foligné ◽  
Coline Plé ◽  
Marie Titécat ◽  
Arnaud Dendooven ◽  
Aurélien Pagny ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Trinitrobenzene Sulfonic Acid ◽  
T Helper ◽  
Anti Inflammatory ◽  
Transplantation Experiments

An original immuno-regulatory strategy against inflammatory bowel diseases based on the use of 28 kDa glutathione S-transferase (P28GST), a unique schistosome protein, was recently proposed. Improvement of intestinal inflammation occurs through restoration of the immunological balance between pro-inflammatory T-helper 1 (Th1) responses and both T-helper 2 (Th2) and regulatory responses. However, detailed mechanisms explaining how P28GST prevents colitis and promotes gut homeostasis remain unknown. Considering the complex interplay between the adaptive and innate immune system and the intestinal microbiota, we raised the question of the possible role of the microbial ecosystem in the anti-inflammatory effects mediated by the helminth-derived P28GST protein. We first analyzed, by 16S rRNA sequencing, the bacterial profiles of mice fecal microbiota at several time points of the P28GST-immunomodulation period prior to trinitrobenzene sulfonic acid (TNBS)-colitis. The influence of gut microbiota in the P28GST-mediated anti-inflammatory effects was then assessed by fecal microbiota transplantation experiments from P28GST-immunized mice to either conventional or microbiota depleted naïve recipient mice. Finally, the experimental data were supplemented by the temporal fecal microbiota compositions of P28GST-treated Crohn’s disease patients from a pilot clinical study (NCT02281916). The P28GST administration slightly modulated the diversity and composition of mouse fecal microbiota while it significantly reduced experimental colitis in mice. Fecal microbiota transplantation experiments failed to restore the P28GST-induced anti-inflammatory effects. In Crohn’s disease patients, P28GST also induced slight changes in their overall fecal bacterial composition. Collectively, these results provide key elements in both the anti-inflammatory mechanisms and the safe therapeutic use of immunomodulation with such promising helminth-derived molecules.

Beneficial effect of Bidens pilosa L. (Asteraceae) in a rat model of colitis

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Oyindamola O. Abiodun ◽  
Aderemi S. Sosanya ◽  
Norah Nwadike ◽  
Adedunke O. Oshinloye
Keyword(s):  
Oxidative Stress ◽  
Wistar Rats ◽  
Intestinal Inflammation ◽  
Inflammatory Cells ◽  
Response To Treatment ◽  
Trinitrobenzene Sulfonic Acid ◽  
Bidens Pilosa ◽  
Treatment Groups ◽  
Beneficial Effects ◽  
Anti Inflammatory

AbstractBackgroundBidens pilosa (BP) possessed anti-inflammatory, antioxidant, and immunomodulatory activities. Its beneficial effects on intestinal inflammation and oxidative stress in 2,4,6 trinitrobenzene sulfonic acid (TNBS) induced colitis in Wistar rats was evaluated.MethodsThirty female Wistar rats weighing 180–200 g were distributed into six groups (n = 5): non-colitic, untreated colitic and colitic rats treated graded doses of methanol extract of BP (50–400 mg/kg). Colitis was induced in rats by intracolonic instillation of 0.2 mL of 40 mg/mL TNBS. BP was administered two days pre-colitis induction and treatments continued until seven days post-colitis induction. A day after the last treatment, rats were euthanized, colon removed aseptically and response to treatment assessed. Phytochemical composition of BP was determined using the GC-MS.ResultsBP significantly reduced macroscopic colonic damage score, weight/length ratio, colonic lipid peroxidation level, leukocytes infiltration, and TNF-α level in comparison to untreated colitic rats (p ≤ 0.008). Similarly, treatment with 200 and 400 mg/kg BP prevented depletion of colonic glutathione level than other treatment groups (p ≤ 0.0002). Histological findings revealed that treatment with 400 mg/kg BP significantly preserved the mucosal epithelial layer. It also prevented ulceration and sloughing of the mucosal layers and reduced infiltration of inflammatory cells compared to other treatment groups. Among the 16 compounds identified were oleic acid (6.2%) and n-hexadecanoic acid (2.0%) with antioxidant anti-inflammatory activities.ConclusionsThe beneficial effects of BP in rat colitis might be related to the reduction of leucocytes infiltration, inhibition of oxidative stress and pro-inflammatory cytokines.

scholarly journals Physalis angulata Calyces Modulate Macrophage Polarization and Alleviate Chemically Induced Intestinal Inflammation in Mice

Biomedicines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 24
Author(s):  
David Rivera ◽  
Yanet Ocampo ◽  
Luis A. Franco
Keyword(s):  
Intestinal Inflammation ◽  
Macrophage Polarization ◽  
Body Weight Loss ◽  
Mannose Receptor ◽  
Sucrose Esters ◽  
Dss Colitis ◽  
Physalis Angulata ◽  
Anti Inflammatory ◽  
Inflammatory Profile

As part of the search for new bioactive plants from the Colombian Caribbean, the dichloromethane fraction of the calyces of Physalis angulata L. (PADF) was selected for its anti-inflammatory activity. In this work, we investigated the immunomodulatory effect of PADF in activated macrophages and during dextran sulfate sodium (DSS)-induced colitis. PADF displayed a low content of withanolides or phenolic compounds, and a higher content of sucrose esters, representative anti-inflammatory metabolites of the Physalis genus. The PADF fraction at 12.5 μg/mL prevented the induction of interleukin (IL)-1β, tumor necrosis factor (TNF-α), IL-6, IL-12, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS), while increased the levels of arginase (ARG1), IL-10, and mannose receptor C (MRC1). The polarization towards an anti-inflammatory profile was also observed in resting macrophages, without promoting the typical gene profile induced by IL-4, suggesting that PADF promotes a shift to a regulatory status rather than to an alternative one. In vivo, the administration of PADF to mice with chronic DSS-colitis reduced disease signs (i.e., body weight loss and colon shortening), and improved the histology score by diminishing the levels of pro-inflammatory cytokines and increasing the production of IL-10. Overall, results suggest that the regulatory effect on PADF towards macrophages might contribute to the therapeutic activity observed in the murine model of inflammatory bowel disease.

scholarly journals Partially hydrolysed guar gum ameliorates murine intestinal inflammation in association with modulating luminal microbiota and SCFA

2016 ◽  
Vol 116 (7) ◽  
pp. 1199-1205 ◽  
Author(s):  
Tomohisa Takagi ◽  
Yuji Naito ◽  
Yasuki Higashimura ◽  
Chihiro Ushiroda ◽  
Katsura Mizushima ◽  
...  
Keyword(s):  
Real Time ◽  
Intestinal Microbiota ◽  
Real Time Pcr ◽  
Colonic Mucosa ◽  
Guar Gum ◽  
Intestinal Inflammation ◽  
Neutrophil Infiltration ◽  
Water Soluble ◽  
Mucosal Inflammation ◽  
Trinitrobenzene Sulfonic Acid

AbstractPartially hydrolysed guar gum (PHGG), a water-soluble dietary fibre produced by the controlled partial enzymatic hydrolysis of guar gum beans, has various physiological roles. This study aimed to elucidate the beneficial effects of PHGG on colonic mucosal damage in a murine 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Acute colitis was induced in male C57BL/6 mice with TNBS after 2 weeks of pre-feeding with PHGG (5 %). The colonic mucosal inflammation was evaluated using macroscopic damage scores, and neutrophil infiltration was assessed by measuring tissue-associated myeloperoxidase (MPO) activity in the colonic mucosa. TNF-αexpression in the colonic mucosa was measured by ELISA and real-time PCR. Moreover, the intestinal microbiota and production of SCFA were assessed by real-time PCR and HPLC, respectively. Colonic damage due to TNBS administration was significantly ameliorated by PHGG treatment. Furthermore, PHGG significantly inhibited increases in MPO activity and TNF-αprotein and mRNA expression in the colonic mucosa in TNBS-induced colitis. On analysis of intestinal microbiota, we found that the concentration of theClostridium coccoidesgroup (Clostridiumcluster XIVa), theClostridium leptumsubgroup (Clostridiumcluster IV) and theBacteroides fragilisgroup had significantly increased in PHGG-fed mice. On analysis of SCFA, we found that the caecal content of acetic acid, propionic acid and butyric acid had significantly increased in PHGG-fed mice. Together, these results suggest that chronic ingestion of PHGG prevents the development of TNBS-induced colitis in mice by modulating the intestinal microbiota and SCFA, which may be significant in the development of therapeutics for inflammatory bowel disease.

scholarly journals Yoghurt Consumption Regulates the Immune Cells Implicated in Acute Intestinal Inflammation and Prevents the Recurrence of the Inflammatory Process in a Mouse Model

2011 ◽  
Vol 74 (5) ◽  
pp. 801-811 ◽  
Author(s):  
SILVINA CHAVES ◽  
GABRIELA PERDIGON ◽  
ALEJANDRA de MORENO de LeBLANC
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cell ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Disease Model ◽  
Interleukin 10 ◽  
Trinitrobenzene Sulfonic Acid ◽  
Industrialized Countries ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

Crohn's disease and ulcerative colitis, two forms of inflammatory bowel disease, are important problems in industrialized countries. The complete etiology of these two diseases is still unknown but likely involves genetic, environmental, and immunological factors. The aim of the present work was to determine whether the anti-inflammatory effects reported for yoghurt in acute trinitrobenzene sulfonic acid–induced intestinal inflammation in mice also could prevent or attenuate the recurrent intestinal inflammation, thus maintaining remission. The innate response also was evaluated through participation of Toll-like receptors (TLRs) and the analysis of T-cell populations to determine the effects of yoghurt in an acute inflammatory bowel disease model. Yoghurt exerted a beneficial effect on acute intestinal inflammation by regulating T-cell expansion and modulating the expression of TLRs, with decrease of TLR4+ and increase of TLR9+ cells. The anti-inflammatory effect of yoghurt also was demonstrated in a recurrent inflammation model. Yoghurt administration during the remission phase prevented the recurrence of inflammation without producing undesirable side effects. The yoghurt effect may be mediated by increased interleukin 10 production and changes in intestinal microbiota.

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