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 Measurement of the Intestinal pH in Mice under Various Conditions Reveals Alkalization Induced by Antibiotics

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 180
Author(s):  
Kouki Shimizu ◽  
Issei Seiki ◽  
Yoshiyuki Goto ◽  
Takeshi Murata
Keyword(s):  
Antibiotic Treatment ◽  
High Protein Diet ◽  
Intestinal Bacteria ◽  
High Protein ◽  
Protein Diet ◽  
Germ Free ◽  
Treatment Regimens ◽  
Ph Values ◽  
Specific Pathogen ◽  
The Stability

The intestinal pH can greatly influence the stability and absorption of oral drugs. Therefore, knowledge of intestinal pH is necessary to understand the conditions for drug delivery. This has previously been measured in humans and rats. However, information on intestinal pH in mice is insufficient despite these animals being used often in preclinical testing. In this study, 72 female ICR mice housed in SPF (specific pathogen-free) conditions were separated into nine groups to determine the intestinal pH under conditions that might cause pH fluctuations, including high-protein diet, ageing, proton pump inhibitor (PPI) treatment, several antibiotic treatment regimens and germ-free mice. pH was measured in samples collected from the ileum, cecum and colon, and compared to control animals. An electrode, 3 mm in diameter, enabled accurate pH measurements with a small amount of gastrointestinal content. Consequently, the pH values in the cecum and colon were increased by high-protein diet, and the pH in the ileum was decreased by PPI. Drastic alkalization was induced by antibiotics, especially in the cecum and colon. The alkalized pH values in germ-free mice suggested that the reduction in the intestinal bacteria caused by antibiotics led to alkalization. Alkalization of the intestinal pH caused by antibiotic treatment was verified in mice. We need further investigations in clinical settings to check whether the same phenomena occur in patients.

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 OP32 Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis in Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S031-S031
Author(s):  
W GONG ◽  
K Guo ◽  
J Ren
Keyword(s):  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Mitogen Activated Protein Kinase ◽  
Mucosal Inflammation ◽  
Neutrophil Chemotaxis ◽  
Knock Out ◽  
Mitogen Activated Protein ◽  
Proinflammatory Role

Abstract Background Macrophage-inducible C-type lectin (Mincle) signalling plays a proinflammatory role in different organs such as the brain and liver, but its role in intestinal inflammation remains unknown. Methods We studied the characteristics of Mincle signalling expression in CD patients and experimental colitis. The functional role of Mincle signalling in the intestine was addressed in experimental colitis models in vivo by using mice with Mincle knock out (Mincle−/−), neutralising anti-Mincle antibody, Mincle pharmacologic agonist and RNA-seq genome expression analysis. Bone marrow-derived macrophages were collected from mice and used to further verify the effect of Mincle signalling in macrophages. Results Mincle signalling was significantly elevated in active human CD and experimental colitis, and macrophages were the principal leukocyte subset that up-regulates Mincle signalling. Mincle deficiency ameliorated the colitis by reducing induced macrophage pyroptosis (Figure 1), whereas activation of Mincle with the pharmacologic agonist worsened the intestinal inflammation (Figure 2). Moreover, the ex vivo studies confirmed that Mincle signalling activation promoted and its absence restricted release of proinflammatory cytokines from pyroptosis of macrophage (Figure 3). Finally, Mincle/Syk signalling could promote the production of chemokines to recruit neutrophils by activating Mitogen-Activated Protein Kinase (MAPK) during inflammation (Figure 4). Conclusion Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis. Modulation of the Mincle/Syk axis emerges as a potential therapeutic strategy to target inflammation and treat CD.

scholarly journals Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis

2010 ◽  
Vol 207 (6) ◽  
pp. 1321-1332 ◽  
Author(s):  
Ting Feng ◽  
Lanfang Wang ◽  
Trenton R. Schoeb ◽  
Charles O. Elson ◽  
Yingzi Cong
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Intestinal Lumen ◽  
T Cell Proliferation ◽  
Specific Pathogen ◽  
Spontaneous Proliferation ◽  
Cognate Antigen

Little is known about how the microbiota regulates T cell proliferation and whether spontaneous T cell proliferation is involved in the pathogenesis of inflammatory bowel disease. In this study, we show that stimulation of innate pathways by microbiota-derived ligands and antigen-specific T cell stimulation are both required for intestinal inflammation. Microbiota-derived ligands promoted spontaneous T cell proliferation by activating dendritic cells (DCs) to produce IL-6 via Myd88, as shown by the spontaneous proliferation of T cells adoptively transferred into specific pathogen–free (SPF) RAG−/− mice, but not in germfree RAG−/− mice. Reconstitution of germfree RAG−/− mice with cecal bacterial lysate–pulsed DCs, but not with IL-6−/− or Myd88−/− DCs, restored spontaneous T cell proliferation. CBir1 TCR transgenic (CBir1 Tg) T cells, which are specific for an immunodominant microbiota antigen, induced colitis in SPF RAG−/− mice. Blocking the spontaneous proliferation of CBir1 Tg T cells by co-transferring bulk OT II CD4+ T cells abrogated colitis development. Although transferred OT II T cells underwent spontaneous proliferation in RAG−/− mice, the recipients failed to develop colitis because of the lack of cognate antigen in the intestinal lumen. Collectively, our data demonstrate that induction of colitis requires both spontaneous proliferation of T cells driven by microbiota-derived innate signals and antigen-specific T cell proliferation.

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 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 Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Sean P. Kessler ◽  
Dana R. Obery ◽  
Carol de la Motte
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Hyaluronan Synthase ◽  
Wild Type ◽  
Colon Tissue ◽  
Dss Colitis ◽  
Chemically Induced ◽  
Inflammatory Bowel ◽  
Colitis Model

Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

scholarly journals Influence of caecal microflora and of two dietary protein levels on the adaptation of the exocrine pancreas: comparative study in germ-free and conventional rats

1996 ◽  
Vol 75 (3) ◽  
pp. 433-444 ◽  
Author(s):  
Evelyne F. Lhoste ◽  
Isabelle Catala ◽  
Michèle Fiszlewicz ◽  
A. M. Gueugneau ◽  
Fran¸oise Popot ◽  
...  
Keyword(s):  
Fatty Acids ◽  
G Protein ◽  
Dietary Protein ◽  
Specific Activity ◽  
High Protein Diet ◽  
Short Chain Fatty Acids ◽  
Protein Diet ◽  
Short Chain ◽  
Germ Free ◽  
Enzyme Content

AbstractDietary proteins are degraded by both endogenous enzymes and the caecal microflora. In conventional rats the enzyme content of the pancreas depends on the amount of dietary protein. The influence of the caecal microflora on this process is unknown. We report here the effect of the caecal microflora on pancreatic enzymes (proteases, amylase (EC3.2.1.l), lipase (EC3.1.1.3)) and on colonic metabolites (NH3, urea, short-chain fatty acids). Germ-free and conventional male Fischer rats were fed for 3 weeks with a diet containing 220 or 450 g protein/kg provided as a mixture of fish concentrate and soyabean isolate. The excretion of NH3, and the pH were specifically increased by the high-protein diet in the germ-free rats. The higher production of isobutyrate, valerate and isovalerate in conventional rats fed on the high-protein diet reflected a high bacterial proteolytic activity since these short-chain fatty acids are specific indicators of this activity. The microflora hydrolysed urea to NH3and maintained the pH at neutrality whatever the amount of protein in the diet since there were changes in germ-free rats but not in conventional ones. In germ-free rats, amylase, trypsin (EC3.4.21.4), elastase (EC3.4.21.36) and carboxypeptidase A (EC3.4.17.1) specific activities were significantly lower than in conventional rats. The adaptation of the pancreas to the 450 g protein/kg diet was not impaired by the bacterial status except for the specific activity of chymotrypsin (EC3.4.21.1) which was more increased by this diet in germ-free than in conventional rats. Moreover, the specific activity of lipase increased only in conventional rats fed on the 450g protein/kg diet. In conclusion, we observed a relationship between the enzyme content of the pancreas and the presence or absence of the caecal microflora suggesting that bacterial fermentation influences pancreatic function.

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