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Representative H&E-stained sections of the small intestine illustrate villous blunting with normal and altered villi from the duodenum and ileum (×100, scale bar 100 μm).
Source publication
Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models.
Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating interstudy comparisons. Sampl...
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Context 1
... interspersing in the epithelial cell layer of the crypt in terms of a cryptitis ( Figure 3A ) intensified to crypt abscesses where neu - trophils accumulate in the crypt lumen eventu- ally disrupting the crypt epithelium ( Figure 3B ). Erosions, i.e. the loss of surface epithelium with underlying inflammation where the epithe - lial defect reached the basement membrane presented itself mostly focal ( Figure 3C ). Scoring this feature especially depended upon the model used as indicated by the wide range of final score values ( Table 1 ). With a “first hit” from the outside erosion was even abundant at a value of 1 ( Table 2 ); erosion resulting from severe mucosal inflammation due to an inside event accompanied values of 4 ( Table 4 ). All changes reaching deeper than the surface epithelial cell layer were considered alterations in the overall mucosal architecture and graded from the presence of ulcerations, granulation tissue, irregular crypts or of crypt loss. Specifics like the ratio of villous length to crypt depth accounted for general anatomical differences along the whole small intestine ( Table 1 ). Ulcerations i.e. erosions exceeding to the sub- mucosa ( Figure 3D ) were occasionally covered by an exudate rich in iNOS + neutrophils ( Figure 3E ) or by granulocyte-fibrin eschar ( Figure 3F ). Connective tissue repair was the hallmark of granulation tissue underlying ulcerations ( Figure 3G ). It comprised new capillaries lined by CD31 + endothelial cells ( Figure 3H ), myofi - broblasts, iNOS + macrophages and neutrophils ( Figure 3I ) as well as lymphocytes and cell debris. Generally, crypt appearance throughout the intestine and the villous morphology within the small intestine defined a major level of mucosal architecture. Irregular crypts with vari- able diameters along the depth of single crypts or dilated crypts ( Figure 4A ), crypts that did not run parallel ( Figure 4B ), bifurcation at the base of the crypt ( Figure 4C , 4D ) that might extend to branched crypts ( Figure 4E ), to a mucosa com- pletely devoid of crypts ( Figure 4F , 4G ) or crypts herniated to the submucosa ( Figure 4H ) mar- ked mucosal histopathology. In the duodenum and jejunum, the villi are long with a villous-to- crypt length ratio on the order of 3:1 to 5:1, while in the ileum the villi are typically shorter ( Figure 5 ). Thus, progressive broadening and blunting of the villi up to complete loss of villous structures clearly indicated pathological chang- es. We found two degrees of villous blunting ( Figure 5 ) and villous atrophy sufficient to grade the severity. As for epithelial changes and the mucosal architecture, each model system had different key aspects regarding degree, quality, extent and depth that made overall generalization in terms of a single generalized scoring system using all criteria for each model not feasible. Our schemata propose maximum severity rated 4-5 from combined changes in all three catego- ries. Characteristic discontinuities in inflamma - tory cell infiltrates and intestinal architecture were best reflected by additive scores with a maximum of 6 or 8, relating to the well-estab- lished evaluation of DSS-induced colitis [11] . We methodically inspected widely used rele- vant murine IBD models according to the defined categories and criteria and suggested scoring schemata. Evaluating histomorphology from H&E stained sections grouped our models according to the initial step weakening the bar- rier rather than the exact nature of immune interactions in the whole processes of acute or chronic intestinal inflammation. “First hits” from the outside, the luminal side, induced his- topathological specifics that were comparable among each other but distinguishable from those models resulting from inside events, i.e. from imbalanced immune dispositions ( Table 2 , Supplementary Figure 1). Additionally, in line with representative tissue samples excised from the most affected organ, the most affected section should be ...
Context 2
... interspersing in the epithelial cell layer of the crypt in terms of a cryptitis ( Figure 3A ) intensified to crypt abscesses where neu - trophils accumulate in the crypt lumen eventu- ally disrupting the crypt epithelium ( Figure 3B ). Erosions, i.e. the loss of surface epithelium with underlying inflammation where the epithe - lial defect reached the basement membrane presented itself mostly focal ( Figure 3C ). Scoring this feature especially depended upon the model used as indicated by the wide range of final score values ( Table 1 ). With a “first hit” from the outside erosion was even abundant at a value of 1 ( Table 2 ); erosion resulting from severe mucosal inflammation due to an inside event accompanied values of 4 ( Table 4 ). All changes reaching deeper than the surface epithelial cell layer were considered alterations in the overall mucosal architecture and graded from the presence of ulcerations, granulation tissue, irregular crypts or of crypt loss. Specifics like the ratio of villous length to crypt depth accounted for general anatomical differences along the whole small intestine ( Table 1 ). Ulcerations i.e. erosions exceeding to the sub- mucosa ( Figure 3D ) were occasionally covered by an exudate rich in iNOS + neutrophils ( Figure 3E ) or by granulocyte-fibrin eschar ( Figure 3F ). Connective tissue repair was the hallmark of granulation tissue underlying ulcerations ( Figure 3G ). It comprised new capillaries lined by CD31 + endothelial cells ( Figure 3H ), myofi - broblasts, iNOS + macrophages and neutrophils ( Figure 3I ) as well as lymphocytes and cell debris. Generally, crypt appearance throughout the intestine and the villous morphology within the small intestine defined a major level of mucosal architecture. Irregular crypts with vari- able diameters along the depth of single crypts or dilated crypts ( Figure 4A ), crypts that did not run parallel ( Figure 4B ), bifurcation at the base of the crypt ( Figure 4C , 4D ) that might extend to branched crypts ( Figure 4E ), to a mucosa com- pletely devoid of crypts ( Figure 4F , 4G ) or crypts herniated to the submucosa ( Figure 4H ) mar- ked mucosal histopathology. In the duodenum and jejunum, the villi are long with a villous-to- crypt length ratio on the order of 3:1 to 5:1, while in the ileum the villi are typically shorter ( Figure 5 ). Thus, progressive broadening and blunting of the villi up to complete loss of villous structures clearly indicated pathological chang- es. We found two degrees of villous blunting ( Figure 5 ) and villous atrophy sufficient to grade the severity. As for epithelial changes and the mucosal architecture, each model system had different key aspects regarding degree, quality, extent and depth that made overall generalization in terms of a single generalized scoring system using all criteria for each model not feasible. Our schemata propose maximum severity rated 4-5 from combined changes in all three catego- ries. Characteristic discontinuities in inflamma - tory cell infiltrates and intestinal architecture were best reflected by additive scores with a maximum of 6 or 8, relating to the well-estab- lished evaluation of DSS-induced colitis [11] . We methodically inspected widely used rele- vant murine IBD models according to the defined categories and criteria and suggested scoring schemata. Evaluating histomorphology from H&E stained sections grouped our models according to the initial step weakening the bar- rier rather than the exact nature of immune interactions in the whole processes of acute or chronic intestinal inflammation. “First hits” from the outside, the luminal side, induced his- topathological specifics that were comparable among each other but distinguishable from those models resulting from inside events, i.e. from imbalanced immune dispositions ( Table 2 , Supplementary Figure 1). Additionally, in line with representative tissue samples excised from the most affected organ, the most affected section should be ...
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Citations
... After paraffin embedding, 5-μm-thick sections were cut and stained with H&E. Histological scoring was based on a previously described method (79). Briefly, H&E-stained cross sections of the descending colon tissue were scored microscopically in a blinded fashion on a scale from 0 to 4, based on the following histological criteria: 0, no change from normal tissue; 1, low level of inflammation with scattered infiltrating mononuclear cells (foci, 1 to 2); 2, moderate inflammation with multiple foci; 3, high level of inflammation with increased vascular density and marked wall thickening; and 4, maximal severity of inflammation with transmural leukocyte infiltration and loss of goblet cells. ...
... Next, quality-controlled samples were aligned to the human reference genome using the STAR aligner (78). Subsequently, featureCounts (79) was employed on the generated BAM files to produce a count table. This count table underwent further analysis using the DESeq2 (80) package in R. Additionally, KEGG pathway over-representation analysis was conducted separately for upregulated and downregulated genes, based on specific criteria (log2fold change <= -0.5 or >= 0.5 and a p-value less than 0.05), utilizing the clusterProfiler (81) package. ...
The pathophysiology of Inflammatory Bowel Disease (IBD) is significantly influenced by the decline in B regulatory (B10) cells, which produce IL-10. Therefore, it is important to identify the key genes and pathways that regulate the B10 cell generation in order to develop more effective therapies. Here, we have shown that one of the short chain fatty acid, butyrate regulates the expression of RNA binding protein, AUF1 which is responsible for increasing the half-life of p28 mRNA, coding for p28 protein which associates with overexpressed EBI3 and forms functional IL-27. This effect is mediated through AUF1 binding to 3-prime-UTR of IL-27p28 mRNA. As a consequence, IL-27 signals splenic CD19+CD5+ (B1a) cells but not CD19+CD23+ (B2) cells to polarize to B10 cells. We proved the importance of AUF1 and the sequential downstream players in unique cell penetrating morpholino induced AUF1 knockdown (AUF1-KD) in mice, establishing the roster of events in splenic B1a cells: butyrate-AUF1-IL-27-IL-10. We showed that there was a significant decrease in AUF1, IL-27 and IL-10 expression in the colon biopsy of IBD patients compared to non-IBD control. We have used DSS induced colitis in mice as a surrogate of IBD in human and showed the reduction in AUF1 in spleen and colon could be correlated with the decrease in IL-27 and B10 cells in spleen and mesenteric lymph nodes which were reversed with butyrate treatment. We further established AUF1 as the role player by showing adoptive transfer of butyrate stimulated B1a cells from wild type mice conferring protection against colitis while adoptive transfer of butyrate stimulated B1a cells from AUF1 KD mice failed to suppress the disease. Finally, we propose that butyrate driven B1a cells as a glimmer of new hope of therapeutic possibility against colitis.
... Histopathological analyses were performed in colonic ex vivo biopsies that had been fixed in 5% formalin and embedded in paraffin. 5-μm-thick sections were stained with hematoxylin and eosin (H&E), examined under light microscopy at 100-times magnification, and histopathological changes in the large intestines quantitatively assessed applying a defined histopathological score [72]: Score 0, intact epithelium, no inflammatory cell infiltrates. Score 1, minimal inflammatory cell infiltrates in the mucosa with intact epithelium. ...
Serious risks to human health are posed by acute campylobacteriosis, an enteritis syndrome caused by oral infection with the food-borne bacterial enteropathogen Campylobacter jejuni. Since the risk for developing post-infectious autoimmune complications is intertwined with the severity of enteritis, the search of disease-mitigating compounds is highly demanded. Given that benzoic acid is an organic acid with well-studied health-promoting including anti-inflammatory effects we tested in our present study whether the compound might be a therapeutic option to alleviate acute murine campylobacteriosis. Therefore, microbiota-depleted IL-10−/− mice were perorally infected with C. jejuni and received benzoic acid through the drinking water from day 2 until day 6 post-infection. The results revealed that benzoic acid treatment did not affect C. jejuni colonization in the gastrointestinal tract, but alleviated clinical signs of acute campylobacteriosis, particularly diarrheal and wasting symptoms. In addition, benzoic acid mitigated apoptotic cell responses in the colonic epithelia and led to reduced pro-inflammatory immune reactions in intestinal, extra-intestinal, and systemic compartments tested on day 6 post-infection. Hence, our preclinical placebo-controlled intervention trial revealed that benzoic acid constitutes a promising therapeutic option for treating acute campylobacteriosis in an antibiotic-independent fashion and in consequence, also for reducing the risk of post-infectious autoimmune diseases.
... The pathological changes were assessed under an Olympus BX51 microscope (Olympus Life Science, Waltham, MA, USA). The intestinal histological inflammation score was determined as described by Erben et al. (2014) [43]. Briefly, the histopathological score evaluation included the sum of two scores: Score 1 (0-3 points), related to the inflammatory cell infiltration (mucosa; mucosa and submucosa; or transmural), and Score 2 (0-3 points), related to the intestinal architecture (focal erosions; erosions and focal ulcerations; or erosions with extended ulcerations). ...
... The pathological changes were assessed under an Olympus BX51 microscope (Olympus Life Science, Waltham, MA, USA). The intestinal histological inflammation score was determined as described by Erben et al. (2014) [43]. Briefly, the histopathological score evaluation included the sum of two scores: Score 1 (0-3 points), related to the inflammatory cell infiltration (mucosa; mucosa and submucosa; or transmural), and Score 2 (0-3 points), related to the intestinal architecture (focal erosions; erosions and focal ulcerations; or erosions with extended ulcerations). ...
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... The mounted sections were deparaffinized and stained with hematoxylin and eosin. The tissue sections were viewed and photographed at 20× and 100× using brightfield microscopy with a digital Keyence BZ-X microscope (Itaska, IL, USA) and scored with a previously designed scoring system for chemicalinduced colitis [35]. Briefly, a score of 1-3 is assigned based on the severity and extent of inflammatory cells within each tissue layer. ...
... Scoring system used for evaluation of colon histology. Reprinted/adapted with permission from Ref.[35]. Copyright 2014, IJCEP. ...
Inflammation and oxidative stress are implicated in the pathogenesis of Crohn’s disease. Cerium oxide nanoparticle (CNP) conjugated to microRNA 146a (miR146a) (CNP-miR146a) is a novel compound with anti-inflammatory and antioxidative properties. We hypothesized that local administration of CNP-miR146a would improve colitis in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS) mouse model for Crohn’s disease by decreasing colonic inflammation. Balb/c mice were instilled with TNBS enemas to induce colitis. Two days later, the mice received cellulose gel enema, cellulose gel with CNP-miR146a enema, or no treatment. Control mice received initial enemas of 50% ethanol and PBS enemas on day two. The mice were monitored daily for weight loss and clinical disease activity. The mice were euthanized on days two or five to evaluate their miR146a expression, inflammation on histology, and colonic IL-6 and TNF gene expressions and protein concentrations. CNP-miR146a enema successfully increased colonic miR146a expression at 12 h following delivery. At the end of five days from TNBS instillation, the mice treated with CNP-miR146a demonstrated reduced weight loss, improved inflammation scores on histology, and reduced gene expressions and protein concentrations of IL-6 and TNF. The local delivery of CNP-miR146a in a TNBS mouse model of acute Crohn’s colitis dramatically decreased inflammatory signaling, resulting in improved clinical disease.
... Tissue morphology was observed using a microscope (B80i, Nikon Corporation, Tokyo, Japan) with image acquisition software. The histological scoring of the small intestine was determined based on epithelial lesions and inflammation infiltration, following the same criteria as previously reported [28]. ...
Background:
Infection with pathogenic bacteria during nonantibiotic breeding is one of the main causes of animal intestinal diseases. Oleanolic acid (OA) is a pentacyclic triterpene that is ubiquitous in plants. Our previous work demonstrated the protective effect of OA on intestinal health, but the underlying molecular mechanisms remain unclear. This study investigated whether dietary supplementation with OA can prevent diarrhea and intestinal immune dysregulation caused by enterotoxigenic Escherichia coli (ETEC) in piglets. The key molecular role of bile acid receptor signaling in this process has also been explored.
Results:
Our results demonstrated that OA supplementation alleviated the disturbance of bile acid metabolism in ETEC-infected piglets (P < 0.05). OA supplementation stabilized the composition of the bile acid pool in piglets by regulating the enterohepatic circulation of bile acids and significantly increased the contents of UDCA and CDCA in the ileum and cecum (P < 0.05). This may also explain why OA can maintain the stability of the intestinal microbiota structure in ETEC-challenged piglets. In addition, as a natural ligand of bile acid receptors, OA can reduce the severity of intestinal inflammation and enhance the strength of intestinal epithelial cell antimicrobial programs through the bile acid receptors TGR5 and FXR (P < 0.05). Specifically, OA inhibited NF-κB-mediated intestinal inflammation by directly activating TGR5 and its downstream cAMP-PKA-CREB signaling pathway (P < 0.05). Furthermore, OA enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating the expression of FXR (P < 0.05), thereby upregulating the expression of endogenous defense molecules in intestinal epithelial cells.
Conclusions:
In conclusion, our findings suggest that OA-mediated regulation of bile acid metabolism plays an important role in the innate immune response, which provides a new diet-based intervention for intestinal diseases caused by pathogenic bacterial infections in piglets.
... On day 8, mice were sacrificed and colons were collected for length measuring and H&E staining. The histological scoring scheme was based on the previous work (Table S5) [25]. ...
Background
Macrophages are key inflammatory immune cells that orchestrate the initiation and progression of autoimmune diseases. The characters of macrophage in diseases are determined by its phenotype in response to the local microenvironment. Ficolins have been confirmed as crucial contributors to autoimmune diseases, with Ficolin-2 being particularly elevated in patients with autoimmune diseases. However, whether Ficolin-A stimulates macrophage polarization is still poorly understood.
Methods
We investigated the transcriptomic expression profile of murine bone marrow-derived macrophages (BMDMs) stimulated with Ficolin-A using RNA-sequencing. To further confirm a distinct phenotype activated by Ficolin-A, quantitative RT-PCR and Luminex assay were performed in this study. Additionally, we assessed the activation of underlying cell signaling pathways triggered by Ficolin-A. Finally, the impact of Ficolin-A on macrophages were investigated in vivo through building Collagen-induced arthritis (CIA) and Dextran Sulfate Sodium Salt (DSS)-induced colitis mouse models with Fcna-/- mice.
Results
Ficolin-A activated macrophages into a pro-inflammatory phenotype distinct to LPS-, IFN-γ- and IFN-γ + LPS-induced phenotypes. The transcriptomic profile induced by Ficolin-A was primarily characterized by upregulation of interleukins, chemokines, iNOS, and Arginase 1, along with downregulation of CD86 and CD206, setting it apart from the M1 and M2 phenotypes. The activation effect of Ficolin-A on macrophages deteriorated the symptoms of CIA and DSS mouse models, and the deletion of Fcna significantly alleviated the severity of diseases in mice.
Conclusion
Our work used transcriptomic analysis by RNA-Seq to investigate the impact of Ficolin-A on macrophage polarization. Our findings demonstrate that Ficolin-A induces a novel pro-inflammatory phenotype distinct to the phenotypes activated by LPS, IFN-γ and IFN-γ + LPS on macrophages.
... IL-1ß forward primer sequence was T G C C A C C T T T T G A C A G T G A T G and reverse primer was A T G T G C T G C T G C G A G A T T T G. Tissue samples for histology were fixed in 10% neutral-buffered formalin (Merck), and paraffinembedded. Sections were stained with hematoxylin and eosin (H&E, Merck) and classified by a pathologist without prior knowledge of treatment status of individual mouse according to the classification published by Erben et al. [31], Table S4. BX43 microscope equipped with CCD camera was employed (Olympus, Tokio, Japan). ...
Background
Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target.
Methods
An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking.
Results
We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells.
Conclusion
We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.
... It was drained and embedded in paraffin and cut into sections (3 μm). The inflammation score with H&E staining was based on the method of Erben et al. (36). Briefly, the density of leukocytes in the lamina propria was classified as 1 (<10%), 2 (10-25%), 3 (26-50%), and 4 (>50%). ...
Background
Allergic Asthma is a disease presenting various endotypes and no current therapies act curative but alleviate disease symptoms. Dietary interventions are gaining increasing importance in regulating immune responses. Furthermore, short chain fatty acids (SFCA), as the main products of dietary fiber’s fermentation by the gut bacteria, ameliorate the pathogenesis and disease burden of different illnesses including asthma. Nevertheless, the connection and crosstalk between the gut and lung is poorly understood.
Objective
In this work, the role of high fiber diet on the development of allergic asthma at baseline and after exacerbation of disease induced by respiratory viruses was investigated.
Methods
Hereby, SCFA in serum of asthmatic and non-asthmatic pre-school children before and after airway disease symptoms were analyzed. Moreover, the effect of high fiber diet in vivo in a murine model of house dust mite extract (HDM) induced allergic asthma and in the end in isolated lung and spleen cells infected ex vivo with Rhinovirus was analyzed.
Results
In this study, a decrease of the SCFA 3-Hydroxybutyric acid in serum of asthmatic children after symptomatic episodes at convalescent visit as compared to asthmatic and control children at baseline visit was observed. In experimental asthma, in mice fed with high fiber diet, a reduced lung GATA3 + Th2 type mediated inflammation, mucus production and collagen deposition and expression of Fc epsilon receptor Ia (FcεRIa) in eosinophils was observed. By contrast, the CD8+ memory effector T cells were induced in the lungs of asthmatic mice fed with high fiber diet. Then, total lung cells from these asthmatic mice fed with either standard food or with fiber rich food were infected with RV ex vivo. Here, RV1b mRNA was found significantly reduced in the lung cells derived from fiber rich food fed mice as compared to those derived from standard food fed asthmatic mice. Looking for the mechanism, an increase in CD8+ T cells in RV infected spleen cells derived from fiber rich fed asthmatic mice, was observed.
Conclusion
Convalescent preschool asthmatic children after a symptomatic episode have less serum ß-Hydroxybutyric acid as compared to control and asthmatic children at baseline visit. Fiber rich diet associated with anti-inflammatory effects as well as anti-allergic effects by decreasing Type 2 and IgE mediated immune responses and inducing CD8+ memory effector T cells in a murine model of allergic asthma. Finally, ex vivo infection with Rhinovirus (RV) of total lung cells from asthmatic mice fed with fiber rich food led to a decreased RV load as compared to mice fed with standard food. Moreover, spleen cells derived from asthmatic mice fed with fiber rich food induced CD8+ T cells after ex vivo infection with RV.
Clinical implications
Dietary interventions with increased content in natural fibers like pectins would ameliorate asthma exacerbations. Moreover, respiratory infection in asthma downregulated SCFA in the gut contributing to asthma exacerbations.
... Briefly, paraffin tissue slices (thickness, 5 µm) were deparaffinized with xylene, stained with hematoxylin and eosin (H&E), and observed through light microscopy (Axio Vision, Zeiss, Milan, Italy). The degree of inflammation on microscopic cross-sections of the colon was graded semiquantitatively from 0 to 4 as previously described by [18,19]; in particular, the morphological criteria were considered as described in Table 2 [19]. ...
... A shorter colon length and increased colon weight are considered as hallmarks of experimental colitis [18,25]. Our results revealed a significant reduction in colon length in mice given 4% DSS compared to the mice given water whereas no change in colon length was observed in mice given 5% DSS ( Figure 2A). ...
Inflammatory bowel disease (IBD) is a group of chronic disorders characterized by pain, ulceration, and the inflammation of the gastrointestinal tract (GIT) and categorized into two major subtypes: ulcerative colitis (UC) and Crohn’s disease. The inflammation in UC is typically restricted to the mucosal surface, beginning in the rectum and extending through the entire colon. UC patients typically show increased levels of pro-inflammatory cytokines, leading to intestinal epithelial apoptosis and mucosal inflammation, which impair barrier integrity. Chronic inflammation is associated with the rapid recruitment and inappropriate retention of leukocytes at the site of inflammation, further amplifying the inflammation. While UC can be managed using a number of treatments, these drugs are expensive and cause unwanted side effects. Therefore, a safe and effective treatment for UC patients is needed. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide and an analog of the endocannabinoid anandamine. PEA administration has been found to normalize intestinal GIT motility and reduce injury in rodents and humans. In the current study, we examined the efficacy of PEA encapsulated in phytosomes following oral administration in experimental ulcerative colitis. Here, we showed that PEA at a human-equivalent dose of 123 mg/kg (OD or BID) attenuated DSS-induced experimental colitis as represented by the reduction in clinical signs of colitis, reduction in gross mucosal injury, and suppression of leukocyte recruitment at inflamed venules. These findings add to the growing body of data demonstrating the beneficial effects of PEA to control the acute phase of intestinal inflammation occurring during UC.
... Immune response to Trichuris in wild versus laboratory mice Gut responsiveness score A 'gut responsiveness score' was derived based on variation in colonic crypt length, extent of inflammatory infiltrate, depth of inflammatory infiltrate, and goblet cell numbers per crypt in wild mice. We chose an alternative phrase to 'gut pathology score', standardly used in laboratory colitis models or human IBD samples [71,72], as we cannot ascertain whether a higher score is a pathological response in wild animals. Scoring systems have previously been deployed by ourselves in the context of whipworm infection [73] and experimental colitis [74]. ...
Laboratory model organisms have provided a window into how the immune system functions. An increasing body of evidence, however, suggests that the immune responses of naive laboratory animals may differ substantially to those of their wild counterparts. Past exposure, environmental challenges and physiological condition may all impact on immune responsiveness. Chronic infections of soil-transmitted helminths, which we define as establishment of adult, fecund worms, impose significant health burdens on humans, livestock and wildlife, with limited treatment success. In laboratory mice, Th1 versus Th2 immune polarisation is the major determinant of helminth infection outcome. Here we compared antigen-specific immune responses to the soil-transmitted whipworm Trichuris muris between controlled laboratory and wild free-ranging populations of house mice ( Mus musculus domesticus ). Wild mice harbouring chronic, low-level infections produced lower levels of cytokines in response to Trichuris antigen than laboratory-housed C57BL/6 mice. Wild mouse effector/memory CD4+ T cell phenotype reflected the antigen-specific cytokine response across the Th1/Th2 spectrum. Increasing worm burden was associated with body condition loss. However, local Trichuris -specific Th1/Th2 balance was positively associated with worm burden only in older wild mice. Thus, although the fundamental relationships between the CD4+ T helper cell response and resistance to T . muris infection are similar in both laboratory and wild M . m . domesticus , there are quantitative differences and age-specific effects that are analogous to human immune responses. These context-dependent immune responses demonstrate the fundamental importance of understanding the differences between model and natural systems for translating mechanistic models to ‘real world’ immune function.
