Small Intestinal Inflammation Research Articles

Celecoxib and rofecoxib have different effects on small intestinal ischemia/reperfusion injury in rats

IntroductionIntestinal ischemia/reperfusion (I/R) injury is associated with high mortality and there is an unmet need for novel therapies. The intestinal expression of cyclooxygenase-2 (COX-2) increases rapidly after mesenteric I/R, but it is still a question of debate whether selective COX-2 inhibitors can mitigate I/R-induced gut injury. Here we aimed to compare the effect of celecoxib and rofecoxib, two selective COX-2 inhibitors, on intestinal I/R-induced injury in rats.MethodsWistar rats were treated with celecoxib (10 and 100 mg/kg), rofecoxib (5 and 50 mg/kg), or vehicle for 8 days via gavage and then were subjected to sham operation or mesenteric I/R. Small intestinal inflammation and tissue damage were assessed by histology and quantification of inflammatory and tight junction proteins. The intestinal activity of COX enzymes was determined by a COX activity assay.ResultsThe higher dose of celecoxib reduced the I/R-associated increase in inflammatory mediators (myeloperoxidase, pentraxin 3, COX-2, interleukin-1β) and loss of tight junction proteins (claudin-1, occludin), whereas the lower dose of celecoxib was only marginally effective. However, even high-dose celecoxib failed to prevent the histological injury of the mucosa. In contrast to celecoxib, rofecoxib did not affect intestinal inflammation and injury at any of the tested doses. Neither celecoxib nor rofecoxib affected the I/R-induced changes of HO-1 and PPAR-γ, known off-targets of COX-inhibitors, but celecoxib increased the I/R-induced elevation of Bax/Bcl-2, a marker of apoptosis, whereas rofecoxib reduced the elevation of phospho-Akt. Importantly, high-dose celecoxib, but not rofecoxib, has already reduced intestinal COX-1 activity.ConclusionOur study provides evidence for the higher anti-inflammatory efficacy of celecoxib compared to rofecoxib in mesenteric I/R injury, which is likely due to its lower selectivity for COX-2. However, even high-dose celecoxib was unable to reduce the mucosal damage. Our results suggest that selective COX-2 inhibitors have only limited therapeutic value in intestinal I/R injury.

Short-peptide-based enteral nutrition affects rats MDP translocation and protects against gut-lung injury via the PepT1-NOD2-beclin-1 pathway in vivo.

Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.

A case of small intestine inflammation after administration of an immune checkpoint inhibitor

A case of small intestine inflammation after administration of an immune checkpoint inhibitor

Utilizing Telemedicine Applications in Celiac Disease and Other Gluten-Free-Diet-Dependent Conditions: Insights from the COVID-19 Pandemic.

Globally, approximately 1.4% of people have celiac disease (CD), induced by gluten sensitivity. If left untreated, it causes small intestinal inflammation and villous atrophy, which can result in failure to thrive, anemia, osteoporosis, malabsorption, and even malignancy. The only treatment option available is a gluten-free diet (GFD). Few studies have looked at the role and perception of telehealth in relation to CD and selective nutrition both before and after the COVID-19 pandemic. Our goal was to screen and investigate the research conducted both before and after the COVID-19 pandemic concerning the utilization of telehealth applications and solutions in CD and other GFD-dependent circumstances. We employed a narrative review approach to explore articles that were published in scholarly journals or organizations between the years 2000 and 2024. Only English-language publications were included. PubMed and Google Scholar searches were mainly conducted using the following keywords: telemedicine, telehealth, telecare, eHealth, m-health, COVID-19, SARS-CoV-2, celiac disease, and gluten-free diet (GFD). Manual searches of the references in the acquired literature were also carried out, along with the authors' own personal contributions of their knowledge and proficiency in this field. Only a few studies conducted prior to the COVID-19 outbreak examined the viewpoints and experiences of adult patients with CD with relation to in-person clinic visits, as well as other options such as telehealth. The majority of patients believed that phone consultations were appropriate and beneficial. Video conferencing and telemedicine became more popular during the COVID-19 pandemic, demonstrating the effectiveness of using these technologies for CD on a global basis. In recent years, urine assays for gluten identification have become accessible for use at home. These tests could be helpful for CD monitoring with telemedicine assistance. The extended knowledge gathered from the COVID-19 pandemic is expected to complement pre-COVID-19 data supporting the usefulness of telemedicine even after the emergent pandemic, encouraging its wider adoption in standard clinical practice. The monitoring and follow-up of CD patients and other GFD-dependent conditions can greatly benefit from telemedicine.

Astragaloside IV ameliorates indomethacin-induced intestinal inflammation in rats through inhibiting the activation of NLRP3 inflammasome

The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause significant intestinal alteration and inflammation and lead to the occurrence of inflammatory diseases resembling duodenal ulcers. Astragaloside IV (AS-IV) is a glycoside of cycloartane-type triterpene isolated from the dried root of Astragalus membranaceus (Fisch.) Bge. (family Fabaceae), and has been used for ameliorating the NSAID-induced inflammation in the small intestine. The present study aimed to investigate the effects of AS-IV on indomethacin (IND)-induced inflammation in the small intestine of rats and its underlying mechanisms. Hematoxylin-eosin (H&E) staining, transmission and scanning electron microscopy were carried out to observe the surface morphology and ultrastructure of the small intestinal mucosa. Immunofluorescence and ELISA tests were employed to detect the expressions of NLRP3, ASC, caspase-1, and NF-κB proteins, as well as inflammatory factors IL-1β and IL-18, to uncover potential molecular mechanisms responsible for mitigating small intestinal inflammation. The results demonstrated that AS-IV significantly decreased the ulcer index, improved the surface morphology and microstructure of the small intestinal mucosa, and increased mucosal blood flow. Molecular docking revealed a strong and stable binding capacity of AS-IV to NLRP3, ASC, caspase-1, and NF-κB proteins. Further experimental validation exhibited that AS-IV markedly decreased levels of IL-1β and IL-18, and inhibited the protein expression of NLRP3, ASC, caspase-1, and NF-κB. Our data demonstrate that AS-IV ameliorates IND-induced intestinal inflammation in rats by inhibiting the activation of NLRP3 inflammasome and reducing the release of IL-1β and IL-18, thereby representing a promising therapy for IND-induced intestinal inflammation.

A microbiota derived metabolite and pediatric celiac disease pathogenesis

Abstract Celiac Disease (CD) is an autoimmune condition triggered by gluten ingestion and defined by small intestine inflammation leading to villous atrophy in genetically predisposed individuals. 20-40% of the general population possess the predisposing HLA-DQ2 or HLA-DQ8 alleles, however only 1-2% of the population develops CD, indicating that there are additional environmental factors at play in the pathogenesis of the disease. In a prospective cohort study using fecal and plasma samples from children at ages 2.5 and 5 years, before the onset of celiac disease (CD progressors), we found that CD progressors have an altered gut microbiome, plasma metabolome and cytokine profile years before diagnosis. IgA sequencing revealed an increased IgA response and unique microbial targets of IgA. One metabolite increased in CD progressors is taurodeoxycholic acid (TDCA), a secondary bile acid produced by gut microbes. Treating C57BL/B6 mice with TDCA caused villous atrophy as well as upregulated CD4+T-cells in intraepithelial lymphocytes and natural killer cells in the lamina propria (LP). TDCA increased the expression of Qa-1 and NKG2D on T-cells. The DQ8-Dd-villin-IL-15tg mouse model of CD possesses the predisposing HLA-DQ8 molecule and overexpresses IL-15 in the LP. Treating these mice with TDCA caused the villi/crypt ratio to decrease in the treatment group of pooled villi. Our results indicate that TDCA and TDCA-producing bacteria could potentially contribute to the pathogenesis of CD.

Comparing the Effects of Anti-TNF Agent and Ustekinumab on Small Bowel Inflammation in Crohn’s Disease: Inverse Probability Weighting With Stabilized Weights of Propensity Scores

Abstract Background Endoscopic mucosal healing serves as a critical predictor for achieving long-term remission in Crohn’s disease treatment. Recent data indicate that the effectiveness of healing varies based on the location of gastrointestinal inflammation. Additionally, reports suggest that antitumor necrosis factor-α (anti-TNF-α) agents exhibit reduced efficacy in treating small intestinal inflammation compared to colorectal inflammation. Conversely, limited research exists regarding the impact of the anti-IL12/23 agent ustekinumab (UST) on small intestinal inflammation. This study aimed to compare the effects of anti-TNF-α agents and UST on small intestinal inflammation using propensity score analysis. Methods This retrospective observational study involved 70 patients with Crohn’s disease who had inflammation in the small intestine and had initiated treatment with either anti-TNF agents or UST between March 2015 and August 2021. Endoscopic findings were evaluated before treatment commencement and at 1–2 years post-treatment initiation. The propensity score was employed to compare the efficacy of TNF agents and UST on small bowel inflammation. Results Ustekinumab exhibited greater improvement in the small intestinal endoscopy score than anti-TNF-α antibodies according to the propensity score analysis (inverse probability weighting; P = .0448). However, no significant disparity was observed in the overall improvement of endoscopic scores between UST and anti-TNF-α antibodies (P = .5938). Conclusions This study suggests that UST might be more effective than anti-TNF-α agents in treating small intestinal inflammation in Crohn’s disease.

Evaluation of Ki-67, goblet cell and MUC2 mucin RNA expression in dogs with lymphoplasmacytic and granulomatous colitis

Intestinal mucus barrier disruption may occur with chronic inflammatory enteropathies. The lack of studies evaluating mucus health in dogs with chronic colitis arises from inherent challenges with assessment of the intestinal mucus layer. It is therefore unknown if reduced goblet cell (GBC) numbers and/or mucin 2 (MUC2) expression, which are responsible for mucus production and secretion, correlate with inflammation severity in dogs with granulomatous colitis (GC) or lymphocytic-plasmacytic colitis (LPC). It is undetermined if Ki-67 immunoreactivity, which has been evaluated in dogs with small intestinal inflammation, similarly correlates to histologic severity in GC and LPC. Study objectives included comparing Ki-67 immunoreactivity, GBC population and MUC2 expression in dogs with GC, LPC and non-inflamed colon; and exploring the use of ribonucleic acid (RNAscope®) in-situ hybridization (ISH) to evaluate MUC2 expression in canine colon. Formalin-fixed endoscopic colonic biopsies were obtained from 48 dogs over an eight-year period. A blinded pathologist reviewed all biopsies. Dogs were classified into the GC (n=19), LPC (n=19) or no colitis (NC) (n=10) group based on final histopathological diagnosis. Ki-67 immunohistochemistry, Alcian-Blue/PAS staining to highlight GBCs, and RNAscope® ISH using customized canine MUC2-targeted probes were performed. At least five microscopic fields per dog were selected to measure Ki-67 labelling index (KI67%), GBC staining percentage (GBC%) and MUC2 expression (MUC2%) using image analysis software. Spearman’s correlation coefficients were used to determine associations between World Small Animal Veterinary Association histologic score (WHS) and measured variables. Linear regression models were used to compare relationships between WHS with KI67%, GBC%, and MUC2%; and between GBC% and MUC2%. Median WHS was highest in dogs with GC. Median KI67% normalised to WHS was highest in the NC group (6.69%; range, 1.70–23.60%). Median GBC% did not correlate with colonic inflammation overall. Median MUC2% normalised to WHS in the NC group (10.02%; range, 3.05–39.09%) was two- and three-fold higher than in the GC and LPC groups respectively. With increased colonic inflammation, despite minimal changes in GBC% overall, MUC2 expression markedly declined in the LPC group (-27.4%; 95%-CI, −49.8, 5.9%) and mildly declined in the GC and NC groups. Granulomatous colitis and LPC likely involve different pathways regulating MUC2 expression. Decreased MUC2 gene expression is observed in dogs with chronic colitis compared to dogs without colonic signs. Changes in MUC2 expression appear influenced by GBC activity rather than quantity in GC and LPC.

Effect of chronic stress on gel-forming mucins in the small intestine of BALB/c mice.

Intestinal homeostasis involves the collaboration of gut barrier components, such as goblet cells and IgA-microbiota complexes, that are under the control of stress that promotes inflammatory responses addressed primarily in the colon. The aim of this study was to evaluate the effect of stress on mucins, goblet cells, and proinflammatory parameters in the proximal and distal regions of the small intestine. A group (n = 6) of female 8-week-old BALB/c mice underwent board immobilization stress (2 h per day for 4 days) and were sacrificed with isoflurane. Samples from proximal and distal small segments were collected to analyze the following: 1) goblet cells stained with periodic acid-Schiff (PAS) and with alcian blue (AB) to visualize histologically neutral and acidic mucins, respectively; 2) IgA-microbiota complexes identified by flow cytometry in intestinal lavages; and 3) MUC2, MUC5AC, and IL-18 mRNA levels in whole mucosal scrapings by reverse transcription-qPCR. Regarding the unstressed group, in the proximal region of small intestine both PAS+ and AB+ goblet cells were unchanged; however, MUC5AC and IL-18 mRNA levels were increased, and the percentage of IgA-microbiota complexes was reduced. In the distal segment, the number of PAS+ goblet cells was increased, whereas the number of AB+ goblet cells was reduced and did not affect the remaining parameters. The data suggest that stress induces inflammation in the proximal small intestine; these findings may provide an experimental reference for human diseases that may affect the proximal small intestine, such as Crohn's disease, in which stress contributes to the progression of intestinal inflammation or relapse.

MSCs mediate long-term efficacy in a Crohn’s disease model by sustained anti-inflammatory macrophage programming via efferocytosis

Mesenchymal stem cells (MSCs) are novel therapeutics for the treatment of Crohn’s disease. However, their mechanism of action is unclear, especially in disease-relevant chronic models of inflammation. Thus, we used SAMP-1/YitFc (SAMP), a chronic and spontaneous murine model of small intestinal inflammation, to study the therapeutic effects and mechanism of action of human bone marrow-derived MSCs (hMSC). hMSC dose-dependently inhibited naïve T lymphocyte proliferation via prostaglandin E2 (PGE2) secretion and reprogrammed macrophages to an anti-inflammatory phenotype. We found that the hMSCs promoted mucosal healing and immunologic response early after administration in SAMP when live hMSCs are present (until day 9) and resulted in a complete response characterized by mucosal, histological, immunologic, and radiological healing by day 28 when no live hMSCs are present. hMSCs mediate their effect via modulation of T cells and macrophages in the mesentery and mesenteric lymph nodes (mLN). Sc-RNAseq confirmed the anti-inflammatory phenotype of macrophages and identified macrophage efferocytosis of apoptotic hMSCs as a mechanism that explains their long-term efficacy. Taken together, our findings show that hMSCs result in healing and tissue regeneration in a chronic model of small intestinal inflammation and despite being short-lived, exert long-term effects via sustained anti-inflammatory programming of macrophages via efferocytosis.

Pathomorphological changes in monieziosis of goats

The article describes the state of the body, changes in the mucous membranes, subcutaneous tissue, the appearance of blood, internal organs, lymph nodes, integumentary organs, changes in the stomach and intestines of goats that died due to monieziosis in natural conditions (spontaneously). As a result of the mechanical, toxic and biological effects of moniezia in the digestive organs, especially in the intestines, deep and complex changes have been studied, such as alterative, exudative and immunopathological, dystrophic, necrotic, catarrhal-hemorrhagic. In the mucous membranes of the small intestine, acute and chronic inflammation, hemorrhage, hemorrhagic infarction, intussusception, and intoxication were detected. A pathological examination revealed that these changes in the body of goats consist of hemodynamic and necrotic processes. The article presents histological changes in the parenchymal organs of goats with monieziosis. Hyperemia of the sinusoidal capillaries of the liver, hemorrhages, cardiac destrophy, disquamation, lobar pneumonia, and hemorrhages in the spleen pulp were determined. The article provides information about histiological changes in the digestive organs: abomasum, rumen, mesh and booklet, small and large intestines, in their lymph nodes - fibrinoid dystrophy, necrosis, thrombosis, acute inflammation, destruction of the endothelium, embolism, decomplexation of extravasation, desquamation, neutrophil infiltration with monieziosis of goats.

Unveiling the Link: A Comprehensive Narrative Review of the Relationship Between Type 1 Diabetes Mellitus and Celiac Disease.

Type 1 diabetes mellitus (T1DM) is an autoimmune condition with a genetic predisposition. It has underlying autoimmune destruction of the pancreatic cells that produce insulin. It is often accompanied by other autoimmune conditions. This article focuses on celiac disease (CD), also an autoimmune disease. It is caused by gluten exposure. Both these conditions have genetic predisposing factors. Apart from the genetic background, aberrant small intestine immune response, inflammation, and different grades of enteropathy present in T1DM and CD are the same. With a mean frequency of 8%, the CD frequency of T1DM ranges from 3 to 16%. All T1DM patients should undergo serological testing for CD using antibodies to tissue transglutaminase at the time of T1DM onset. Individuals with T1DM and those accompanied by CD must follow a diet with no gluten. To outline the steps that can avert the development of these disorders and reduce the morbidity of the affected people, a complete understanding of the intricate pathophysiology of T1DM and its connection to CD has been undertaken in this review. The use of resources, such as PubMed and Google Scholar, has made this possible.

Characterization of gastrointestinal inflammatory cell type in equine glandular gastric disease.

To compare small intestinal inflammation with gastric inflammation in horses with and without equine gastric glandular disease (EGGD), we evaluated endoscopic, macroscopic, and microscopic findings of the glandular stomach and microscopic findings of the small intestine. 36 horses. Horses underwent endoscopy and were scored for EGGD. After euthanasia, stomachs were collected and macroscopically evaluated. Normal pyloric mucosa, glandular lesions, and small intestinal (duodenum, mid-jejunum, and ileum) samples were collected and processed for microscopic examination. Cellular infiltrate was scored. Immunohistochemistry (CD3, CD20, and Iba-1) was performed on the ventral pylorus and small intestine of horses with mild to moderate lymphoplasmacytic infiltrate. A Spearman's correlation coefficient was used to evaluate the relationship of EGGD grade with gastric glandular inflammation, and the relationships of cellular infiltrate type and severity among glandular stomach, duodenum, jejunum, and ileum. Gastrointestinal inflammation was common, with gastric inflammatory infiltrate identified in 92%, duodenal inflammatory infiltrate in 83%, jejunal inflammatory infiltrate in 92%, and ileal inflammatory infiltrate in 92% of horses. Endoscopic evidence of gastric disease (hyperemia or EGGD grade ≥ 2/4) was not associated with the presence or severity of duodenal, jejunal, or ileal inflammation. Gastric lymphoplasmacytic inflammation grade ≥ 2 was associated with duodenal lymphoplasmacytic inflammation grade ≥ 2. This was a convenience sample of horses presenting for euthanasia. Medical history (including deworming history) was unknown. Gastric lymphoplasmacytic inflammation is associated with duodenal lymphoplasmacytic inflammation but not more distal small intestinal inflammation. Intestinal inflammation is not associated with endoscopic findings (hyperemia or EGGD grade ≥ 2/4).

Paneth cells protect intestinal stem cell niche to alleviate deoxynivalenol-induced intestinal injury

Deoxynivalenol (DON) is a common toxin in grains and feeds, and DON exposure triggers severe small intestinal injury and inflammation, which harms the health of humans and livestock. DON treatment leads to a decrease in Paneth cells, whereas the role of Paneth cells in DON-induced intestinal injury is poorly understood. We utilized dithizone (40 mg/kg) to keep murine Paneth cell number at a low level. The results showed that dithizone-mediated long-term disruption of Paneth cells aggravated intestinal injury, intestinal stem cell (ISC) loss, and microbiota disorder in DON (2 mg/kg)-treated mice. Unexpectedly, the number of goblet cells and proliferative cells was boosted in mice treated with dithizone and DON. After dithizone and DON treatments, the Firmicutes/Bacteroidetes (F/B) ratio was reduced, and the increased abundance of Dubosiella and the decreased abundance of Lactobacillus were observed in mice. The functional recovery of Paneth cells by lysozyme (200 U/day) supplementation improved intestinal injury and ISC loss in mice after DON challenge. In addition, lysozyme also promoted the growth and ISC activity of intestinal organoids. Taken together, these results demonstrate the protective role of Paneth cells in DON-induced intestinal injury. Our study raises a novel target, Paneth cell, for the treatment of DON exposure.

Chia Phenolic Extract Appear to Improve Small Intestinal Functionality, Morphology, Bacterial Populations, and Inflammation Biomarkers In Vivo (Gallus gallus).

Phenolic compounds can act as a substrate for colonic resident microbiota. Once the metabolites are absorbed and distributed throughout the body, they can have diverse effects on the gut. The objective of this study was to evaluate the effects of the intra-amniotic administration of a chia phenolic extract on intestinal inflammation, intestinal barrier, brush border membrane functionality, intestinal microbiota, and morphology in vivo (Gallus gallus model). Cornish-cross fertile broiler eggs, at 17 days of embryonic incubation, were separated into groups as follows: non-injected (NI; this group did not receive an injection); 18 MΩ H2O (H2O; injected with ultrapure water), and 10 mg/mL (1%) chia phenolic extract (CPE; injected with phenolic extract diluted in ultrapure water). Immediately after hatch (21 days), chickens were euthanized and their small intestine, cecum, and cecum content were collected and analyzed. The chia phenolic extract reduced the tumor necrosis factor-alpha (TNF-α) and increased the sucrose isomaltase (SI) gene expression, reduced the Bifidobacterium and E. coli populations, reduced the Paneth cell diameter, increased depth crypt, and maintained villus height compared to the non-injected control group. Chia phenolic extract may be a promising beneficial compound for improving intestinal health, demonstrating positive changes in intestinal inflammation, functionality, microbiota, and morphology.

Lycopene alleviates food allergy by modulating the PI3K/AKT pathway in peanut-sensitized BALB/c mice

Food allergies, which lead to life-threatening acute symptoms, are considered an important public health problem. Therefore, it is essential to develop efficient preventive and treatment measures. We developed a crude peanut protein extract (PPE)–induced allergy mouse model to investigate the effects of lycopene on peanut allergy. Mice were divided into four groups: 5 mg/kg lycopene, 20 mg/kg lycopene, no treatment, and control groups. Serum inflammatory factors were detected using enzyme-linked immunosorbent assay. In addition, pathology and immunohistochemistry analyses were used to examine the small intestine of mice. We found that lycopene decreased PPE-specific immunoglobulin E (IgE) and IL-13 levels in the serum, relieved small intestine inflammation, attenuated the production of histamine and mouse mast cell protease-1, and downregulated PI3K and AKT1 expression in the small intestine tissues of mice allergic to peanuts. Our results suggest that lycopene can ameliorate allergy by attenuating the PI3K/AKT pathway and the anaphylactic reactions mediated by PPE-specific IgE.

Microfluidics-Enabled Nanovesicle Delivers CD47/PD-L1 Antibodies to Enhance Antitumor Immunity and Reduce Immunotoxicity in Lung Adenocarcinoma.

The CD47/PD-L1 antibodies combination exhibits durable antitumor immunity but also elicits excessive immune-related adverse events (IRAEs) caused by the on-target off-tumor immunotoxicity, hindering their clinical benefits greatly. Here, a microfluidics-enabled nanovesicle using ultra-pH-sensitive polymer mannose-poly(carboxybetaine methacrylate)-poly(hydroxyethyl piperidine methacrylate) (Man-PCB-PHEP) is developed to deliver CD47/PD-L1 antibodies (NCPA) for tumor-acidity-activated immunotherapy. The NCPA can specifically release antibodies in acidic environment, thereby stimulating the phagocytosis of bone marrow-derived macrophages. In mice bearing Lewis lung carcinoma, NCPA shows significantly improved intratumoral CD47/PD-L1 antibodies accumulation, promoted tumor-associated macrophages remodeling to antitumoral status, and increased infiltration of dendritic cells and cytotoxic T lymphocytes, resulting in more favorable treatment effect compared to those of free antibodies. Additionally, NCPA also shows less IRAEs, including anemia, pneumonia, hepatitis, and small intestinal inflammation in vivo. Altogether, a potent dual checkpoint blockade immunotherapy utilizing NCPA with enhanced antitumor immunity and reduced IRAEs is demonstrated.

Analysis of Circulating Food Antigen-Specific T-Cells in Celiac Disease and Inflammatory Bowel Disease.

To demonstrate and analyze the specific T-cell response following barrier disruption and antigen translocation, circulating food antigen-specific effector T-cells isolated from peripheral blood were analyzed in patients suffering from celiac disease (CeD) as well as inflammatory bowel disease (IBD). We applied the antigen-reactive T-cell enrichment (ARTE) technique allowing for phenotypical and functional flow cytometric analyses of rare nutritional antigen-specific T-cells, including the celiac disease-causing gliadin (gluten). For CeD, patient groups, including treatment-refractory cases, differ significantly from healthy controls. Even symptom-free patients on a gluten-free diet were distinguishable from healthy controls, without being previously challenged with gluten. Moreover, frequency and phenotype of nutritional antigen-specific T-cells of IBD patients directly correlated to the presence of small intestinal inflammation. Specifically, the frequency of antigen specific T-cells as well as pro-inflammatory cytokines was increased in patients with active CeD or Crohn's disease, respectively. These results suggest active small intestinal inflammation as key for the development of a peripheral food antigen-specific T-cell response in Crohn's disease and celiac disease.

Study on the involvement of Zinc in homeostasis under intestinal Inflammation

Background & Aim: Zinc is one of the essential trace elements, and adequate amounts of zinc are crucial for good health. It is thought that zinc is absorbed primarily in the small intestine and also plays an important role in maintaining intestinal homeostasis. Small intestine is a key organ involved in digestion/absorption and is also sensitive to intestinal bacteria and easily inflamed. Alkaline phosphatase (ALP), which has zinc as its active center, detoxifies lipopolysaccharide and is thought to be involved in the suppression of small intestinal inflammation. In this study, we investigated the role of zinc in small intestinal inflammation using a mouse model, as well as the transporters ZIP4 and ZIP14, which are involved in ALP and zinc absorption. Materials & Methods: Male ICR mice were used. Indomethacin (IM, 12 mg/kg s.c.) was administered to mice to induce small intestinal inflammation. Four days prior to IM administration, zinc sulfate heptahydrate (Zn) was administered twice daily for 6 days. Forty-eight hours after IM administration, the animals were sacrificed and the lesion area was measured. Hematoxylin and eosin staining was performed. Myeloperoxidase (MPO) activity in the ileum was measured as an indicator of the degree of inflammation. ZIP4 and ZIP14 mRNA expression levels were examined by RT-PCR. ALP activity of the ileal was examined. IEC-6 cells, a rat small intestinal epithelial cell line, were seeded in 96-well plates, and Zn was applied 24 hours after seeding, and IM was added 24 hours after seeding. Cell viability was measured 24 hours after the addition of IM. Results: After administration of IM, bloody stools were observed from 24 hours after administration. At 48 hours after IM administration, disruption of villi structure and shortening of small intestine length were observed in the jejunum and ileum, and MPO activity was significantly increased. ZIP4 and ZIP14 mRNA expression levels were decreased in the small intestine 48 hours after IM treatment, and ALP activity was increased compared to the Vehicle group. On the other hand, pretreatment with Zn suppressed the occurrence of small intestinal inflammation, and the disruption of small intestinal villi structure was weak. The increase in MPO activity induced by IM tended to be suppressed by Zn pre-administration. ZIP4 and ZIP14 mRNA expression in Zn pre-administration group was same as in the IM alone group, and ALP activity was higher than in the IM alone group. IM treatment of IEC-6 also decreased cell viability in a concentration-dependent manner, which was inhibited by pretreatment with Zn in a concentration-dependent manner. Conclusion: These results suggest that zinc is effective in preventing the occurrence of NSAID-induced small intestinal inflammation. ZIP4 and ZIP14 are normally highly expressed in the intestinal epithelium and contribute greatly to zinc absorption, but the amount of zinc absorption may be decreased during inflammation induc University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glutamate alliviate the intestinal damage caused by chemotherapeutic agents

Background & Aim: 5-fluorouracil (5-FU), a type of anticancer drug, induces enteritis with diarrhea in high frequency and significantly reduces the quality of life of patients. Though inhibition of cell growth, induction of apoptosis, and changes in the intestinal microflora have been reported in the pathogenesis of 5-FU-induced enteritis, efficient treatment and prevention have not yet been established. In recently years, the usefulness of amino acids for various gastrointestinal disorders has been reported. Glutamate is the most abundant nonessential amino acid in the diet and is involved in the regulation and maintenance of function of gastrointestinal tract. The purpose of this study is to examine the protective effect of glutamate against 5-FU-induced small intestinal inflammation and to propose new targets for prevention and treatment. Materials & Methods: Intestinal mucositis was induced in male C57BL/6 mice by repeated administration of 5-FU (50 mg/kg, i.p.) for 6 days. glutamate was administered twice daily for 7 days prior to the start of 5-FU administration, and body weight and fecal status were measured daily during 5-FU administration. Twenty-four hours after the last dose of 5-FU, ileal tissue was removed for histological and immunohistological evaluation. The epithelial barrier function was also examined by using 4kDa FITC-labeled dextran (FD-4). Rat intestinal cell line (IEC-6) was also used to measure the epithelial barrier function. To analyze the factors that were involved in mucositis by 5-FU, Western blotting were performed. Results: Continuous administration of 5-FU was observed to cause weight loss and exacerbation of diarrhea. Administration of 5-FU shortened the villi, decreased the number of proliferative cells, induced apoptotic cells around the crypts, and reduced intestinal barrier function. Glutamate showed a protective effect against 5-FU-induced diarrhea, shortening of small intestinal villi, inhibition of proliferating cells and induction of apoptosis. The translocation of FD-4 into the blood was significantly increased by 5-FU, while glutamate had no significant effect. However, it clearly reduced FD-4 infiltration into ileal tissue. The effect of glutamate was associated with epithelial barrier function and the pretreatment of glutamate significantly recovered the decrease of epithelial electrical resistance by 5-FU. Moreover, glutamate inhibited the decrease of the expression of excitatory amino acid transporter 3 (EAAT3) by 5-FU. Conclusion: We conclude that glutamate prevents 5-FU-induced intestinal mucositis. It is suggested that glutamate improves epithelial damages caused by 5-FU through enhancing glutamate uptake and improves intestinal morphology and functions. Thus, glutamate may be helpful for preventing and treating intestinal mucositis during cancer chemotherapy. University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.