Small Intestinal Inflammation Research Articles

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.

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.

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.

Altered fecal and serum aromatic amino acids and transporters in small intestinal inflammation

Inflammatory Bowel Diseases (IBD) are characterized by chronic inflammation of the gastrointestinal tract. Emerging metabolomic studies show aromatic amino acids (AA) L-phenylalanine (Phe) and L-tryptophan (Trp) levels are increased in the feces of patients with active Crohn’s Disease (CD) and decreased in the serum of patients with active CD and Ulcerative Colitis (UC) when compared to healthy controls or patients in remission. Trp is the precursor to serotonin (5-HT), a neurotransmitter that regulates mood in the brain and gut homeostasis. The altered amino acid profile in IBD may contribute to malnutrition, oxidative stress, disruption of tight junctions, and pro-inflammatory signals such as increased nitric oxide synthases. A decrease in transport proteins, including the serotonin transporter (SERT, SLC6A4) involved in the NaCl-dependent reuptake of 5-HT, was also implicated in the pathophysiology of IBD. However, the mechanism underlying the altered aromatic amino acid profile in IBD remains unknown. We hypothesized that alteration of Phe and Trp in the feces and serum occurs by a decrease in their absorption via amino acid transporters located on the apical and/or basolateral sides of enterocytes. Methods: SAMP/YitFC (SAMP; spontaneous ileitis mouse model; M/F, 20wks), AKR/J (SAMP controls; M/F, 20wks), C57BL/6 (M, 6-10wks), TNFΔARE (chronic ileitis via elevated TNF levels; M, 6-10wks), and SERT KO mice (M, 8-12wks) were used. Fecal phenylalanine levels were determined using a phenylalanine detection kit (Sigma, MAK005). Serum amino acid levels from SERT KO mice were analyzed by LC-MS/MS. Results: Fecal phenylalanine levels were significantly increased in SAMP mice compared to the AKR control. The basolateral AA transporter MCT10 (SLC16A10) mRNA levels in the ileum were decreased by 36% (p<0.05) as compared to AKR with no changes in the apical AA transporter BOAT1 (SLC6A19).TNFΔARE mice had a reduction in mRNA levels of both AA transporters, BOAT1 and MCT10, in the ileum (52%, p<0.005, and 34% decrease, p<0.01, respectively, compared to WT). There was no change in AA transporter LAT1 (SLC7A5) in the ileum of SAMP and TNFΔARE mice compared to their controls. SAMP and TNFΔARE mice also exhibited significant decreases in the ileal SERT mRNA. We utilized SERT KO mice to examine if decreased SERT is implicated in altered amino acid levels. SERT deletion resulted in a significant decrease of Phe and Trp in serum by LC-MS/MS, as well as a significant reduction in mRNA levels of MCT10 by 36% (p<0.0328) compared to WT, and no change in BOAT1 and LAT1 in the ileum. Conclusion: These data demonstrate that intestinal inflammation and/or SERT deficiency results in an altered aromatic amino acid profile, possibly via the downregulation of MCT10 in the ileum. NIH/NIDDK and Crohn's and Colitis Foundation of America 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.

Video capsule endoscopy can identify occult luminal Crohn's disease in patients with isolated perianal fistulas.

Accurate tools to distinguish Crohn's disease (CD) from cryptoglandular disease in patients with perianal fistulas without detectable luminal inflammation on ileocolonoscopy and abdominal enterography (isolated perianal fistulas [IPF]) are lacking. We assessed the ability of video capsule endoscopy (VCE) to detect luminal inflammation in patients with IPF. We studied consecutive adults (>17 years) with IPF who were evaluated by VCE after a negative ileocolonoscopy and abdominal enterography between 2013 and 2022. We defined luminal CD by VCE as diffuse erythema, three or more aphthous ulcers, or a Lewis score greater than 135. We compared rates of intestinal inflammation in this cohort to age- and sex-matched controls without perianal fistulas who underwent VCE for other indications. We excluded persons with pre-existing IBD and exposure to non-steroidal anti-inflammatories drugs or immunosuppressive treatments. A total of 45 patients with IPF underwent VCE without complications. Twelve patients (26%) met our definition of luminal CD. Luminal CD was more common in patients with IPF than controls (26% vs. 3%; p < 0.01). Among patients with IPF, male sex (OR, 9.2; 95% CI (1.1-79.4), smoking (OR, 4.5; 95% CI, 0.9-21.2), abscess (OR, 6.3; 95% CI (1.5-26.8), rectal enhancement on MRI (OR, 9.0; 95% CI (0.8-99.3) and positive anti-microbial serology (OR, 7.1; 95% CI, 0.7-70.0) were more common in those with a positive VCE study. VCE detected small intestinal inflammation suggestive of luminal CD in approximately one quarter of patients with IPF. Larger studies are required to validate these findings.

Nutritional Management of Celiac Disease

Celiac disease (CD) is a chronic disease causing inflammation of the proximal small intestine that occurs in genetically predisposed individuals when they eat gluten which is a binding protein common in grains wheat, barley, and rye. The disease injury usually resolves when gluten is excluded from the diet. Although the injury will heal, the reaction to gluten is permanent and will recur with the reintroduction of gluten. The condition is surprisingly common, affecting as many as 1% of white populations. The consequences of the disease are predominantly those of malnutrition due to maldigestion and malabsorption, such as diarrhea, weight loss, and anemia. Symptoms caused by inflammation of the small intestine are also common. CD, although it is common and its pathology is well understood, frequently goes undiagnosed, probably because of the nonspecific or vague nature of many of the symptoms that occur. The cornerstone of treatment for CD is elimination of gluten from the diet. In most patients diagnosed with CD, a strict gluten‐free diet (GFD) alone should result in complete symptomatic and histologic resolution of the disease and reduce risk of complications. Noncompliance with diet is the leading cause of failure to respond in patients with CD. For these reasons, thorough assessment and counseling and management at the time of diagnosis and ongoing care are crucial. This article addresses the overview and diagnosis of CD and addresses its nutritional management in detail.

Glepaglutide, a novel glucagon-like peptide-2 agonist, has anti-inflammatory and mucosal regenerative effects in an experimental model of inflammatory bowel disease in rats

BackgroundGlucagon-like peptide-2 (GLP-2) enhances intestinal repair and attenuates inflammation in preclinical inflammatory bowel disease (IBD) models, making GLP-2 analogues attractive candidates for IBD therapy. Glepaglutide is a long-acting GLP-2 receptor agonist in clinical development for treatment of short bowel syndrome. Here, we investigated if glepaglutide is therapeutically beneficial in rats with small intestinal inflammation.MethodsSmall intestinal inflammation was induced with indomethacin in naive Wistar rats, followed by glepaglutide administration at different disease stages. Glepaglutide was administered in co-treatment and post-treatment regimens. Small intestinal length and concentrations of inflammatory markers α-1-acid glycoprotein and myeloperoxidase were used to assess anti-inflammatory effects. Small intestinal mass was evaluated to determine intestinotrophic effects.ResultsGlepaglutide co- and post-treatment significantly reduced severity of small intestinal inflammation, evidenced by reversed small intestinal shortening and decreased α-1-acid glycoprotein and/or myeloperoxidase concentration(s). Co- and post-treatment with glepaglutide also significantly increased small intestinal mass, indicating intestinal regenerative effects. Similar effects were observed in naive rats after glepaglutide treatment.ConclusionGlepaglutide has anti-inflammatory and intestinotrophic effects without the need for pre-treatment in a rat model of small intestinal inflammation. Thus, glepaglutide is of potential clinical interest for patients with IBD.

A164 IDENTIFYING THE MOST IMPORTANT PREDICTORS TO CORRELATE SERUM METABOLITES WITH MRE CHANGES IN PATIENTS WITH PEDIATRIC CROHN DISEASE

Abstract Background Endoscopy has been the gold standard for assessing activity in Pediatric Crohn disease (pCD); however, it is limited by its invasiveness and partial assessment of small intestine and transmural inflammation. To that end, the Pediatric Inflammatory Crohn's MRE Index (PICMI) is a valid, reliable, non-invasive, and responsive index that includes transmural inflammation when assessing disease activity. The pathogenesis of pCD remains poorly understood, but evidence suggests that endogenous metabolites produced in the intestinal tract might mediate pathogenesis. Despite the important applicability of metabolomics in increasing the understanding of pCD, there has been limited research on this topic. Purpose Serum metabolomic profiles are linked to disease activity in pediatric Crohn disease. Method ImageKids is a multicenter, prospective, observational cohort study, designed to develop PICMI for pCD. The study was conducted over 18 months with paired serum specimens collected at study initiation and completion for 56 pCD patients. Due to the long time between the visits and the fact that during the study variables that highly affect serum metabolites were not controlled, we considered each patient visit as an individual measure point. Metabolites were identified using a quantitative metabolomics approach through The Metabolomics Innovation Centre (TMIC; University of Alberta). Disease activity was determined by the cutoff values in the total PICMI score of each patient. The most relevant serum metabolites were identified by medium-level and high-level variable selection analysis. Pearson correlation and hypothesis testing were used to select important metabolites. Decision trees, regularization techniques, and support vector machines were used to assess explicit importance of metabolites in disease activity. Result(s) This work provides a strategy to reduce a dimensional dataset from a metabolomic experiment. By medium-level selection analysis we were able to identify 117 statistical important metabolites for disease activity. The high-level selection analysis allowed to indicate the importance of the top 10 metabolites trough disease activity (defined by PICMI index). Results, also show that the evaluation of importance of metabolites through multivariate statistical models is dependent of the intrinsic variable selection model. Figure 1 reveals that Tryptophan ranked highest in the feature importance scoring. Histidine, Methylhistidine, Citric acid, Isoleucine, and Decanoylcarnitine also correlated well with disease severity. Image Conclusion(s) This work uses a unique approach of multivariate statistical analyses, to identify metabolites associated with pCD disease activity. Tryptophan has been previously identified as significantly altered in the blood of IBD patients compared to controls. Histidine is known to be involved in the mediation of oxidative stress, potentially influencing intestinal inflammation. These metabolites could serve as biomarkers and help define pCD pathogenesis. Disclosure of Interest None Declared

Is There a Need to Undertake Conventional Gastroscopy and Biopsy When Making the Diagnosis of Coeliac Disease in Adults?

Celiac disease is a common autoimmune condition characterized by small intestinal inflammation and mucosal damage triggered by an inappropriate immune response to ingested gluten. Gastroscopy and duodenal biopsy are currently the gold standard approach to diagnosing celiac disease in adults. However, the emergence of highly accurate serological tests for celiac disease in the last 2 decades led to a change in the pediatric guidelines to diagnose celiac disease without biopsy in selected patients. Adopting this no-biopsy approach to diagnose celiac disease in adults remains controversial, but the evidence supporting it is growing.

S125 Oral and Esophageal Manifestations in a Patient With Severe Ulcerative Colitis

Case: Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon with a growing prevalence. Traditionally, UC is thought to affect the rectum and colon exclusively, and spare the remainder of the gastrointestinal (GI) tract. The course of illness can range from mild colitis to full blown toxic megacolon requiring complete colonic resection. While various treatment options are available, total colectomy is viewed as potentially curative since it has been shown to result in complete cessation of symptoms. We report an unusual case of UC in a patient who presented with oral and esophageal ulcers that resolved completely following total colectomy. A 26-year-old male with no significant past medical history presented with a 1-week history of severe oral ulceration, odynophagia and fevers along with a 4-month history of intermittent bloody diarrhea. Infectious workup was negative. CT scan of the abdomen and pelvis showed evidence of pancolitis concerning for inflammatory bowel disease (IBD). An upper endoscopy (UE) showed multiple clear base, non-bleeding esophageal ulcers and a colonoscopy revealed severe ulceration spanning the entire colon. Patient’s hospital course was complicated by development of toxic megacolon requiring urgent total colectomy with end ileostomy. Following surgery patient reported significant improvement in overall symptoms. Biopsies from the colon revealed evidence of mucosal inflammation with crypt abscesses and absence of granulomas. Biopsies from the esophagus revealed acute esophagitis with no evidence of viral or fungal infection. Patient was discharged with 4 weeks of pantoprazole therapy and inhaled budesonide however no treatment for IBD was started. A follow up magnetic resonance enterography was obtained which showed no evidence of small bowel inflammation. Postoperatively patient continued to have improvement in symptoms with adequate weight gain. His budesonide and pantoprazole therapy was discontinued. An UE was repeated 5 months later which showed normal esophageal mucosa and no evidence of ulceration. Biopsies from the esophagus showed normal mucosa with no signs of inflammation. An ileoscopy was performed which was unremarkable and biopsies showed no evidence of small intestinal inflammation. Patient continues to do well off therapy with plans of undergoing a proctocolectomy with ileal pouch-anal anastomosis. There have been approximately 20 case reports that describe upper gastrointestinal (GI) involvement in patients with UC. These patients tend to be young and have evidence of severe UC. Clean base esophageal ulcers were observed in majority of these cases. Significant advances have been made in the treatment of UC however total proctocolectomy with ileo-anal anastomosis remains as a last resort therapy which can alleviate all symptoms including extraintestinal manifestations in up to 58% of UC patients. We therefore describe a rare case of UC that presented with primarily upper GI manifestations and emphasize the notion that UC may not be restricted to the colon only and that a total colectomy can serve as a treatment option for resolution of these symptoms.