Differential expression of intestinal genes in necrotic enteritis challenged broiler chickens with 2 different Clostridium perfringens strains.

The primary cause of necrotic enteritis (NE) disease in chickens is the NetB-positive Clostridium perfringens bacterium. Many factors are known to affect the severity of NE in the challenge models of broiler chickens, and one of these factors is the virulence of C. perfringens strain. This study was conducted to evaluate the effect of 2 pathogenic C. perfringens strains in a NE challenge model on gut health and mRNA expression of genes encoding apoptosis, tight junction, immunity, and nutrient transporters in broilers. Day-old Ross-308 male broilers (n = 468) were allocated in a 2 × 3 factorial arrangement of treatments with in-feed antibiotics (no or yes) and challenge (Non, C. perfringens strain NE18, and C. perfringens strain NE36) as the factors. The birds in the challenged groups were inoculated with Eimeria species on day 9 and with a fresh suspension of C. perfringens NE18 or NE36 on day 14 and 15. Sample collection was performed on 2 birds of each pen on day 16. Necrotic enteritis challenge, impaired feed conversion ratio during day 0 to 16 compared with the control group where the effect of the NE36 challenge was more severe than that with NE18 (P < 0.001). The mRNA expression of mucin-2, immunoglobulin-G, occludin (P < 0.001), and tight junction protein-1 (P < 0.05) genes were downregulated in both challenged groups compared with the nonchallenged counterparts. Antibiotic supplementation, on the other hand, increased weight gain, and feed intake in all challenged birds (P < 0.01), but upregulated mucin-5ac and alanine, serine, cysteine, and threonine transporter-1 (P < 0.05) only in the NE18 challenged birds. The challenge with NE36 significantly upregulated caspase-8 and claudin-1 (P < 0.001), but downregulated glucose transporter-2 (P < 0.001) compared with the NE18 challenge. These results suggest that NE challenge is detrimental to the performance of broilers through compromised intestinal health, and different C. perfringens strains can affect the severity of the disease through modulating the expression of intestinal genes encoding proteins responsible for apoptosis, gut integrity, immunity, mucus production, and nutrient transporters.

Disease Course and Treatment Response of Eosinophilic Gastrointestinal Diseases in Children With Liver Transplantation: Long-Term Follow-Up.

INTRODUCTION: To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs). METHODS: All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study. RESULTS: During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred. DISCUSSION: EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Eosinophilic Gastrointestinal Diseases in Children: A Practical Review.

Primary eosinophilic gastrointestinal diseases (EGIDs) represent a heterogeneous group of disorders characterized by eosinophilic inflammation in the absence of known causes for eosinophilia, selectively affecting different segments of the gastrointestinal tract. While pediatric eosinophilic esophagitis (EoE) is a well-defined disease with established guidelines, Eosinophilic Gastritis (EoG), Eosinophilic Gastroenteritis (EoGE) and Eosinophilic Colitis (EoC) remain a clinical enigma with evidence based on limited anecdotal case reports. Large cross-sectional studies in the US defined a prevalence of EoG and EoGE ranging from 1,5 to 6,4/100.000 and from 2,7 to 8,3/100.000 subjects respectively, while the prevalence of EoC ranges from 1,7 to 3,5/100.000 subjects. Regarding the pathogenesis, it is hypothesized that EGIDs result from the interplay between genetic predisposition, intestinal dysbiosis and environmental triggers. Clinically, EGIDs might present with different and nonspecific gastrointestinal symptoms depending on the involved intestinal tract and the extension of eosinophilic inflammatory infiltrate. The diagnosis of EGIDs requires: 1. recurrent gastrointestinal symptoms, 2. increased eosinophils for high power field in biopsy specimens, 3. absence of secondary causes of gastrointestinal eosinophilia. No validated guidelines are available on the clinical management of patients with EGIDs. Evidence from case reports and small uncontrolled case series suggests the use of dietary and corticosteroids as the first-line treatments. Considering the clinical follow-up of EGIDs, three different patterns of disease course are identified: single flare, recurring course-disease and chronic course-disease. This review will focus on pediatric EGIDs distal to esophagus, including Eosinophilic Gastritis (EoG), Eosinophilic Gastroenteritis (EoGE) and Eosinophilic Colitis (EoC).

Lupus enteritis masquerading as Crohn's disease.

BACKGROUND: Systemic lupus erythematosus is an autoimmune disease which can affect multiple organs, resulting in significant mortality and morbidity. Lupus enteritis is one of the rare complications of SLE, defined as vasculitis of the intestinal tract, with supportive biopsy findings and/or image. However, lupus enteritis is seldom confirmed on histology or image and the changes of intestinal mucosa are nonspecific. Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract which affects any part of the gastrointestinal tract. The diagnosis of CD is confirmed by clinical evaluation and a combination of endoscopic, histology, radiology, and/or biochemical investigations. CASE PRESENTATION: Here we report a rare case of a 71-years-old Chinese male has been diagnosed with lupus enteritis which similar to CD in the aspects of endoscopic, histology, and radiology. So far, there are no relevant cases reported. CONCLUSIONS: The endoscopic appearance of lupus enteritis is nonspecific, on the basis of our case, the features of lupus enteritis can be described as spacious, clean and no moss ulcers which discontinuous involved all gastrointestinal tract.

ß-Arrestin1-mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation.

Gastrointestinal toxicity limits the clinical application of abdominal and pelvic radiotherapy and currently has no effective treatment. Intestinal leucine-rich-repeat-containing GPCR 5 (Lgr5)-positive stem cell depletion and loss of proliferative ability due to radiation may be the primary factors causing intestinal injury following radiation. Here, we report the critical role of ß-arrestin1 (ßarr1) in radiation-induced intestinal injury. Intestinal ßarr1 was highly expressed in radiation enteritis and in a radiation model. ßarr1 knockout (KO) or knockdown mice exhibited increased proliferation in intestinal Lgr5+ stem cell, crypt reproduction, and survival following radiation. Unexpectedly, the beneficial effects of ßarr1 deficiency on intestinal stem cells in response to radiation were compromised when the endoplasmic reticulum stress-related protein kinase RNA-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α) pathway was inhibited, and this result was further supported in vitro. Furthermore, we found that ßarr1 knockdown with small interfering RNA significantly enhanced intestinal Lgr5+ stem cell proliferation after radiation via directly targeting PERK. ßarr1 offers a promising target for mitigating radiation-induced intestinal injury.-Liu, Z., Jiang, J., He, Q., Liu, Z., Yang, Z., Xu, J., Huang, Z., Wu, B. ß-Arrestin1-mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation.

[Physiopathology and pharmacological perspectives in the treatment of radiation enteritis]. / Physiopathologie et modulation pharmacologique de l'entérite radique.

The small intestine is an organ frequently exposed in abdominal and pelvic irradiations. Acute and late toxicity can sometimes be difficult to manage and can significantly affect the quality of life of patients. Currently there is no guideline on the management of acute and late side effects induced by therapeutic irradiation. The aim of this review is to summarize available data on the pathophysiology of radiation enteritis, and to highlight potential preventive strategies and principles of treatment of radiation enteritis.

Endoscopic Features and Diagnostic Procedures of Eosinophilic Gastroenteritis.

No specific endoscopic features for eosinophilic gastroenteritis (EGE) have been reported previously. This study therefore evaluated the endoscopic findings of six patients with EGE. The diagnosis was confirmed based on gastrointestinal symptoms, pathological findings on biopsy, and the absence of other diseases. The site of the lesion was identified based on eosinophilic infiltration with ≥20 cells per high-power field during a pathological specimen analysis. Flattening of the small intestinal villi was observed in four patients; we speculate that this may be a specific feature in the diagnosis of EGE.

COX-2/EP2-EP4/ß-catenin signaling regulates patulin-induced intestinal cell proliferation and inflammation.

Patulin (PAT), a mycotoxin, is a natural contaminant that is produced by certain species of Penicillium, Aspergillus and Byssochlamys. The major contamination of PAT is in apple and apple based products. PAT is known to cause glutathione depletion, oxidative DNA damage and cell proliferation. Recently, in vitro studies have indicated that PAT can also increase the intestinal epithelial permeability, modulate tight junctions and decrease transepithelial electrical resistance. Nonetheless, no previous study has evaluated the mechanisms responsible for PAT-induced intestinal toxicity or its relevance to the in vivo situation. Here, Wistar rats were orally treated with 100 µg/kg body weight (b.wt.) of PAT, either alone or along with 100 mg/kg b. wt. of celecoxib for 3 days. We found that PAT exposure led to significantly higher levels of PGE2 in serum and intestinal tissue and high expression of COX-2 and Ki-67 compared to controls. Interestingly, our results showed that celecoxib treatment could decrease the PAT-induced PGE2 and reduce the PAT-induced intestinal damage. To study the mechanistic aspect, normal rat intestinal epithelial cells (IEC-6) were treated with non-toxic concentrations (100 nM, 250 nM and 500 nM) of PAT for 6 h. It was observed that PAT exposure caused enhanced proliferation, higher expression of COX-2, and EP2 and EP4 receptors, along with increased PGE2 secretion. Additionally, PAT exposure caused enhanced Akt expression, which in turn inhibits GSK-3ß and stabilizes ß-catenin. Overall, our study suggests that the COX-2/EP2-EP4/ß-catenin signaling cascades are involved in the regulation of PAT-induced intestinal cell proliferation and inflammation.

Stenotic Ischemic Enteritis with Concomitant Hepatic Portal Venous Gas and Pneumatosis Cystoides Intestinalis.

A 69-year-old man was admitted to a hospital with complaints of abdominal pain. Computed tomography showed hepatic portal venous gas and pneumatosis cystoides intestinalis. Conservative treatment was effective; however, after discharge, he developed complaints of vomiting. Fluoroscopic enteroclysis revealed a stricture in the jejunum necessitating admission to our hospital. Transoral balloon-assisted enteroscopy showed a circumferential ulcer with a stricture. The stricture was surgically resected, and a histopathological examination was consistent with ischemic enteritis. Stenotic ischemic enteritis should be considered among the differential diagnoses in a patient presenting with hepatic portal venous gas and pneumatosis cystoides intestinalis showing small intestinal obstruction.

A Rat Model of Ischemic Enteritis: Pathogenic Importance of Enterobacteria, iNOS/NO, and COX-2/PGE2.

BACKGROUND: We introduced a rat model of ischemic enteritis and investigated the roles of enterobacteria, Nitric Oxide (NO), and Prostaglandins (PGs) in its pathogenesis. METHODS: Male rats were used after 18 h of fasting. Ischemic enteritis was induced by partial ligation of the superior mesenteric artery (SMA). Under ether anesthesia, SMA was isolated, and a stenosis was made by placing a needle (23 guage) on the vessel and ligating both the vessel and needle, and then a needle was removed from the ligature. Animals were then fed normally after surgery. Various drugs such as antibiotics, cyclooxygenase (COX) inhibitors, NO synthase (NOS) inhibitors and PGE2 were administered for 2 days after surgery. RESULTS: Stenosis of the SMA caused mucosal ischemia and damaged the small intestine, particularly the ileum, within 3 days. The development of enteritis was accompanied by mucosal invasion of enterobacteria, with the bacterial count being significantly increased 8 h after surgery. The severity of enteritis was prevented by the prior administration of ampicillin, L-NAME, or aminoguanidine, but aggravated by that of indomethacin or rofecoxib. The deleterious effects of indomethacin were antagonized by the co-administration of PGE2; these effects were mimicked by AE1-329, an EP4 agonist, and abrogated by AE3-208, an EP4 antagonist. The expression of iNOS and COX-2 was up-regulated in the small intestine in a time-dependent manner after ischemia caused by stenosis of the SMA, with increases in the mucosal contents of NO and PGE2. CONCLUSION: These results suggest that enterobacteria played a major pathogenic role in this model of ischemic enteritis, and that iNOS/NO was deleterious in the pathogenesis of these lesions, while COX-2/PGE2 prevented the development of ischemic enteritis by activating EP4 receptors.

Distinct differences in serum eicosanoids in healthy, enteritis and colorectal cancer individuals.

BACKGROUND: Eicosanoids as inflammatory mediators take part in the regulation of disease progression. However, the application of serum eicosanoid in disease progression identification was still uncertain. METHODS: Serum from 52 healthy volunteers, 34 enteritis patients and 55 colorectal cancer (CRC) patients were collected. Ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used to analyze the change of serum eicosanoids. RESULTS: Of 158 eicosanoids, we found that lower levels of anti-inflammatory eicosanoids 13-HOTrE, 9-HOTrE, DHA, 11-HETE and 12-HHT were observed in enteritis and CRC group compared with healthy group, meanwhile the content of 5-iPF2α-VI as oxidative stress mediator in enteritis and CRC group was greater than that in healthy groups. Moreover, 9-HODE, 13-HODE, 12,13-diHOME, 8-HETE and 15-HETE were dramatically decrease in CRC group compared with non-CRC group. Additionally, the change of 5-, 12- and 15-HETE content in serum sample was associated with progression from healthy to enteritis, finally to CRC. No significant difference between serum eicosanoids and the expression of CerbB-2 and Ki67 were observed. CONCLUSION: Serum eicosanoids might be used as a possible biomarker for identifying among health, enteritis and CRC.

Case series of Cryptogenic Multifocal Ulcerating Stenosing Enteritis (CMUSE).

BACKGROUND AND STUDY AIMS: Small bowel ulceration poses a limited, but difficult differential diagnosis. The most common causes are Crohn's disease (CD), NSAID-associated enteritis, lymphoma, cytomegaly virus infection and tuberculosis. A less known and relatively novel differential diagnosis is cryptogenic multifocal ulcerative stenosing enteritis (CMUSE). PATIENTS AND METHODS: ive patients referred for balloon-assisted enteroscopy for various reasons showed endoscopic features of CMUSE. These findings and, when available, medical imaging were reviewed in order to increase general knowledge on CMUSE. RESULTS: Five patients, 3 males and 2 females, with a mean age of 39±5 years, underwent balloon-assisted enteroscopy. Typical short, circular, ulcerative stenoses were detected in the jejunum in 2 and in the ileum in 3 patients. The number of stenoses ranged from 1 to 7 per patient. Histopathology revealed nonspecific granulocyte inflammation without specific CD findings. Stenoses were often missed on pre-enteroscopy CT or MRI enteroclysis due to their short length. Treatment consisted of endoscopic balloon dilation in 3, corticosteroids in 3, azathioprine in 1 and anti-TNFα biologicals in 3 patients. 3 patients needed additional surgery because of ongoing symptomatic small bowel stenosis or retained wireless videocapsule. CONCLUSION: In patients with short, ulcerative small intestinal stenoses CMUSE is an important but often neglected differential diagnosis. The pathophysiology and relationship to CD are subject of ongoing debate, but specific endoscopic characteristics, different histopathological findings and lack of clear abnormalities on CT or MRI enterography suggest that CMUSE is a distinct albeit rare chronic inflammatory bowel disease.

Eosinophilic Disorders of the Gastrointestinal Tract.

Eosinophilic gastrointestinal disorders represent a spectrum of disorders demonstrating gastrointestinal eosinophilia without any known cause for eosinophilia. Pathogenesis is not clearly established, but immune responses to dietary antigens are implicated. These disorders affect children and adults and are seen in association with allergic disorders. Eosinophilic esophagitis is diagnosed in the setting of mucosal eosinophilia on endoscopic biopsy and symptoms of esophageal dysfunction. Eosinophilic gastroenteritis is also diagnosed with endoscopic biopsies. Eosinophilic colitis commonly presents with lower gastrointestinal symptoms and is a diagnosis of exclusion.

Nitric oxide-induced oxidative stress impairs pacemaker function of murine interstitial cells of Cajal during inflammation.

The pacemaker function of interstitial cells of Cajal (ICC) is impaired during intestinal inflammation. The aim of this study is to clarify the pathophysiological mechanisms of ICC dysfunction during inflammatory condition by using intestinal cell clusters. Cell clusters were prepared from smooth muscle layer of murine jejunum and treated with interferon-gamma and lipopolysaccharide (IFN-γ+LPS) for 24h to induce inflammation. Pacemaker function of ICC was monitored by measuring cytosolic Ca(2+) oscillation in the presence of nifedipine. Treatment with IFN-γ+LPS impaired the pacemaker activity of ICC with increasing mRNA level of interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6 in cell clusters; however, treatment with these cytokines individually had little effect on pacemaker activity of ICC. Treatment with IFN-γ+LPS also induced the expression of inducible nitric oxide synthase (iNOS) in smooth muscle cells and resident macrophages, but not in ICC. Pretreatment with NOS inhibitor, L-NAME or iNOS inhibitor, 1400W ameliorated IFN-γ+LPS-induced pacemaker dysfunction of ICC. Pretreatment with guanylate cyclase inhibitor, ODQ did not, but antioxidant, apocynin, to suppress NO-induced oxidative stress, significantly suppressed the impairment of ICC function induced by IFN-γ+LPS. Treatment with IFN-γ+LPS also decreased c-Kit-positive ICC, which was prevented by pretreatment with L-NAME. However, apoptotic ICC were not detected in IFN-γ+LPS-treated clusters, suggesting IFN-γ+LPS stimulation just changed the phenotype of ICC but not induced cell death. Moreover, ultrastructure of ICC was not disturbed by IFN-γ+LPS. In conclusion, ICC dysfunction during inflammation is induced by NO-induced oxidative stress rather than NO/cGMP signaling. NO-induced oxidative stress might be the main factor to induce phenotypic changes of ICC.

Pathophysiological mechanisms of diarrhea caused by the Vibrio cholerae O1 El Tor variant: an in vivo study in mice.

Cholera is caused by infection with Vibrio cholerae. This study aimed to investigate the pathophysiology of diarrhea caused by the V. cholerae O1 El Tor variant (EL), a major epidemic strain causing severe diarrhea in several regions. In the ligated ileal loop model of EL-induced diarrhea in the ICR mice, a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor and a calcium-activated chloride channel (CaCC) inhibitor similarly inhibited intestinal fluid secretion. In addition, barrier disruption and NF-κB-mediated inflammatory responses, e.g., iNOS and COX-2 expression, were observed in the infected ileal loops. Interestingly, intestinal fluid secretion and barrier disruption were suppressed by NF-κB and COX-2 inhibitors, whereas an iNOS inhibitor suppressed barrier disruption without affecting fluid secretion. Furthermore, EP2 and EP4 PGE2 receptor antagonists ameliorated the fluid secretion in the infected ileal loops. The amount of cholera toxin (CT) produced in the ileal loops by the EL was ∼2.4-fold of the classical biotype. The CT transcription inhibitor virstatin, a toll-like receptor-4 (TLR-4) antibody and a CT antibody suppressed the EL-induced intestinal fluid secretion, barrier disruption and COX-2 expression. The CT at levels detected during EL infection induced mild intestinal barrier disruption without inducing inflammatory responses in mouse intestine. Collectively, this study indicates that CT-induced intestinal barrier disruption and subsequent TLR-4-NF-κB-mediated COX-2 expression are involved in the pathogenesis of EL-induced diarrhea and represent promising novel therapeutic targets of cholera.

NQO1-Knockout Mice Are Highly Sensitive to Clostridium Difficile Toxin A-Induced Enteritis.

Clostridium difficile toxin A causes acute gut inflammation in animals and humans. It is known to downregulate the tight junctions between colonic epithelial cells, allowing luminal contents to access body tissues and trigger acute immune responses. However, it is not yet known whether this loss of the barrier function is a critical factor in the progression of toxin A-induced pseudomembranous colitis. We previously showed that NADH:quinone oxidoreductase 1 (NQO1) KO (knockout) mice spontaneously display weak gut inflammation and a marked loss of colonic epithelial tight junctions. Moreover, NQO1 KO mice exhibited highly increased inflammatory responses compared with NQO1 WT (wild-type) control mice when subjected to DSS-induced experimental colitis. Here, we tested whether toxin A could also trigger more severe inflammatory responses in NQO1 KO mice compared with NQO1 WT mice. Indeed, our results show that C. difficile toxin A-mediated enteritis is significantly enhanced in NQO1 KO mice compared with NQO1 WT mice. The levels of fluid secretion, villus disruption, and epithelial cell apoptosis were also higher in toxin A-treated NQO1 KO mice compared with WT mice. The previous and present results collectively show that NQO1 is involved in the formation of tight junctions in the small intestine, and that defects in NQO1 enhance C. difficile toxin A-induced acute inflammatory responses, presumably via the loss of epithelial cell tight junctions.