Small Intestinal Mucosal Damage Research Articles

Heat shock protein 90 and prolyl hydroxylase 2 co-regulate hypoxia-inducible factor-1α expression in porcine small intestinal epithelial cells under heat stress

Heat stress (HS) poses a substantial threat to animal growth and development, resulting in declining performance and economic losses. The intestinal system is susceptible to HS and undergoes intestinal hyperthermia and pathological hypoxia. Hypoxia-inducible factor-1α (HIF-1α), a key player in cellular hypoxic adaptation, is influenced by prolyl-4-hydroxylase 2 (PHD2) and heat shock protein 90 (HSP90). However, the comprehensive regulation of HIF-1α in the HS intestine remains unclear. This study aims to explore the impact of HS on pig intestinal mucosa and the regulatory mechanism of HIF-1α. Twenty-four Congjiang Xiang pigs were divided into the control and five HS-treated groups (6, 12, 24, 48, and 72 h). Ambient temperature and humidity were maintained in a thermally-neutral state (temperature–humidity index (THI) < 74) in the control group, whereas the HS group experienced moderate HS (78 < THI <84). Histological examination revealed villus exfoliation after 12 h of HS in the duodenum, jejunum, and ileum, with increasing damage as HS duration extended. The villus height to crypt depth ratio (V/C) decreased and goblet cell number increased with prolonged HS. Quantitative real-time PCR, Western blot, and immunohistochemistry analysis indicated increased expression of HIF-1α and HSP90 in the small intestine with prolonged HS, whereas PHD2 expression decreased. Further investigation in IPEC-J2 cells subjected to HS revealed that overexpressing PHD2 increased PHD2 mRNA and protein expression, while it decreases HIF-1α. Conversely, interfering with HSP90 expression substantially decreased both HSP90 and HIF-1α mRNA and protein levels. These results suggest that HS induces intestinal hypoxia with concomitant small intestinal mucosal damage. The expression of HIF-1α in HS-treated intestinal epithelial cells may be co-regulated by HSP90 and PHD2 and is possibly linked to intestinal hyperthermia and hypoxia.

Interleukin-13 Mediates Non-Steroidal Anti-Inflammatory-Drug-Induced Small Intestinal Mucosal Injury with Ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs), which are antipyretics and analgesics, cause gastrointestinal disorders, such as inflammation and ulcers. To prescribe NSAIDs more safely, it is important to clarify the mechanism of NSAID-induced gastrointestinal mucosal injury. However, there is a paucity of studies on small intestinal mucosal damage by NSAIDs, and it is currently unknown whether inflammation and ulceration also occur in the small intestine, and whether mediators are involved in the mechanism of injury. Therefore, in this study, we created an animal model in which small intestinal mucosal injury was induced using NSAIDs (indomethacin; IDM). Focusing on the dynamics of immune regulatory factors related to the injury, we aimed to elucidate the pathophysiological mechanism involved. We analyzed the pathological changes in the small intestine, the expression of immunoregulatory factors (cytokines), and identified cytokine secretion and expression cells from isolated lamina propria mononuclear cells (LPMCs). Ulcers were formed in the small intestine by administering IDM. Although the mRNA expression levels of IL-1β, IL-6, and TNFα were decreased on day 7 after IDM administration, IL-13 mRNA levels increased from day 3 after IDM administration and remained high even on day 7. The IL-13 mRNA expression and the secretion of IL-13 were increased in small intestinal LPMCs isolated from the IDM-treated group. In addition, we confirmed that IL-13 was expressed in CD4-positive T cells. These results provided new evidence that IL-13 production from CD4-positive T cells in the lamina propria of the small intestine contributes to NSAID-induced mucosal injury.

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.

Butyrate Ameliorates Insufficient Sleep-Induced Intestinal Mucosal Damage in Humans and Mice.

Insufficient sleep is a key factor in the occurrence of intestinal diseases. This study was performed to clarify how sleep deficiency mediates the intestinal microbiota, metabolite butyrate disturbance induces intestinal mucosal damage, and butyrate ameliorates it. A questionnaire was launched for sleep and intestinal health issues. Twenty-two healthy volunteers were interviewed, and the influence of insufficient sleep on the gut microbiota and metabolite composition was explored. Moreover, a 72-h sleep deprivation (SD) mouse model with or without butyrate supplementation was used to reveal the effect of butyrate on ameliorating small intestines damage caused by SD. The questionnaire survey of 534 college students showed that among 85.39% of the students who slept less than 7 h, 41.76% were suffering from various bowel disorders. High-throughput 16S rRNA pyrosequencing demonstrated that SD and sleep restriction (SR) resulted in downregulation of Faecalibacterium and butyrate abundance in the feces of college students. Furthermore, we observed that butyrate supplementation markedly reversed sleep-deprivation-induced small intestinal mucosal injury in mice. Meanwhile, butyrate supplementation inverted the SD-caused inflammation response and oxidative stress and the decline of phospho-glycogen synthase kinase 3β (p-GSK-3β), β-catenin, Nrf2, and cyclin D1 and the increase in histone deacetylase 3 (HDAC3) and phospho-P65 (p-P65) proteins in the small intestines. Furthermore, in vitro, the ameliorative effects of butyrate were blocked by treatment with the HDAC3 agonist ITSA-1 and the Nrf2 antagonist ML385 and mimicked by treatment with the HDAC3 antagonist RGFP966 and p-P65 antagonist PDTC. Our study revealed that SD and SR downregulated butyrate production, further causing intestinal homeostasis dysfunction via the HDAC3-p-GSK-3β-β-catenin-Nrf2-NF-κB pathway. IMPORTANCE Radical inflammatory bowel disease (IBD) induced by sleep deficiency is a serious global public health threat. Butyrate, a member of the short-chain fatty acids, exerts multiple effects on it. However, existing research focuses on injury to the colon caused by insufficient sleep, while the changes in the small intestines are often overlooked. This study focused on revealing the influence of insufficient sleep on the intestinal microbiota and its metabolites and further revealed the ameliorative effect of butyrate on sleep deprivation (SD)-induced small intestinal mucosal damage in human and mice. Our studies suggest that butyrate can be used as a probiotic to restore SD-induced IBD and contribute to a better understanding of the mechanisms that govern the beneficial effects of butyrate.

Dietary Glucose Ameliorates Impaired Intestinal Development and Immune Homeostasis Disorders Induced by Chronic Cold Stress in Pig Model.

Endotherms are easily challenged by chronic cold stress. In this study, the development and injury of the small intestine in the Min pig model and Yorkshire pig model under chronic cold stress, and the molecular mechanisms by which glucose supplementation reduces small intestinal mucosal damage were investigated. The results showed that morphological structure lesions of the jejunal mucosa and ileal mucosa were visible in Yorkshire pigs under chronic cold stress. Meanwhile, the Occludin mRNA and protein expression in jejunal mucosa of Yorkshire pigs was decreased. Chronic cold stress enhanced the expression of Toll-like receptor 4 (TLR4), the myeloid differentiation main response 88 (MyD88), nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3), cleaved caspase-1, mature-IL-1β, and high-mobility group box 1 (HMGB 1) mRNA and protein expression in jejunal mucosa of Yorkshire pigs, whereas the mRNA and protein of Bax was triggered in ileal mucosa. In Min pigs, no such deleterious consequences were observed. Dietary glucose supplementation ameliorates small intestinal mucosal injury, declined TLR4 and MyD88 expression in jejunal mucosa. In conclusion, chronic cold stress induced the small intestinal mucosa damage in Yorkshire pigs, whereas glucose supplementation mitigated the deleterious effects of chronic cold stress on the small intestine.

Effect of Lactobacillus rhamnosus MN-431 Producing Indole Derivatives on Complementary Feeding-Induced Diarrhea Rat Pups Through the Enhancement of the Intestinal Barrier Function.

Many infants suffer from complementary feeding-induced diarrhea (CFID). Studies have shown that intestinal microbes can enhance the intestinal barrier and prevent diarrhea by producing indole derivatives that promote pregnane X receptor (PXR) expression. In this study, the indole test and determination of the PXR concentration are performed on tryptophan broth cultures of 320-suspected Lactobacillus and Enterococcus strains. Four strains that produce indole derivatives that promote the expression of PXR are screened as potential functional probiotics. Both Lactobacillus rhamnosus MN-431 (L. rhamnosus MN-431) and Lactobacillus oris FN-448 (L. oris FN-448) can colonize the intestine of rat pups, and L. rhamnosus MN-431 can significantly decrease the incidence of diarrhea and intestinal permeability in rat pups. Using real-time qPCR and the analysis of the intestinal morphology using immunohistochemistry, it is observed that the metabolized tryptophan from L. rhamnosus MN-431 can reduce small intestinal mucosal damage by stimulating PXR/NF-κB signaling and activating PXR and aryl hydrocarbon receptor. The intestinal barrier is also enhanced by promoting the expression of tight junction proteins such as Occludin and zonula occludens-1 in baby rats. The results demonstrate that L. rhamnosus MN-431 can metabolize tryptophan to prevent infantile CFID by promoting the expression of PXR.

Celiac Disease.

Celiac Disease.

Protective Effect of Nigella Sativa Oil Against Indomethacin-Related Small Intestine and Gastric Mucosal Damage in Rats

Protective Effect of Nigella Sativa Oil Against Indomethacin-Related Small Intestine and Gastric Mucosal Damage in Rats

Precision medicine and machine learning towards the prediction of the outcome of potential celiac disease

Potential Celiac Patients (PCD) bear the Celiac Disease (CD) genetic predisposition, a significant production of antihuman transglutaminase antibodies, but no morphological changes in the small bowel mucosa. A minority of patients (17%) showed clinical symptoms and need a gluten free diet at time of diagnosis, while the majority progress over several years (up to a decade) without any clinical problem neither a progression of the small intestine mucosal damage even when they continued to assume gluten in their diet. Recently we developed a traditional multivariate approach to predict the natural history, on the base of the information at enrolment (time 0) by a discriminant analysis model. Still, the traditional multivariate model requires stringent assumptions that may not be answered in the clinical setting. Starting from a follow-up dataset available for PCD, we propose the application of Machine Learning (ML) methodologies to extend the analysis on available clinical data and to detect most influent features predicting the outcome. These features, collected at time of diagnosis, should be capable to classify patients who will develop duodenal atrophy from those who will remain potential. Four ML methods were adopted to select features predictive of the outcome; the feature selection procedure was indeed capable to reduce the number of overall features from 85 to 19. ML methodologies (Random Forests, Extremely Randomized Trees, and Boosted Trees, Logistic Regression) were adopted, obtaining high values of accuracy: all report an accuracy above 75%. The specificity score was always more than 75% also, with two of the considered methods over 98%, while the best performance of sensitivity was 60%. The best model, optimized Boosted Trees, was able to classify PCD starting from the selected 19 features with an accuracy of 0.80, sensitivity of 0.58 and specificity of 0.84. Finally, with this work, we are able to categorize PCD patients that can more likely develop overt CD using ML. ML techniques appear to be an innovative approach to predict the outcome of PCD, since they provide a step forward in the direction of precision medicine aimed to customize healthcare, medical therapies, decisions, and practices tailoring the clinical management of PCD children.

RETRACTED: Protective effect of naringin on small intestine injury in NSAIDs related enteropathy by regulating ghrelin/GHS-R signaling pathway

To investigate the mechanism of Ghrelin/GHS-R signaling pathway in small intestine injury induced by NSAIDs related enteropathy. To clarify the mechanism network of intestinal mucosal repair with naringin as a new therapeutic method. Naringin was used as the intervention method, observed the damage of small intestinal mucosa and detected the expression of ghrelin, GHS-R, leptin and TNF-α by electron microscopy, HE staining and immunohistochemistry. Compared with the control group, the weight of rats in the model group decreased, the thickness of intestinal mucosa became thinner, the structure of intestinal mucosa changed, the expression of ghrelin, GHS-R and leptin decreased, the expression of TNF-α increased. Compared with the model group, the intestinal mucosa of the treatment group was repaired, the expression of ghrelin, GHS-R and leptin was increased, and the expression TNF-α was decreased. The mechanism of intestinal mucosal damage in patients with NSAIDs related enteropathy may be related to the decreased expression of ghrelin, GHS-R and leptin, and promotion of TNF-α secretion. Naringin can effectively promote the secretion of ghrelin and leptin, the expression of GSH-R, and inhibit the release of TNF-α, so as to repair intestinal mucosa naringin will become a new method to treat and prevent NSAIDs related intestinal diseases.

Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers

Enteric bacteria and/or their products are necessary for doxorubicin (DXR)-induced small intestine mucosal damage. While DXR does not induce gross loss of epithelium, others have shown elevated serum endotoxin after DXR administration. However, the mechanism of movement is unknown. We hypothesized that DXR treatment resulted in increased paracellular translocation of bacteria or bacterial products through the small intestinal epithelium. We measured permeability after DXR administration using transepithelial resistance and macromolecular flux and assessed tight junctional gene expression and protein localization both in vitro using T84 cells and ex vivo using murine jejunum. DXR treatment increased flux of 4 kDa dextrans in mouse jejenum, but increased flux of 4, 10 and 20 kDa dextrans in T84 cells. Following DXR, we observed increased permeability, both in vitro and ex vivo, independent of bacteria. DXR induced increased expression of Cldn2 and Cldn4 in murine small intestine but increased only CLDN2 expression in T84 cells. DXR treatment induced disorganization of tight junctional proteins. We conclude that DXR increases paracellular transit of small macromolecules, including bacterial products, through the epithelium, by altering expression of tight junctional components and dynamic loosening of cellular tight junctions.

Small intestinal mucosal injury and its risk factors in patients with gastrointestinal cancer who developed complicated fluoropyrimidine-induced diarrhea

BackgroundDiarrhea is a common adverse event of fluoropyrimidine-based chemotherapy. However, limited data are available on the frequency and risk factors of complicated chemotherapy-induced diarrhea (CID) and small intestinal mucosal damage. In this current study, we aimed to determine the incidence of complicated CID and mucosal injury among patients with complicated CID receiving fluoropyrimidine via small bowel capsule endoscopy (CE) and determined baseline risk factors associated with complicated CID.MethodsIn total, 536 patients with advanced or recurrent gastrointestinal cancer who received fluoropyrimidine-based chemotherapy were retrospectively analyzed. Diarrhea was evaluated using the Common Terminology Criteria for Adverse Events version 4. Complicated CID was defined according to the American Society of Clinical Oncology guidelines. To evaluate small intestinal mucosal injury in patients with complicated CID, CE was performed. Multivariate analysis was performed to identify risk factors for complicated CID.ResultsTotal number of 32 (6%) patients developed complicated CID. Complicating symptoms were noted in 25 (78%) patients, with cramping, vomiting, and sepsis being observed in 15 (60%), 8 (32%), and 3 (12%) patients, respectively. Among the 13 patients who underwent CE, 11 (85%) showed abnormal findings. Multivariate analysis revealed that oral fluoropyrimidine administration was a risk factor for complicated CID (odds ratio 2.95; 95% confidence interval 1.06–8.19).ConclusionsDespite the relatively low incidence of complicated CID, mucosal injury of small intestine was common in patients with complicated fluoropyrimidine-induced diarrhea and oral fluoropyrimidine was an independent risk factor.

Partially hydrolyzed guar gum alleviates small intestinal mucosal damage after massive small bowel resection along with changes in the intestinal microbiota

PurposeShort bowel syndrome is associated with intestinal mucosal inflammation and microbial dysbiosis, leading to intractable complications. Partially hydrolyzed guar gum (PHGG) has trophic and anti-inflammatory effects on the intestine. We investigated whether PHGG ameliorates small intestinal mucosal damage and alters the intestinal microbiota using a rat small bowel resection (SBR) model. MethodsSprague Dawley rats were divided into sham operation (Sham), Sham/PHGG, SBR, and SBR/PHGG groups. On day 21, all rats were euthanized. To assess small intestinal mucosal damage, the degeneration rate was morphometrically evaluated and immunohistochemically examined using anti-CD45 antibodies. Analyses of fecal microbiota using 16S rRNA and short-chain fatty acid production were also performed. ResultsThe mucosal degeneration rate was significantly higher in the SBR group than in the Sham or SBR/PHGG groups. The number of CD45-positive cells was significantly higher in the SBR group than in the Sham, Sham/PHGG, or SBR/PHGG groups. The relative abundance of family Lachnospiraceae was significantly higher in the SBR/PHGG group than in the SBR group. ConclusionsPHGG administration alleviated small intestinal mucosal damage which could be associated with modulation of the intestinal microbiota.

ZO‐1‐Deficient Enterocytes Undergo Abortive Proliferative Expansion in Response to Mucosal Injury

Intestinal damage can be caused by physical, infectious, and immune‐mediated injury. Rapid repair, which is essential for return to mucosal homeostasis, depends on integration of epithelial migration, as in restitution, proliferation and differentiation. These are, in turn, regulated by growth factors and other stimuli that promote expansion of stem and transit‐amplifying cells. Barrier restoration is essential to recovery, but it is not known if tight junction proteins also contribute to critical events prior to junctional repair.AIMTo determine the contributions of the intestinal epithelial tight junction protein zonula occludens‐1 (ZO‐1) to mucosal wound repair.RESULTSIntestinal epithelial ZO‐1 expression is reduced in biopsies from inflammatory bowel disease (IBD) patients and mice with experimental IBD. To determine if this ZO‐1 loss contributes to disease pathogenesis, we created intestinal epithelial ZO‐1‐deficient (Tjp1f/fx villin‐Cre) mice (ZO1IEC.KO). These mice are fertile, reproduce with Mendelian genetics, and, in the absence of stress, mice grow and gain weight normally and are indistinguishable from ZO‐1‐expressing (Tjp1f/f) mice (ZO1IEC.WT). However, 2% DSS induced greater mucosal damage and weight loss in ZO1IEC.KO, relative to ZO1IEC.WT, mice, likely reflecting competition between injury and repair, as 3% DSS induced similar weight loss in ZO1IEC.KO and ZO1IEC.WT mice. Consistent with inadequate repair, ZO1IEC.KO mice failed to recover, even 4 weeks after DSS discontinuation. Labeling with EdU (2h before sacrifice) demonstrated blunted proliferative responses in ZO1IEC.KO, relative toZO1IEC.WT, mice. More striking however, was the loss and nuclear fragmentation, suggestive of apoptosis, of BrdU‐labeled epithelial cells (24h before sacrifice) in ZO1IEC.KO mice. Partial rescue by the caspase‐3 inhibitor z‐DEVD‐FMK indicates that this abortive proliferation contributes to the enhanced severity of DSS colitis in ZO1IEC.KO mice. These defects were not limited to the colon, as ZO1IEC.KO mice also displayed delayed and abortive proliferative responses following T cell activation‐induced (anti‐CD3) small intestinal mucosal damage that were partially rescued by z‐DEVD‐FMK. ZO1IEC.KO mice demonstrated greater Olfm4+ stem cells loss than ZO1IEC.WT mice, and analyses of gene expression showed reduced expression of Lgr5, Ascl2, Oflm4, Bmi1, Lrig1, Wnt3, Dll1, Jag1, Dll4, Notch1, and Hes1, reflecting stem cell loss and defective wnt and notch signaling. In contrast, Tgfbr2 and Smad4 expression were relatively increased in ZO1IEC.KO mice.CONCLUSIONThese data indicate that ZO‐1 plays critical roles in stem cell activation and epithelial survival that are distinct from contributions to tight junction structure. We therefore conclude that non‐canonical ZO‐1 functions are central to stem cell survival, epithelial proliferation, and repair that are necessary for recovery after intestinal mucosal damage. These data further suggest that ZO‐1 loss may contribute to the defective wound healing observed in human and experimental IBD.Support or Funding InformationSupported by NIH R01 DK061931.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Isolated hypertransaminasemia in children up to two years with classical celiac disease

Introduction/Objective Isolated hypertransaminasemia (IHTS) is a common, benign, and transient appearance in patients with celiac disease (CD). The aim of this study is to determine the frequency of IHTS in children up to two years old with clinically classical CD, as well as its connection with the onset of the first symptoms of the disease, the age of diagnosis, the clinical and laboratory nutritional parameters, and the degree of damage of small intestinal mucosa. Methods The study was based on a sample of 82 children, 55 female and 27 male, ages 7?24 (14.28 ? 4.41) months. The diagnosis of CD was based on the revised ESPGHAN criteria and the activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by standard laboratory methods. Results IHTS was found in 39 (47.56%) patients, 27 of whom (69.23%) had elevated levels of both transaminases and 12 of only one ? eight of AST and four of ALT. The increase in relation to the aforementioned reference value for ALT was 1.1?10.08 (1.67 ? 1.73), and for AST it was 1.08?7.91 (1.56 ? 1.29) times. In patients with IHTS compared to those with normal transaminasemia, the age of onset of CD was significantly lower (9.83 ? 3.69 vs. 12.95 ? 4.43 months, p = 0.001), as well as the age of diagnosis (12.97 ? 3.88 vs. 15.47 ? 4.56 months; p = 0.01), while the differences in the other observed parameters were not significant. Conclusions IHTS occurs in almost half of children up to two years old with classical CD. Hypertransaminasemia is in most cases mild and significantly more frequent in patients with earlier clinical expression of the CD.

P-198 - Relationship between aspirin-induced small intestinal mucosal injury and oxidative stress

Background Endoscopic observation has clearly demonstrated the intestinal mucosal damage induced by aspirin, however, its mechanism remains unclear. We have reported that aspirin induces oxidative stress in the small intestinal epithelial cells. Aim The aim of this study is to investigate the involvement of oxidative stress on aspirin-induced small intestinal mucosal damage by using nuclear factor-erythroid 2-related factor 2 knock out (nrf2KO) mice, in which anti-oxidative defense system is disturbed. Method Under the anesthesia, aspirin (2–10 mg/body) suspended in 0.5% methylcellulose was injected into the proximal duodenum of C57Bl/6 wild type (WT) and nrf2KO mice (male, 8 weeks old). At 1.5 h after treatment, the mice were killed with ether and the small intestine was removed for histological examination. Result Aspirin significantly caused small intestinal mucosal injury in WT mice as assessed histologically in a concentration-dependent manner. Although low concentration of aspirin did not cause small intestinal mucosal injury in WT mice, it caused significant mucosal damage in nrf2KO mice. Conclusion The deficient of nrf2-driven oxidative stress detoxification pathway is important for the protection against aspirin-induced small intestinal mucosal injury.

Mucosal injury of small intestine in patients with advanced gastric cancer who developed chemotherapy induced diarrhea (CID).

28 Background: Fluoropyrimidine is a key drug for patients with advanced or recurrent gastric cancer. It causes diarrhea, a common non-hematological toxicity. The consensus guideline suggests aggressive treatment including intravenous fluids and antibiotics, is necessary for patients with severe diarrhea accompanied by fever and sepsis. However, the frequency of complicating signs and the actual degree of damage of small intestinal mucosa have not been reported. We evaluated complicating signs and mucosal injury in patients with complicated CID. Methods: Between April 2007 and December 2016, 170 patients with advanced or recurrent gastric cancer who underwent S-1 or capecitabine based chemotherapy were retrospectively analyzed. Diarrhea was evaluated with CTCAE v4.0, and complicated CID was defined as CTC grade 3 or 4 diarrhea or grade 1 or 2 diarrhea with following signs: cramping, vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, and dehydration. To evaluate mucosal injury of small intestine, capsule endoscopy was performed in patients with complicated CID. Results: Among 170 patients, 15 patients (8.8%) showed complicated CID during chemotherapy (S-1 based chemotherapy, n = 13/148; capecitabine based chemotherapy, n = 2/22). Among the profile of complicated signs, cramping, fever, and vomiting were frequent, and observed in 11 (73%), 7 (47%), and 5 (33%) patients, respectively. Ten patients received capsule endoscopy after improvement of CID, and 6 (60%) patients had multiple erosions or ulcerations in small intestine. Conclusions: The incidence of complicated CID caused by fluoropyrimidine based chemotherapy was less frequent in patients with advanced or recurrent gastric cancer. However, most patients showed mucosal injury of small intestine in capsule endoscopy. Therefore, these findings strongly support the guideline that recommends aggressive therapeutic approach for patients with complicated CID.

Effect of egualen sodium hydrate on small-intestinal mucosal damage induced by low-dose aspirin: a prospective randomized clinical trial.

Low-dose aspirin, which is widely used to reduce the risk of cardio- and cerebrovascular thrombosis, often induces gastroenteropathy by increasing the permeability of the mucosa. However, therapeutic strategies for patients with low-dose aspirin-induced small intestinal injury have not been determined. We evaluated the preventative effect of egualen sodium hydrate, a gastro-protective agent that suppresses indomethacin-induced small-intestinal damage in rats, against small-intestinal mucosal damage induced by low-dose aspirin in healthy adult male volunteers. Participants were randomly allocated to receive aspirin 100 mg/kg daily (control group, n = 10) or aspirin 100 mg/kg plus egualen sodium 30 mg daily (egualen sodium group, n = 10). Small intestinal mucosal injury was evaluated by capsule endoscopy two weeks after initiation of drug administration. Fecal analyses (occult blood test, immunochemical test, transferrin measurement and calprotectin measurement) were carried out before and after treatment. Egualen sodium significantly suppressed the total number of small intestinal injuries detected by capsule endoscopy and the positive ratio for the fecal occult blood test. Daily use of 30 mg of egualen sodium showed a preventative effect on low-dose aspirin-induced small intestinal injury. Since acid suppression therapy was reported to exacerbate NSAIDs-induced enteropathy via dysbiosis, egualen sodium may be useful for patients treated with low-dose aspirin.

The approach to Celiac Disease in children

Celiac Disease (CD) is a permanent, irreversible but treatable multifactorial disease triggered by the ingestion of gluten (a plant storage protein contained in wheat, barley and rye) in genetically predisposed individuals and resulting in an autoimmune small intestinal inflammation with systemic implications. While the gastrointestinal manifestations secondary to an inflammatory enteropathy with variable degrees of severity are what defined it for many decades, CD is in fact characterized also by a wide range of extra-intestinal complaints and elevated titers of celiac-specific autoantibodies. 1.1. Epidemiology and pathogenesis The prevalence of CD is increasing at a remarkable pace during the past few decades [1], [2], [3]. Once thought to be a rare condition, affecting no more than 1/10,000 people, thanks to the availability and widespread use of specific and sensitive serological markers, CD is now recognized worldwide as a common disorder, with a prevalence varying between 0.3 and 3 per 100. Only a limited portion of the expected celiac patients are however actually identified, with proportions varying between different countries: in the USA, even though overall CD prevalence is estimated to be around 1%, only about 15% of this population (including children and adults) has been diagnosed and can therefore be treated [4]. This phenomenon of under-diagnosis is likely due to a combination of inadequate awareness and a high prevalence of asymptomatic or oligo-symptomatic patients. Like most multifactorial disorders, CD is the result of a complex interaction between genes, immune status of the host, and environmental triggers. Gluten is a heterogeneous molecule. The gluten fractions that are toxic to celiac patients are a mixture of alcohol-soluble proteins called gliadins. Gliadins are rich in glutamine and proline residues, which even the healthy human intestine cannot fully digest. As a result, intact gliadin peptides are left in the lumen, and some cross the intestinal barrier. These fragments come into contact with the intracellular enzyme tissue transglutaminase (tTG), which deamidates them, leading to a change in shape and increased negative charge. This creates peptides that can easily be captured by the HLA-DQ2 and/or DQ8 molecules expressed on the surface of the lamina propria-associated antigen-presenting cells (APCs) and are presented to CD4+ T cells triggering an inflammatory reaction [5]. The end result of this autoimmune-triggered inflammatory reaction is a varied degree of small intestinal mucosal damage, typically more severe proximally than distally. The role of additional environmental factors is still the object of an intense research. Recently, our group showed evidence for a plausible role of an otherwise innocuous viral infection (Reovirus) in creating a pro-inflammatory milieu conducive to the development of overt CD [6].

Congestive Preconditioning by Portal Venous Clamping: A Novel Preventive Concept for Small Intestinal Congestive Re-Outflow Injury.

BACKGROUND Congestion of the small intestine, which induces mucosal damage via apoptosis, is a common pathophysiological change in hepato-biliary-pancreatic surgery, including liver transplantation. Small intestinal mucosal damage can trigger postoperative complications via various pathways. Therefore, we investigated the efficacy of intermittent portal venous clamping, which we named congestive preconditioning (CPC), for decreasing congestive re-outflow injury (CRoI) of the small intestine. MATERIAL AND METHODS Small intestinal CRoI was induced in rats by clamping the portal vein (PV) for 30 min, followed by re-outflow. The CPC group underwent 3 episodes of 5 min PV clamping and 5 min re-outflow before CRoI. The Control group underwent CRoI after 30 min simple laparotomy without any preconditioning. Survival and histological changes in the small intestine after CRoI were analyzed. The histological changes were compared CPC group to Control group using a scoring system that expressed histopathological severity. Also, small intestinal apoptosis and expression of apoptosis-related genes were analyzed by immunohistochemistry. RESULTS The survival rate of the CPC group was significantly higher than Control group. Histological scoring of small intestinal damage was significantly lower in the CPC group after 6 h of CRoI. Expression of anti-apoptotic gene, Bcl-xL was significantly increased, but pro-apoptotic gene caspase-3 and apoptotic cells did not differ significantly between the CPC group and Control group. CONCLUSIONS Induction of CPC for small intestinal CRoI was effective, which suggests that an anti-apoptotic pathway is involved in the beneficial mechanism.