Extent Of Intestinal Injury Research Articles

Melatonin alleviates necrotizing enterocolitis by reducing bile acid levels through the SIRT1/FXR signalling axis

Bile acids (BAs) have increasingly been implicated in the onset and progression of necrotizing enterocolitis (NEC); multiple findings have demonstrated their ability to induce damage to the intestinal epithelium, thereby exacerbating disease severity. Although we previously showed that melatonin was able to treat NEC by correcting the Treg/Th17 imbalance, the modulatory effect of melatonin on BAs remains unclear. In this study, we conducted transcriptome analysis on intestinal tissues from patients with NEC and validated these findings. Subsequently, we treated mice with melatonin alone or in combination with an agonist/inhibitor of Sirtuin 1 (SIRT1) to assess faecal and serum BA levels, the expression levels of BA transporters and regulators, and the extent of intestinal injury. Our transcriptome results indicated dysregulation of BA metabolism and abnormal expression of BA transporters in patients with NEC, which were also observed in our NEC mouse model. Furthermore, exogenous BAs were found to aggravate NEC severity in mice. Notably, melatonin effectively restored the aberrant expression of BA transporters, such as apical membrane sodium-dependent bile acid transporters (ASBT), ileal bile acid-binding protein (IBABP), and organic solute transporter-alpha (OST-α), by upregulating SIRT1 expression while reducing farnesoid X receptor (FXR) acetylation, consequently leading to decreased serum and faecal BA levels and mitigated NEC severity. Thus, we propose a potential mechanism through which melatonin reduces BA levels via the SIRT1/FXR signalling axis in an NEC mouse model. Collectively, these results highlight that melatonin holds promise for reducing BA levels and represents a promising therapeutic strategy for treating NEC.

Oral intake of bovine lactoferrin alleviates intestinal injury induced by perinatal hypoxia and hypothermia in newborn rats

Introduction/Objectives. To investigate whether oral administration of lactoferrin attenuates intestinal injury induced by perinatal hypoxia and hypothermia. Methods. Newborn Wistar rat pups were exposed to perinatal asphyxia, followed by global hypothermia. The pups were distributed into two groups: lactoferrin group (LG) ? pups that received lactoferrin orally for seven days (20 mg/day), control group (CG) ? pups that received normal saline orally during first seven days of life. After seven days macroscopic examination of the bowels and pathohistological analyses of tissue samples have been performed. Results. The incidence of macroscopic injuries was significantly lower in LG group compared to CG. The incidence of pathological findings, as well as the values of injury scores used to assess the intensity and extent of intestinal injury at microscopic level were significantly lower in LG group. Conclusions. Lactoferrin attenuates perinatal hypoxia/hypothermia-induced intestinal injury in newborn rats.

Quercetin protects against hyperglycemia-induced retinopathy in Sprague Dawley rats by regulating the gut-retina axis and nuclear factor erythroid-2–related factor 2 pathway

Hyperglycemia-related retinopathy is a disease with a high blindness rate. Recent reports indicate that many flavonol compounds have the potential to prevent the occurrence of disease in the retina by regulating the gut–retina axis. Here, we hypothesized that quercetin could alleviate the symptoms of retinopathy. To clarify the mechanism, Sprague Dawley rats were fed a high-fat diet containing quercetin for 12 weeks and injected with streptozotocin in the ninth week. Additionally, neomycin and ampicillin were used to establish a pseudo-sterile rat model. Afterward, changes in the retina were investigated by using electroretinogram and optical coherence tomography. Blood and tissue samples were collected and biochemical components were analyzed. The extent of intestinal injury was determined via hematoxylin-eosin staining. Microbial community structure was analyzed by using 16S ribosomal RNA sequencing. Finally, the expression of genes was analyzed using real-time polymerase chain reaction. The results showed that quercetin reduced the decline in electroretinography amplitude and outer nuclear layer thickness, increased the activities of antioxidant enzymes, decreased the contents of proinflammatory factors and blood glucose, enhanced the concentration of insulin, and inhibited intestinal dysbiosis and improved gut morphology. Importantly, the underexpression of nuclear factor erythroid-2 related factor 2 in the retina was reversed by quercetin. However, trend changes were no longer significant in most of the indicators after antibiotic treatment. In summary, quercetin has therapeutic effects on retinopathy by regulating the gut–retina axis and nuclear factor erythroid-2 related factor 2 pathway, and the presence of gut microbiota helps quercetin exert its effects on the retina.

Relationships Between Systemic Inflammation, Intestinal Damage and Postoperative Organ Dysfunction in Adults Undergoing Low-Risk Cardiac Surgery.

Approximately half of patients who undergo cardiac surgery develop systemic inflammatory response syndrome. Extracorporeal circulation and intestinal injury may play a role in this inflammatory response, although their relative contributions remain elusive. Moreover, it is largely unknown to what extent these factors contribute to cardiac surgery-induced postoperative organ dysfunction. In this secondary analysis, we measured circulating levels of the intestinal damage marker intestinal fatty acid binding protein (I-FABP) and of the inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, IL-1RA, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and MIP-1β in 180 patients undergoing on-pump cardiac surgery. The average Z-score of levels of the different cytokines was used as an integral measure of the cytokine response. Relationships between duration of extracorporeal circulation, extent of intestinal injury, inflammation, and postoperative organ dysfunction were explored. Plasma I-FABP levels increased during surgery, with peak levels observed at the end of cardiopulmonary bypass (CPB). Except for TNF-α, the levels of all cytokines increased during surgery, with peak levels observed either 2 (MCP-1, MIP-1α, and MIP-1β), 4 (IL-6, IL-8, and IL-1RA) or 6 (IL-10) hours after the end of CPB. While the duration of CPB significantly correlated with cytokine Z-score (r=0.544, p<0.05), no relationship with I-FABP levels was found. Furthermore, no significant correlations between I-FABP and cytokine levels were observed. The duration of CPB correlated with a deterioration in postoperative kidney function (estimated glomerular filtration rate [eGFR]) and troponin levels. Cytokine Z-score was associated with postoperative troponin levels, fluid administration, inotropic score, pulmonary alveolar-arterial gradient on the first postoperative morning, and deterioration of kidney function (eGFR). I-FABP levels did not correlate with any of the cardiovascular, pulmonary, or renal parameters. In patients undergoing low-risk cardiac surgery, the duration of CPB represents an important determinant of the systemic cytokine response, whereas both the CPB duration and the systemic inflammatory response contribute to subsequent organ dysfunction. Intestinal damage does not appear to play a relevant role in the postoperative inflammatory response and development of postoperative organ dysfunction in these patients.

Cryptdin-2 predicts intestinal injury during heatstroke in mice.

Intestinal injury-induced bacterial translocation and endotoxemia are important in the pathophysiological process of heatstroke. However, the underlying mechanism remains to be fully elucidated. Previous studies using 2D-gel electrophoresis found that defensin-related cryptdin-2 (Cry-2), an intestinal α-defensin, is upregulated in intestinal tissues during heatstroke in mice, and that treatment with ulinastatin, a multivalent enzyme inhibitor, reduced heat-induced acute lung injury. To investigate the association between Cry-2 and heat stress (HS)-induced intestinal injury and the probable protective role of ulinastatin, the present study examined the intestinal expression of Cry-2 via histopathologic analysis and reverse transcription-quantitative polymerase chain reaction analysis in mice with heatstroke. The heat-stressed mice were exposed to different core temperatures and cooling treatments, and intestinal pathological changes and Chiu scores were determined. Chemical markers of intestinal injury, serum and intestinal concentrations of diamine oxidase (DAO) and D-lactic acid (D-Lac), and serum and intestinal concentrations of Cry-2 were also determined. Correlations were analyzed using Spearman's correlation analysis. It was found that HS upregulated the expression of Cry-2, and the serum and intestinal concentrations of Cry-2 were correlated with the severity of HS-induced intestinal damage, indicated by pathology scores and concentrations of DAO and D-lac. Ulinastatin protected the intestines from HS-induced injury and downregulated the expression of Cry-2, which was also correlated with the extent of intestinal injury. Therefore, ulinastatin administration may be beneficial for patients with heatstroke, and Cry-2 may be a novel predictor of HS-induced intestinal injury.

Safety of mesenchymal stromal cell therapy for inflammatory bowel diseases: results of a 5-year follow-up

To compare the safety of therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) who have received combination anti-inflammatory therapy using bone marrow mesenchymal stromal cells (MSC) and standard therapy with 5-aminosalicylic acid, glucocorticosteroids, and immunosuppressive agents. Unfavorable consequences were analyzed in 103 patients (56 with UC and 47 with CD) with inflammatory bowel disease (IBD) after MSC administration. The findings were compared with data obtained in 208 patients with UC and CD on standard anti-inflammatory therapy. All the patients were similar in demographic parameters, the duration of disease, the extent of intestinal injury, the nature of a course, the type and degree of disease. The analyzed groups did not include patients who had received therapy with anti-TNF-α drugs. The safety of therapy was evaluated from the presence of complications occurring during the follow-up. By analyzing the unfavorable consequences in 103 patients with IBD and comparing them with treatment results in 208 patients with UC and CD on standard anti-inflammatory therapy, the authors revealed no differences in the development of acute posttransfusion reactions, infectious complications, exacerbations of chronic inflammatory diseases, severe infectious complications, malignant transformation, and fatal cases in patients with UC and CD, except for those with transient fever. The results of this study demonstrate that the innovative method of cell therapy is clinically safe.

Aggravation of Exercise-Induced Intestinal Injury by Ibuprofen in Athletes

Nonsteroidal anti-inflammatory drugs are commonly used by athletes to prevent anticipated exercise-induced pain, thereby putatively improving physical performance. However, these drugs may have potentially hazardous effects on the gastrointestinal (GI) mucosa during strenuous physical exercise. The aim of the current study was to determine the effect of oral ibuprofen administration before exercise on GI integrity and barrier function in healthy individuals. Nine healthy, trained men were studied on four different occasions: 1) 400 mg ibuprofen twice before cycling, 2) cycling without ibuprofen, 3) 400 mg ibuprofen twice at rest, and 4) rest without ibuprofen intake. To assess small intestinal injury, plasma intestinal fatty acid binding protein (I-FABP) levels were determined, whereas urinary excretion of orally ingested multisugar test probes was measured using liquid chromatography and mass spectrometry to assess GI permeability. Both ibuprofen consumption and cycling resulted in increased I-FABP levels, reflecting small intestinal injury. Levels were higher after cycling with ibuprofen than after cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen (peak I-FABP, 875 ± 137, 474 ± 74, 507 ± 103, and 352 ± 44 pg·mL, respectively, P < 0.002). In line, small intestinal permeability increased, especially after cycling with ibuprofen (0-2 h urinary lactulose/rhamnose ratio, 0.08 (0.04-0.56) compared with 0.04 (0.00-0.20), 0.05 (0.01-0.07), and 0.01 (0.01-0.03), respectively), reflecting loss of gut barrier integrity. Interestingly, the extent of intestinal injury and barrier dysfunction correlated significantly (RS = 0.56, P < 0.001). This is the first study to reveal that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals. We conclude that nonsteroidal anti-inflammatory drugs consumption by athletes is not harmless and should be discouraged.

Intestinal thrombotic microangiopathy induced by FK506 in rats

Thrombotic microangiopathy (TMA) is one of the severe complications after stem cell transplantation (SCT) and is associated with graft-versus-host disease (GVHD) prophylaxis including FK506. In this study, we experimented on rats using FK506 to demonstrate the occurrence of intestinal TMA. FK506 was administrated into Wistar/ST rats intraperitoneally for 7 days. Rats were examined histopathologically after FK506 injection using light and electron microscopy and immunohistochemistry. FK506 concentrations in whole blood were measured by enzyme immunoassay. In the acute phase, hemorrhagic lesions with multifocal erosions and crypt loss were found in the small intestines of all treated rats. Capillary vessels were dilated, and a few platelet thrombi were found. Electron microscopy demonstrated degenerative swelling of endothelial cells and platelet aggregates adhering to the vessel walls. In the later phase, epithelial regenerative failure, characterized by crypt ghosts, was found in the affected mucosa. Apoptotic epithelial cells were increased in number. The extent of intestinal injury was proportional to the whole blood levels of FK506. The intestinal lesions in rats were consistent with TMA and induced by the injection of FK506 alone. Apoptotic enteropathy was also observed and similar to intestinal GVHD. In this study, we established an intestinal TMA model induced by immunosuppressant (Tacrolimus) only without irradiation.