Small Intestinal Injury Research Articles

MST1/2 inhibitor XMU-MP-1 alleviates the injury induced by ionizing radiation in haematopoietic and intestinal system.

The Hippo signalling pathway has been considered as potential therapeutic target in self‐renewal and differentiation of stem and progenitor cells. Thus, mammalian Ste20‐like kinase 1/2 (MST1/2) as the core serine‐threonine kinases in the Hippo signalling pathway has been investigated for its role in immunological disease. However, little information of MST1/2 function in bone marrow suppression induced by ionizing radiation was fully investigated. Here, we reported that MST1/2 inhibitor XMU‐MP‐1 could rescue the impaired haematopoietic stem cells (HSCs) and progenitor cells (HPCs) function under oxidative stress condition. Also, XMU‐MP‐1 pretreatment markedly alleviated the small intestinal system injury caused by the total body irradiation 9 Gy and extended the average survival days of the mice exposed to the lethal dose radiation. Therefore, irradiation exposure causes the serious pathological changes of haematopoietic and intestinal system, and XMU‐MP‐1 could prevent the ROS production, the haematopoietic cells impairment and the intestinal injury. These detrimental effects may be associated with regulating NOX/ROS/P38MARK pathway by MST1/2.

A Review of Potential Role of Capsule Endoscopy in the Work-Up for Chemotherapy-Induced Diarrhea.

Chemotherapy-induced diarrhea (CID) is a common, severe side effect of chemotherapy, immunotherapy, and targeted therapy. Because patients are more prone to continuing chemotherapy if they do not suffer from CID, appropriate diagnosis and monitoring of this disease are essential. However, suitable monitoring methods are yet to be developed. To date, several studies have shown that small-bowel capsule endoscopy (SBCE) is useful in visualizing the entire small intestinal mucosa and detecting small intestinal abnormalities, including bleeding, malignant tumors, and mucosal injury, associated with the use of nonsteroidal anti-inflammatory drugs and low-dose aspirin. Currently, limited studies have evaluated the small intestinal mucosa using SBCE in patients receiving fluoropyrimidine-based chemotherapy or immune checkpoint inhibitors. These studies have reported that small intestinal mucosal injury is common in patients with severe fluoropyrimidine-induced diarrhea. SBCE might be a useful screening method for the early detection of enterocolitis induced by immune checkpoint inhibitors. SBCE may be a powerful tool for the diagnosis and monitoring of CID, and understanding its indication, contraindication, and capsule-retention risk for each patient is important for clinicians.

Çocuklarda dalak yaralanmalarının geriye dönük değerlendirilmesi: Tek bir merkezde on yıllık deneyim

Objective: We aimed to assess the causes of trauma that result in spleen and accompanying organ injuries, management types, and results of management in children referred to our clinic for spleen injuries in the last ten years. Material and Method: The reports of 76 (56 boys,20 girls) patients managed for spleen injuries owing to blunt abdominal trauma between June 2011 and May 2021 were reviewed retrospectively. Results: The patients were aged between 2-17 (8.7±5.4) years old; 56 (73.7%) were boys and 20 (26.3%) were girls. Causes of injuries included accidents involving a motorized vehicle (37,48.7%), falls from height (21, 27.6%), sports/bumping into obstacles (14,18.3%), a crash object in the abdomen (3,3,9%), kick from a horse 1(1.3%). Isolated spleen injury was present in 42 patients (55.3%), while 34 patients (44.7%) had other organ injuries. Spleen injuries were grade I in 9 patients (11.8%), grade II in 18 (23.7.%), grade III in 27 (35.6%), grade IV in 19 (25%), and grade V in 3 (3.9%). Splenectomy was performed in three patients (3.9%) owing to hemodynamic instability and small intestine repair owing to a small intestine injury in two patients (2.6%). None of these patients died from splenic injuries, but one of our patients died from brain injury while in nonoperative treatment. Conclusion: Conservative treatment methods should be chosen in patients with a spleen injury who are hemodynamically stable. The shorter duration of hospital stay, less blood transfusion requirement, and lower morbidity, mortality percentages are indispensable reasons for this method to be preferred. The probability of other organ injuries should be thought of besides splenic trauma.

No protective benefits of low dose acute L-glutamine supplementation on small intestinal permeability, epithelial injury and bacterial translocation biomarkers in response to subclinical exertional-heat stress: A randomized cross-over trial

ABSTRACT Exertional heat stress disrupts gastrointestinal permeability and, through subsequent bacterial translocation, can result in potentially fatal exertional heat stroke. Glutamine supplementation is a potential countermeasure although previously validated doses are not universally well tolerated. Ten males completed two 80-minute subclinical exertional heat stress tests (EHSTs) following either glutamine (0.3 g kg FFM−1) or placebo supplementation. Small intestinal permeability was assessed using the lactulose/rhamnose dual sugar absorption test and small intestinal epithelial injury using Intestinal Fatty-Acid Binding Protein (I-FABP). Bacterial translocation was assessed using the total 16S bacterial DNA and Bacteroides/total 16S DNA ratio. The glutamine bolus was well tolerated, with no participants reporting symptoms of gastrointestinal intolerance. Small intestinal permeability was not influenced by glutamine supplementation (p = 0.06) although a medium effect size favoring the placebo trial was observed (d = 0.73). Both small intestinal epithelial injury (p < 0.01) and Bacteroides/total 16S DNA (p = 0.04) increased following exertional heat stress, but were uninfluenced by glutamine supplementation. Low-dose acute oral glutamine supplementation does not protect gastrointestinal injury, permeability, or bacterial translocation in response to subclinical exertional heat stress.

Staphylococcal Enterotoxin A Induces Intestinal Barrier Dysfunction and Activates NLRP3 Inflammasome via NF-κB/MAPK Signaling Pathways in Mice.

Staphylococcal enterotoxin A (SEA), the toxin protein secreted by Staphylococcus aureus, can cause staphylococcal food poisoning outbreaks and seriously threaten global public health. However, little is known about the pathogenesis of SEA in staphylococcal foodborne diseases. In this study, the effect of SEA on intestinal barrier injury and NLRP3 inflammasome activation was investigated by exposing BALB/c mice to SEA with increasing doses and a potential toxic mechanism was elucidated. Our findings suggested that SEA exposure provoked villi injury and suppressed the expression of ZO-1 and occludin proteins, thereby inducing intestinal barrier dysfunction and small intestinal injury in mice. Concurrently, SEA significantly up-regulated the expression of NLRP3 inflammasome-associated proteins and triggered the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in jejunum tissues. Notably, selective inhibitors of MAPKs and NF-κB p65 ameliorated the activation of NLRP3 inflammasome stimulated by SEA, which further indicated that SEA could activate NLRP3 inflammasome through NF-κB/MAPK pathways. In summary, SEA was first confirmed to induce intestinal barrier dysfunction and activate NLRP3 inflammasome via NF-κB/MAPK signaling pathways. These findings will contribute to a more comprehensive understanding of the pathogenesis of SEA and related drug-screening for the treatment and prevention of bacteriotoxin-caused foodborne diseases via targeting specific pathways.

Protective effect of the traditional Korean herbal prescription, Bojangunbi-tang, on non-steroidal anti-inflammatory drug-induced small bowel injury

Background: Bojanggunbi-tang (BGT) is a well-known combination of ancient Korean herbal medicines and has been widely used for treating gastrointestinal symptoms. Objectives: This study was aimed at investigating whether BGT protects against non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury (NSI), by using a murine model of indomethacin-induced NSI. Materials and Methods: NSI was induced in the mice by subcutaneous injections of 15 mg/kg indomethacin. BGT was administered at doses of 50, 150, and 450 mg/kg, while the positive control received sodium alginate. The treatments were orally administered twice, 30 min before and 6 h after the induction of NSI. The body weight, length of small intestine, macroscopic damages, and histological damages were assessed after 24 h of induction. Results: Gross anatomical analysis revealed that BGT inhibited the shortening of the small intestine and reduced the area of ulceration. Histological analysis revealed that BGT lowered the ulceration and inflammation scores. However, there was no difference between the groups with respect to weight loss. Conclusion: BGT ameliorated NSI via its anti-inflammatory and anti-ulcerative properties. The current study suggests that BGT could be a therapeutic option for NSI.

Characterization and Analysis of the Temporal and Spatial Dynamic of Several Enteritis Modeling Methodologies.

Inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis, is a complex disease involving genetic, immune, and microbiological factors. A variety of animal models of IBD have been developed to study the pathogenesis of human IBD, but there is no model that can fully represent the complexity of IBD. In this study, we established two acute enteritis models by oral 3% DSS or intraperitoneal injection of anti-CD3 antibody, and two chronic enteritis models by feeding 3 cycles of 1.5% DSS or 3 months of the high-fat diet, respectively, and then examined the clinical parameters, histological changes, and cytokine expression profiles after the successful establishment of the models. Our results indicated that in 3% DSS-induced acute enteritis, the colorectal injury was significantly higher than that of the small intestine, while in anti-CD3 antibody-induced acute enteritis, the small intestine injury was significantly higher than that of colorectal damage. Besides, in the 1.5% DSS-induced chronic enteritis, the damage was mainly concentrated in the colorectal, while the damage caused by long-term HFD-induced chronic enteritis was more focused on the small intestine. Therefore, our work provides a reference for selecting appropriate models when conducting research on factors related to the pathogenesis of IBD or evaluating the potential diagnosis and treatment possibilities of pharmaceuticals.

Efficacy of complementary medicine for nonsteroidal anti-inflammatory drug-induced small intestinal injuries

Nonsteroidal anti-inflammatory drug-induced small bowel injuries (NSIs) have been largely ignored for decades due to the focus on nonsteroidal anti-inflammatory drug gastropathy. With the visualization of the small intestines enabled by video capsule endoscopy, the frequency and severity of NSIs have become more evident. NSIs have a complex pathophysiology, and no effective preventive or treatment options have been proven. Complementary and alternative medicine (CAM) has been used to treat disorders of the small intestine, and more research on its effectiveness for NSIs has been conducted.We reviewed the current evidence and mechanisms of action of CAMs on NSI. Clinical and experimental studies on the effect of CAMs on NSIs were performed using 10 databases.Twenty-two studies (3 clinical and 19 in vivo experimental studies) were included in the final analysis involving 10 kinds of CAMs: bovine colostrum, Orengedokuto (coptis), muscovite, licorice, grape seed, wheat, brown seaweed, Ganoderma lucidum fungus mycelia, Chaenomeles speciosa (sweet) Nakai (muguasantie), and Jinghua Weikang capsule. The mechanisms of CAM include an increase in prostaglandin E2, reparation of the enteric nervous system, inhibition of pro-inflammatory cytokines, reduction of intestinal permeability and enteric bacterial numbers, decrease in oxidative stress, and modulation of small intestinal motility.CAM may be a novel alternative option for treating and preventing NSI, and further studies on human and animal models with relevant comorbidities are warranted.

Acute L-glutamine supplementation does not improve gastrointestinal permeability, injury or microbial translocation in response to exhaustive high intensity exertional-heat stress

ABSTRACT Purpose: Exertional-heat stress adversely distrupts (GI) barrier integrity and, through subsequent microbial translocation (MT), can result in potentially fatal exertional-heat stroke. Acute glutamine (GLN) supplementation is a potential nutritional countermeasure, although the practical value of current supplementation regimens is questionable. Method: Ten males completed two high-intensity exertional-heat stress tests (EHST) involving running in the heat (40°C and 40% relative humidity) at lactate threshold to volitional exhaustion. Participants ingested GLN (0.3 g kg FFM−1) or a non-calorific placebo (PLA) one hour prior to the EHST. Venous blood was drawn pre-, post- and one-hour post-EHST. GI permeability was assessed using a serum dual-sugar absorption test (DSAT) and small intestinal epithelial injury using plasma Intestinal Fatty-Acid Binding Protein (I-FABP). MT was assessed using the Bacteroides/total 16S DNA ratio. Results: Volitional exhaustion occurred after 22:19 ± 2:22 (minutes: seconds) in both conditions, during which whole-body physiological responses and GI symptoms were not different (p > 0.05). GI permeability (serum DSAT) was greater following GLN (0.043 ± 0.020) than PLA (0.034 ± 0.019) (p = 0.02; d = 0.47), but small intestine epithelial injury (I-FABP) increased comparably (p = 0.22; = 0.16) following the EHST in both trials (GLN Δ = 1.25 ± 0.63 ng ml−1; PLA Δ = 0.92 ± 0.44 ng ml−1). GI MT (Bacteroides/total 16S DNA ratio) was unchanged in either condition following the EHST (p = 0.43). Conclusion: Acute low-dose (0.3 g kg−1 fat free mass) GLN supplementation ingested one hour before high-intesity exertional-heat stress worsened GI permeability, but did not influence either small intestinal epithilial injury or microbial translocation. Abbreviations: ANOVA: Analysis of variance; CV: Coefficient of Variation; DSAT: Dual Sugar Absorption Test; EDTA: Ethylenediaminetetraacetic acid; EHST: Exertional Heat Stress Test; ELISA: Enzyme Linked Immunosorbent Assay; FFM: Fat Free Mass; GI: Gastrointestinal; GFR: Glomerular Filtration Rate; GLN: Glutamine; HPLC: High Performance Liquid Chromatography; HR: Heart Rate; I-FABP: Intestinal Fatty-Acid Binding Protein; ISAK: International Society for the Advancement of Anthropometric Kinanthropometry; L/R: Lactulose-to-Rhamnose; LT: Lactate Threshold; MT: Microbial Translocation; mVAS: Modified Visual Analogue Scale; PBS: Phosphate-Buffered Saline; PLA: Placebo; qPCR: Quantitative Polymerase Chain Reaction; RH: Relative Humidity; RPE: Rate of Perceived Exertion; SD: Standard Deviation; SEM: Sensor Electronics Module; Tcore: Core Body Temperature; Tbody: Mean Body Temperature; Tskin: Mean Skin Temperature; TS: Thermal Sensation; V̇O2max: Maximal Oxygen Uptake. Highlights The pathophysiology of exertional-heat stroke is widely hypothesised to be at least in part attributable to a systemic inflammatory response caused by the leak of gastrointestinal microbes into the circulating blood. Acute high-dose (0.9 g kg FFM−1) L-glutamine supplementation is widely promoted as a practical strategy to protect gastrointestinal barrier integrity during exertional-heat stress. However, previously validated doses are often poorly tolerated and cannot be recommended for widespread implementation. This study examined the efficacy of low-dose (0.30 g kg FFM−1; ∼20 grams) acute L-glutamine supplementation on small intestinal injury, permeability, and microbial translocation in response a high-intensity exertional-heat stress test to exhaustion (20–30 min). This type of exercise accounts for the majority of exertional-heat stroke cases in the military. Despite being universally well-tolerated across all participants, acute low-dose L-glutamine supplementation worsened gastrointestinal permeability, without influencing either small intestinal injury or microbial translocation. These findings do not support the application of low-dose L-glutamine supplementation to help prevent exertional-heat stroke.

Research progress of non-steroidal anti-inflammatory drug-induced small intestinal injury

Research progress of non-steroidal anti-inflammatory drug-induced small intestinal injury

Bclaf1 regulates c-FLIP expression and protects cells from TNF-induced apoptosis and tissue injury.

TNF stimulation generates pro-survival signals through activation of NF-κB that restrict the build-in death signaling triggered by TNF. The competition between TNF-induced survival and death signals ultimately determines the fate of a cell. Here, we report the identification of Bclaf1 as a novel component of the anti-apoptotic program of TNF. Bclaf1 depletion in multiple cells sensitizes cells to TNF-induced apoptosis but not to necroptosis. Bclaf1 exerts its anti-apoptotic function by promoting the transcription of CFLAR, a caspase 8 antagonist, downstream of NF-κB activation. Bclaf1 binds to the p50 subunit of NF-κB, which is required for Bclaf1 to stimulate CFLAR transcription. Finally, in Bclaf1 siRNA administered mice, TNF-induced small intestine injury is much more severe than in control mice with aggravated signs of apoptosis and pyroptosis. These results suggest Bclaf1 is a key regulator in TNF-induced apoptosis, both invitro and invivo.

Yersinia enterocolitica and Lactobacillus fermentum induces differential cellular and behavioral responses during diclofenac biotransformation in rat gut

Non-steroidal anti-inflammatory drugs (NSAIDs) can induce small-intestinal injuries through inhibition of prostaglandin synthesis. Gut has an important role in building and maintaining the barriers to avoid the luminal gut microbiota from invading the host, and cytoskeleton plays a crucial role in the maintenance of cellular barrier. The recent advances suggest a bi-directional interaction between the drugs and gut microbiota, where gut microbes can metabolize the drugs, and in response drugs can alter the composition of gut microbiota. In the present study, we evaluated the effect of diclofenac on rat gut, when co-administrated with either Yersinia enterocolitica strain 8081 (an enteropathogen) or Lactobacillus fermentum strain 9338 (a probiotic). The LC-MS/MS based label-free quantitation of rat gut proteins revealed 51.38% up-regulated, 48.62% down-regulated in diclofenac-Y. enterocolitica strain 8081 (D*Y), and 74.31% up-regulated, 25.69% down-regulated in diclofenac-L. fermentum strain 9338 (D*L) experiments. The identified proteins belonged to cytoskeleton, metabolism, heme biosynthesis and binding, stress response, apoptosis and redox homeostasis, immune and inflammatory response, and detoxification and antioxidant defence. Further, the histopathological and biochemical analysis indicated more pronounced histological alterations and oxidative stress (enhanced malonaldehyde and altered antioxidant levels) in D*Y rats than D*L rats, compared to control rats. Elevated plus maze (EPM) test performed to determine the behavioral changes, suggested increased anxiety in D*Y rats than D*L rats, compared to control rats. These results together suggest the differential role of either bacterium in biotransformation of diclofenac, and inflammatory and cellular redox response.

Diaphragmatic Rupture With Left Colon and Spleen Herniation and Small Intestine Injury After Blunt Trauma

Traumatic Diaphragmatic Rupture (TDR) is a rare type of trauma. Small intestine injuries are the third most common type of injury resulting from blunt trauma to abdominal organs. The immediate diagnosis of TDR and bowel injuries is a daunting task. We reported a 53-year-old male patient who was transferred to the hospital by EMS because of a car accident. The chest X-ray showed the left diaphragm elevation. Also, a computed tomography scan revealed that the greater omentum, a portion of the colon, spleen, and stomach were transposed in the hemithorax through a diaphragm rupture. The patient underwent laparotomy and the incidental findings in laparotomy showed bowel injuries. This case was a common cause of traumatic left-sided diaphragmatic rupture and intestinal injury. The suspicion of diaphragmatic rupture and intestinal injury in a patient with multiple traumas contributes to early diagnosis. Surgical repair remains the only treatment for diaphragmatic rupture. The severe injury in a part of the intestine may result in the resection of that part.

Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa.

The artificial sweetener acesulfame potassium (ACK) is officially approved as safe for intake and has been used in processed foods. However, ACKs have been reported to induce metabolic syndrome, along with alteration of the gut microbiota in mice. In recent years, studies have suggested that this artificial sweetener promotes myeloperoxidase reactivity in Crohn's disease-like ileitis. We aimed to investigate the effect of ACK on the intestinal mucosa and gut microbiota of normal mice. Acesulfame potassium was administered to C57BL/6J mice (8weeks old) via free drinking. Intestinal damage was evaluated histologically, and messenger RNA (mRNA) levels of TNF-α, IFN-γ, IL1-β, MAdCAM-1, GLP1R, and GLP2R were determined with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed to examine the expression of MAdCAM-1 in the small intestine. The composition of gut microbiota was assessed using high-throughput sequencing. We performed intravital microscopic observation to examine if ACK altered lymphocyte migration to the intestinal microvessels. Acesulfame potassium increased the expression of proinflammatory cytokines, decreased the expression of GLP-1R and GLP-2R, and induced small intestinal injury with an increase in intestinal permeability, and ACK treatment induced microbial changes, but the transfer of feces alone from ACK mice did not reproduce intestinal damage in recipient mice. ACK treatment significantly increased the migration of lymphocytes to intestinal microvessels. Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa. Massive use of non-caloric artificial sweeteners may not be as safe as we think.

Gene expression analysis in NSAID-induced rat small intestinal disease model with the intervention of berberine by the liquid chip technology

ObjectiveInvestigate the effect and mechanism of berberine on the small intestinal mucosa of non-steroidal anti-inflammatory drugs (NSAIDs) related small intestinal injury.Materials and methodsTwenty-four SD rats were randomly divided into control group, model group and intervention group. The model group and intervention group were treated with diclofenac (7.5 mg/kg·d, 2/d), a total of 4 days tube feeding, and the intervention group was treated with 50 mg/kg·d intragastric administration of berberine after 2 days. The control group was treated with 7.5 mg/kg·d, 2/d 0.9% saline tube feeding. Then we screened differential expression of colonic mucosal gene by the liquid chip technology.ResultsCompared with the control group, macroscopic and histology score of the model group increased significantly (P < 0.05), HTR4, HTR1a, F2RL3, CALCA, NPY, CRHR2, IL1b, P2RX3, TPH1, HMOX1, TRPV1, VIP, F2RL1, SLC6A4, TFF2, AQP8 content were significantly increased (P < 0.05), NOS1 content decreased significantly (P < 0.05); Compared with the model group, macroscopic and histology score of the intervention group improved significantly (P < 0.05), and HTR4, F2RL3, NPY, CRHR2, IL1b, VIP, AQP8 content were significantly lower (P < 0.05), NOS1 content increased significantly (P < 0.05).ConclusionBerberine has a protective effect on NSAID-associated small intestinal injury, the mechanism may be that berberine decreases the expression of intestinal mucosa HTR4, F2RL3, NPY, CRHR2, IL1b, VIP, AQP8, and increases the expression of NOS1, that to reduce intestinal permeability and protect intestinal mucosal barrier.

Cadmium exposure triggers oxidative stress, necroptosis, Th1/Th2 imbalance and promotes inflammation through the TNF-α/NF-κB pathway in swine small intestine

Cadmium (Cd) is a toxic environmental pollutant and induces toxic effects to organism. Nevertheless, the mechanism of Cd-induced toxicity in swine remains obscure. To explore this, 10 healthy 6-week-old weaned swine were placed into two groups stochastically, the Cd group was treated with a commercial diet containing 20 mg/kg Cd for 40 days. The results of histopathological and ultrastructural observations showed typical necrosis features and inflammatory cell infiltration in Cd group. Excessive Cd suppressed T-AOC and SOD activities, increased MDA content and ROS levels. Cd diet elevated the expression of RIPK1, RIPK3, and MLKL to activate the RIPK3-dependent necroptosis pathway. Results of Th1 and Th2 cytokines indicated that the levels of IL-4, IL-6 and IL10 was increased, while the level of IFN-γ was decreased, illustrating Th1/Th2 immune imbalance leads to aggravate inflammatory responses. Cd activated the TNF-α/NF-κB pathway and induced inflammatory responses via increasing the expression of HO-1, IL-1β, iNOS, COX2. Heat shock proteins were notably elevated in response to inflammatory reactions. And these effects were inhibited by necrostatin-1 (Nec-1) and N-acetyl-cysteine (NAC). Altogether, these data demonstrated that Cd induced necroptosis and inflammation to aggravate small intestine injury in swine by increasing the excessive accumulation of ROS and imbalanced Th1/Th2, respectively.

Protective Effect of TRPM8 against Indomethacin-Induced Small Intestinal Injury via the Release of Calcitonin Gene-Related Peptide in Mice.

Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel activated by mild cooling and chemical agents including menthol. Nonsteroidal anti-inflammatory drugs have antipyretic, analgesic effects, and they can cause stomach and small intestinal injury. The current study investigated the role of TRPM8 in the pathogenesis of indomethacin-induced small intestinal injury. In male TRPM8-deficient (TRPM8KO) and wild-type (WT) mice, intestinal injury was induced via the subcutaneous administration of indomethacin. In addition, the effect of WS-12, a specific TRPM8 agonist, was examined in TRPM8KO and WT mice with indomethacin-induced intestinal injury. TRPM8KO mice had a significantly higher intestinal ulcerogenic response to indomethacin than WT mice. The repeated administration of WS-12 significantly attenuated the severity of intestinal injury in WT mice. However, this response was abrogated in TRPM8KO mice. Furthermore, in TRPM8-enhanced green fluorescent protein (EGFP) transgenic mice, which express EGFP under the direction of TRPM8 promoter, the EGFP signals in the indomethacin-treated intestinal mucosa were upregulated. Further, the EGFP signals were commonly found in calcitonin gene-related peptide (CGRP)-positive sensory afferent neurons and partly colocalized with substance P (SP)-positive neurons in the small intestine. The intestinal CGRP-positive neurons were significantly upregulated after the administration of indomethacin in WT mice. Nevertheless, this response was abrogated in TRPM8KO mice. In contrast, indomethacin increased the expression of intestinal SP-positive neurons in not only WT mice but also TRPM8KO mice. Thus, TRPM8 has a protective effect against indomethacin-induced small intestinal injury. This response may be mediated by the upregulation of CGRP, rather than SP.

Effect of Weikang Capsule () on Aspirin-Related Gastric and Small Intestinal Mucosal Injury.

To investigate the effects of Weikang Capsule (, WKC) on aspirin-related gastric and small intestinal mucosal injury by magnetically controlled capsule endoscopy (MCCE). Patients taking enteric-coated aspirin aged 40-75 years were enrolled in Beijing Anzhen Hospital, Capital Medical University from January 2019 to December 2019. The patients continued taking aspirin Tablet (100 mg per day) and underwent MCCE before and after 1-month combined treatment with WKC (0.9 g per time orally, 3 times per day). The gastrointestinal symptom score, gastric Lanza score, the duodenal, jejunal and ileal mucosal injury scores were used to evaluate the gastrointestinal injury before and after treatment. Adverse events including nausea, vomiting, abdominal pain, abdominal distension, abdominal discomfort, dizziness, or headache during MCCE and combined treatment were observed and recorded. Twenty-two patients (male/female, 13/9) taking enteric-coated aspirin aged 59.5 ± 11.3 years with a duration of aspirin use of 28.0 (1.0, 48.0) months were recruited. Compared with pre-treatment, the gastrointestinal symptom rating scale scores, gastric Lanza scores, and duodenal mucosal injury scores were significantly reduced after 1-month WKC treatment (P<0.05), and jejunal and ileal mucosal injury scores showed no obvious change. No adverse events occurred during the trial. WKC can alleviate gastrointestinal symptoms, as well as gastric and duodenal mucosal injuries, in patients taking enteric-coated aspirin; it does not aggravate jejunal or ileal mucosal injury, which may be an effective alternative for these patients (Clinical trial registry No. ChiCTR1900025451).

ATG16L1 deficiency exacerbates acute small intestinal epithelial damage.

Abstract Polymorphisms of the autophagy-related gene ATG16L1 are known to contribute to the genetic risk for developing Crohn’s Disease (CD), an inflammatory bowel disease that can affect the entire gastrointestinal tract. Previous studies have shown a role for autophagy in the intestinal epithelium both in Paneth cell function and in protection from intestinal damage, but no spontaneous disease at baseline. Here, we challenged mice specifically deleted for Atg16l1 in intestinal epithelial cells (Atg16l1ΔIEC) with the anti-CD3 mediated model of acute small intestinal injury. Rapid T cell activation by anti-CD3 injection results in small intestinal damage within 24 hours of injection, this typically self-resolves in wild-type mice 5 days post treatment. We found that autophagy sufficiency was protective in anti-CD3 induced injury. Atg16l1ΔIEC mice had higher mortality and worsened pathology in comparison to their wild-type littermates. We found indications of increased intestinal barrier permeability and crypt cell apoptosis in Atg16l1ΔIEC mice. In addition, expression of interferon gamma (IFNγ) and tumour necrosis factor (TNF) was significantly increased in Atg16l1ΔIEC mice, cytokines that have been implicated in driving intestinal injury in autophagy-deficient mice. Antibody-mediated blockade of either TNF or IFNγ rescued survival of Atg16l1ΔIEC mice. Interestingly, anti-IFNγ abolished both the crypt cell apoptosis and Paneth cell death at 24 hours, whereas anti-TNF did not decrease the crypt cell apoptosis or Paneth cell death, suggesting IFNγ is the primary contributor to pathology in this model. Overall, this work implicates intestinal epithelial autophagy in the protective response to acute intestinal injury.

Pure Total Flavonoids From Citrus Protect Against Nonsteroidal Anti-inflammatory Drug-Induced Small Intestine Injury by Promoting Autophagy in vivo and in vitro.

Small intestine injury is an adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) that urgently needs to be addressed for their safe application. Although pure total flavonoids from citrus (PTFC) have been marketed for the treatment of digestive diseases, their effects on small intestine injury and the underlying mechanism of action remain unknown. This study aimed to investigate the potential role of autophagy in the mechanism of NSAID (diclofenac)-induced intestinal injury in vivo and in vitro and to demonstrate the protective effects of PTFC against NSAID-induced small intestine disease. The results of qRT-PCR, western blotting, and immunohistochemistry showed that the expression levels of autophagy-related 5 (Atg5), light chain 3 (LC3)-II, and tight junction (TJ) proteins ZO-1, claudin-1, and occludin were decreased in rats with NSAID-induced small intestine injury and diclofenac-treated IEC-6 cells compared with the control groups. In the PTFC group, Atg5 and LC3-II expression, TJ protein expression, and the LC3-II/LC3-I ratio increased. Furthermore, the mechanism by which PTFC promotes autophagy in vivo and in vitro was evaluated by western blotting. Expression levels of p-PI3K and p-Akt increased in the intestine disease-induced rat model group compared with the control, but decreased in the PTFC group. Autophagy of IEC-6 cells was upregulated after treatment with a PI3K inhibitor, and the upregulation was significantly more after PTFC treatment, suggesting PTFC promoted autophagy through the PI3K/Akt signaling pathway. In conclusion, PTFC protected intestinal barrier integrity by promoting autophagy, which demonstrates its potential as a therapeutic candidate for NSAID-induced small intestine injury.