Reduced Colonic Mucosal Injury in 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Poly ADP-Ribose Polymerase (TIPARP/PARP7)-Deficient Mice

Poly-ADP-ribose polymerases (PARPs) are important regulators of the immune system, including TCDD-inducible poly-ADP-ribose polymerase (TIPARP), also known as poly-ADP-ribose polymerase 7 (PARP7). PARP7 negatively regulates aryl hydrocarbon receptor (AHR) and type I interferon (IFN-I) signaling, both of which have been implicated in intestinal homeostasis and immunity. Since the loss of PARP7 expression increases AHR and IFN-I signaling, we used a murine dextran sulfate sodium (DSS)-induced colitis model to investigate the effect of PARP7 loss on DSS-induced intestinal inflammation. DSS-exposed Parp7−/− mice had less body weight loss, lower disease index scores, and reduced expression of several inflammation genes, including interleukin IL-6, C-x-c motif chemokine ligand 1 (Cxcl1), and lipocalin-2, when compared with wild-type mice. However, no significant difference was observed between genotypes in the colonic expression of the AHR target gene cytochrome P450 1A1 (Cyp1a1). Moreover, no significant differences in microbial composition were observed between the genotypes. Our findings demonstrate that the absence of PARP7 protein results in an impaired immune response to colonic inflammation and suggests that PARP7 may participate in the recruitment of immune cells to the inflammation site, which may be due to its role in IFN-I signaling rather than AHR signaling.

Phlegmonous gastritis in 2 yearling horses

Phlegmonous gastritis was diagnosed in 2 yearling fillies that were presented with a 1-wk history of fever, lethargy, and hypoproteinemia, associated with a previous diagnosis of equine proliferative enteropathy based on clinical signs and PCR assay detection of Lawsonia intracellularis in fecal samples. Abdominal ultrasound revealed enlargement of the stomach and expansion of its submucosal layer with hypoechoic fluid, as well as thickened hypomotile small intestinal segments. Given the poor prognosis and poor response to treatment, both horses were euthanized, one on the day of presentation and the other after 3 wk of intensive medical management including a combination of antimicrobials, analgesics, and intravenous colloids. At autopsy, acute mural gastritis characterized by severe submucosal edema with suppurative inflammation (i.e., phlegmonous gastritis) and necroulcerative enteritis compatible with the necrotizing form of equine proliferative enteropathy were identified in both horses. The gastric inflammation was associated with thrombosis and mixed bacterial populations, including Clostridium perfringens, that were confined to the submucosa without evidence of mucosal involvement; toxin genes compatible with C. perfringens type C were identified in one case. Human phlegmonous gastritis is an uncommon, often-fatal pyogenic infection that is often associated with mucosal injury, bacteremia, or immunocompromise. Our finding of this unusual gastric lesion in 2 horses with similar signalment, clinical disease, and spectrum of postmortem lesions suggests a similar etiopathogenesis that possibly involves local, regional, or distant hematogenous origin, and should be considered a potential complication of gastrointestinal mucosal compromise in horses.

Organoids as ex vivo culture system to investigate infection-host interaction in gastric pre-carcinogenesis.

Advancements in stem cell research have enabled the establishment of three-dimensional (3D) primary cell cultures, known as organoids. These culture systems follow the organization of an in vivo organ, as they enclose the different epithelial cell lines of which it is normally composed. Generation of these 3D cultures has bridged the gap between in vitro models, made up by two-dimensional (2D) cancer cell lines cultures, and in vivo animal models, that have major differences with human diseases. Organoids are increasingly used as a model to study colonization of gastric mucosa by infectious agents and to better understand host-microbe interactions and the molecular events that lead to infection, pathogen-epithelial cells interactions and mechanisms of gastric mucosal injury. In this review we will focus on the role of organoids as a tool to investigate molecular interactions of Helicobacter (H.) pylori and Epstein Barr Virus (EBV) and gastric mucosa and how these infections, that affect ≈ 45% of the world population, might progress to gastric cancer, a highly prevalent cancer and the third leading cause of cancer death.

Research on the Protective Effect of MiR-185-3p Mediated by Huangqin-Tang Decoction (HQT) on the Epithelial Barrier Function of Ulcerative Colitis

Introduction. It has been reported that the traditional Chinese medicine Huangqin-Tang decoction (HQT) has a protective effect on the epithelial barrier function of ulcerative colitis, but its mechanism has not been fully clarified. This study intends to explore the protective mechanism of HQT in regulating microRNA (miRNA) for the first time. Methods. Based on the Balb/c mice ulcerative colitis model, the mice were given a gavage of 0.1 mL/10 g HQT every day for 7 days; on the 8th day, the colon of the mice was dissected, the length of the colon for the mice was measured, and the score was given based on this. Analysis of colonic mucosal injury was conducted by hematoxylin-eosin staining. Then, the differential miRNA was screened and sequenced in colon tissue using the HiSeq platform. And the differential miR-185-3p gene was verified by RT-PCR. Finally, the effects of HQT on miR-185-3p, occludin protein expression, and transepithelial electrical resistance (TEER) value were observed in combination with the CaCo2 intestinal epithelial cell model. Results. HQT treatment can alleviate the shortening of colon length and reverse the intestinal mucosal injury. miRNA sequencing of colonic tissue showed that miR-185-3p was significantly downregulated in the model group, while HQT could upregulate miR-185-3p, thereby affecting the myosin light chain kinase (MLCK)/myosin light chain phosphorylation (p-MLC) pathway and leading to increased expression of occludin protein, which ultimately protected the intestinal epithelial barrier function. Conclusion. HQT can protect colon epithelial barrier function by regulating miR-185-3p.

Shugan Hewei Decoction Alleviates Cecum Mucosal Injury and Improves Depressive- and Anxiety-Like Behaviors in Chronic Stress Model Rats by Regulating Cecal Microbiota and Inhibiting NLRP3 Inflammasome

Chronic stress is a significant cause of depression, anxiety, and intestinal mucosal injury. Gut microbiota disturbances are also associated with these disorders. Shugan Hewei Decoction (SHD), which is a traditional Chinese medicine formula developed by our team, has shown superior therapeutic effects in the treatment of depression, anxiety, and functional gastrointestinal diseases caused by chronic stress. In this study, we investigated the modulatory effect of SHD on the cecal microbiota and cecum mucosal NOD-like receptor protein 3 (NLRP3) inflammasome in a chronic unpredictable stress (CUS)/social isolation rat model. After the SHD intervention, the CUS model rats showed improvements in their depressive- and anxiety-like behaviors, as well as sustained body weight growth and improved fecal characteristics. SHD improved the cecal microbiota diversity and changed the abundance of six microbial genera. A Spearman’s correlation analysis showed a strong correlation between the NLRP3 inflammasome and CUS-perturbed cecal biomarker microbiota. SHD regulated the excessive expression of NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18 in the serum and cecum mucosa induced by CUS, as well as the activation of the Toll-like receptor 4/nuclear factor-κB signaling cascades. Our results reveal the pharmacological mechanisms of SHD and provide a validated therapeutic method for the treatment of depression, anxiety, and cecum mucosal injury.

A Fatal Case of Severe Acute Organophosphorus Pesticide Poisoning Complicated with Secondary Hemophagocytic Lympho-Histiocytosis, Severe Lower Intestinal Hemorrhage and Intestinal Mucormycosis

A man in his 50’s, under influence of alcohol, accidentally ingested a pesticide, and was referred for further management and admitted to our hospital. An empty can of Curacron® was found at the site in his farm where he took the alleged pesticide. This raised the suspicion of organophosphorus pesticide poisoning and he was managed at two medical centres before getting admitted to our hospital. His hospital course was complicated with multiorgan dysfunction, shock, respiratory failure and intermediate syndrome. On day five he developed secondary hemophagocytic lymphohistiocytosis (sHLH) and had hematochezia on day six. Colonoscopy revealed multiple circumferential ulcerations in descending and sigmoid colon with luminal narrowing. Biopsy of colonic tissue showed evidence of intestinal Mucormycosis. The clinical presentation of organophosphorus pesticide poisoning in this patient was complicated with multiple issues and included sHLH, chemical gastroenteritis, hemorrhagic ulcers and intestinal zygomycosis. The organophosphorus pesticide ingested by the patient was a 50% emulsifiable concentrate of profenofos along with vegetable oil, soyabean oil and polyglycol ether alkyl aryl sulphate calcium salt 5.25% w/w as an emulsifier/spreading agent. The management of the patient is discussed. Due to the possibility of the emulsifier adhering to the gastrointestinal tract and causing mucosal injury, it is necessary to identify the drug composition and ingredients of the pesticide as soon as possible when managing organophosphorus poisoning.

Role of Secretoglobin+ (club cell) NFκB/RelA-TGFβ signaling in aero-allergen-induced epithelial plasticity and subepithelial myofibroblast transdifferentiation

Repetitive aeroallergen exposure is linked to sensitization and airway remodeling through incompletely understood mechanisms. In this study, we examine the dynamic mucosal response to cat dander extract (CDE), a ubiquitous aero-allergen linked to remodeling, sensitization and asthma. We find that daily exposure of CDE in naïve C57BL/6 mice activates innate neutrophilic inflammation followed by transition to a lymphocytic response associated with waves of mucosal transforming growth factor (TGF) isoform expression. In parallel, enhanced bronchiolar Smad3 expression and accumulation of phospho-SMAD3 was observed, indicating paracrine activation of canonical TGFβR signaling. CDE exposure similarly triggered epithelial cell plasticity, associated with expression of mesenchymal regulatory factors (Snai1 and Zeb1), reduction of epithelial markers (Cdh1) and activation of the NFκB/RelA transcriptional activator. To determine whether NFκB functionally mediates CDE-induced growth factor response, mice were stimulated with CDE in the absence or presence of a selective IKK inhibitor. IKK inhibition substantially reduced the level of CDE-induced TGFβ1 expression, pSMAD3 accumulation, Snai1 and Zeb1 expression. Activation of epithelial plasticity was demonstrated by flow cytometry in whole lung homogenates, where CDE induces accumulation of SMA+Epcam+ population. Club cells are important sources of cytokine and growth factor production. To determine whether Club cell innate signaling through NFκB/RelA mediated CDE induced TGFβ signaling, we depleted RelA in Secretoglobin (Scgb1a1)-expressing bronchiolar cells. Immunofluorescence-optical clearing light sheet microscopy showed a punctate distribution of Scgb1a1 progenitors throughout the small airway. We found that RelA depletion in Secretoglobin+ cells results in inhibition of the mucosal TGFβ response, blockade of EMT and reduced subepithelial myofibroblast expansion. We conclude that the Secretoglobin—derived bronchiolar cell is central to coordinating the innate response required for mucosal TGFβ1 response, EMT and myofibroblast expansion. These data have important mechanistic implications for how aero-allergens trigger mucosal injury response and remodeling in the small airway.