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Inflammatory bowel disease (IBD) impacts patient quality of life significantly. The dysfunction of intestinal immune barrier is closely associated with IBD. The guanylate cyclase-C (GC-C) signaling pathway activated by the guanylin (Gn) ligand is involved in the occurrence and development of IBD. However, how it regulates the intestinal immune barrier is still unclear. To investigate the effect of the GC-C pathway on intestinal mucosal immunity and provide experimental basis for seeking new therapeutic strategies for IBD, we focused on Caco-2 cells and intestinal intra-epithelial lymphocytes (IELs), which displayed inflammatory responses induced by lipopolysaccharide (LPS). GC-C activity was modulated by transfection with Gn overexpression or GC-C shRNA plasmid. Levels of Gn, GC-C, and CFTR; transepithelial electrical resistance (TER); paracellula r permeability; and levels of IL-2, IFN-γ, and secretory IgA (sIgA) were examined. The study found that after stimulation with LPS, Gn, GC-C, CFTR, TER, and sIgA levels were all significantly reduced, IL-2 and IFN-γ levels as well as paracellular permeability were significantly increased. These indicators changed inversely and significantly after transfection with the Gn overexpression vector. Compared to the vector controls, GC-C-silenced cells displayed significantly decreased levels of GC-C, CFTR, and TER and increased levels of IL-2, IFN-γ, and paracellular permeability stimulated by LPS. The results show that Gn ligand can protect the intestinal immune barrier by activating the GC-C signaling pathway, which may be helpful for the development of new treatments for IBD. DATA AVAILABILITY STATEMENT: The data used to support the findings of this study are available from the corresponding author upon request.

Background: Complications are the main cause of the disease burden of diabetes. Genes determining the development and progression of diabetic complications remain to be identified. Diabetic neuropathy is the most common and debilitating complication and mainly affects the nerves of legs and feet. In this study, we attempted to identify diabetic neuropathy-specific genes from reliable large-scale genome-wide association studies (GWASs) for diabetes perse. Methods: Taking advantage of publicly available data, we initially converted the GWAS signals to transcriptomic profiles in the tibial nerve using the functional summary-based imputation (FUSION) algorithm. The FUSION-derived genes were then checked to determine whether they were differentially expressed in the sciatic nerve of mouse models of diabetic neuropathy. The dysregulated genes identified in the sciatic nerve were explored in the blood of patients with diabetes. Results: We found that eleven out of 452 FUSION-derived genes were regulated by diabetes GWAS loci and were altered in the sciatic nerve of mouse models with early-stage neuropathy. Among the eleven genes, significant (P-value#60;0.05) expression alterations of HSD17B4, DHX32, MERTK, and SFXN4 could be detected in the blood of human patients. Conclusions: Our analyses identified genes with an effect in the sciatic nerve and provided the possibility of noninvasive early detection of diabetic neuropathy.

Inflammatory bowel disease (IBD) shares many clinical, endoscopic, and histologic aspects of enteritis and colitis of infectious etiologies, including bacteria, viruses, fungi, and parasites. Patients with infectious enteritis and colitis often have a history of consumption of unclean drinks or foods, especially in the epidemic or endemic area. Patients with acute episodes often present fever, abdominal pain, diarrhea, mucus, and bloody bowel movements. In most cases, infectious enteritis and colitis are self-limited, lasting several days to several weeks. Stool examination often shows red blood cells and white blood cells. However, stool microbiological examination, albeit useful, is only able to identify pathogen(s) in less than 50% of patients. During the acute phase of infectious enteritis or colitis, upper and lower endoscopy usually provide limited value in the diagnosis and differential diagnosis. However, the endoscopy is required, if the symptom persists beyond 4 weeks. Endoscopic features of infectious bowel diseases are mostly nonspecific. However, there are some characteristic endoscopic features in some infectious bowel diseases, such as intestinal tuberculosis. These agents may also cause superimposed or opportunistic infection to underlying IBDs.

Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD) and significantly impacts patient quality of life. Previous research revealed that the guanylate cyclase-C (GC-C) signaling pathway is associated with the severity of UC. We aimed to investigate the effect of the GC-C agonist, guanylin (Gn), on inflammatory injury in mice with colitis. An experimental UC model was established in Balb/c mice. Mesalamine served as a positive control. The Gn overexpression vector was administered once per day for 1 week. Intestinal permeability of the mice was measured using fluorescein isothiocyanate-dextran after the treatment. Histopathologic grading was estimated to assess the inflammatory injury of the colon. The expression level of crucial mediators of the GC-C signaling pathway (Gn, Ugn and GC-C) and tight junction proteins (occludin, claudin-1 and ZO-1) was measured in the colon. Additionally, the level of pro-inflammatory cytokines (IL-8 and TNF-α) in serum was measured. After injecting the UC mice with the Gn overexpression vector, the body weight increased, and the frequency of loose stools and bloody stools was decreased. Intestinal permeability and histopathologic score were significantly reduced (P

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). Glucocorticoids (GCs) are the most effective treatment for moderate to severe active UC. However, one-third of patients are not sensitive to GCs (i.e., they are GC resistant). The mechanism of GC resistance in IBD is unknown, and it remains unclear how to predict resistance in IBD patients. This study aimed to explore the possible correlation between miRNA expression and variability in GC-resistant and GC-sensitive patients with ulcerative colitis. A comparative serum microRNA analysis in GC-resistant and GC-sensitive patients with ulcerative colitis was conducted by microarray. Differential microRNA expression was further validated in serum samples by quantitative real-time PCR. We found that downregulated microRNAs had a significant correlation with several signal transduction pathways (the PI3K-Akt and MAPK signaling pathways) and target genes (HSP90B1, MAPK13, MAPK9, PIK3AP1 and TLR4) related to GC resistance. Eight downregulated microRNAs were chosen for further validation in 76 serum samples. The results showed that miR-16-2-3p, miR-30e-3p, miR-32-5p, miR-642a-5p, miR-150-5p, and miR-224-5p were significantly downregulated in the GC-resistant group. Receiver operating characteristic analysis showed that the area under the curves (AUCs) for those microRNAs were 0.94, 0.93, 0.85, 0.87, 0.92, and 0.99, with specificities of 97.30%, 89.20%, 59.50%, 73.00%, 97.30%, and 97.30% and sensitivities of 74.40%, 84.60%, 97.40%, 92.30%, 66.70%, and 89.70%, respectively. Our study provides preliminary evidence for the pathogenic mechanism of GC resistance and shows that serum microRNAs might serve as biomarkers for GC resistance in IBD.

Butyrate-induced autophagy and anti-inflammatory effects of IECs plays an important role in UC. HSP has been proved to be associated with autophagy. HSF2, as an important regulator of HSP, has been determined to be highly expressed in UC. This study was designed to elucidate the relationship between HSF2, butyrate and epithelial autophagy and the potential mechanism of HSF2-related autophagy in UC. The autophagy levels and HSF2 expression in intestinal mucosa were increased in UC patients compared to controls. In DSS colitis models, hsf2-/- mice exhibited more severe intestinal inflammation and lower autophagy levels than wild-type mice. HSF2 expression could be induced by sodium butyrate and LPS as a dose-response relationship in HT-29 cells, epigenetically via increasing histone acetylation levels at the promoter region by sodium butyrate. Autophagy induced by sodium butyrate was promoted by overexpression HSF2 in HT-29 cells. Moreover, overexpression HSF2 decreased the expression and phosphorylation levels of PI3K, Akt and mTOR induced by sodium butyrate. HSF2 might induced by sodium butyrate and inflammation and played protective roles in UC by enhancing autophagy of IECs. This indicated that HSF2 may be a critical target for autophagy modulation and a new potential therapeutic target in UC.

Inflammatory bowel disease (IBD) is the result of a chronic intestinal inflammatory response which usually occurred in colon and small intestine. Keratins constitute the intermediate filament cytoskeleton in all epithelia. The present study was intended to explore the role of Keratin 1 (KRT1) in the progress of IBD. In normal intestinal tissue, the expression of KRT1 was detected by RT-PCR and Western blot. The levels of KRT1 protein significantly decreased in serum samples of IBD patients as compared with sera of healthy controls. Immunohistochemistry revealed that the expression of KRT1 decreased in various intestinal diseases, especially in Crohn's disease and ulcerative colitis. Furthermore, down-regulated KRT1 was correlated with the severity of IBD. The overexpression of KRT1 maintained epithelial barrier in Caco-2 cells after IL-1β treatment. Furthermore, IL-1β-induced disruption of tight junction became significantly attenuated in KRT1 over-expressing Caco-2 cells as compared with control cells. Thus, KRT1 played an important role of maintaining epithelial barrier and its down-regulation in intestinal tissue was correlated with the progression of IBD.

The transmembrane receptor guanylate cyclase-C (GC-C) signaling pathway has been implicated in several gastrointestinal disorders. Activation of GC-C via guanylin (Gn) and uroguanylin (Ugn) regulates intestinal fluid and electrolyte homeostasis. However, how it regulates the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Here, we investigated the activation of GC-C signaling in ulcerative colitis (UC) of different clinical severities. A total of 60 UC patients and 20 normal controls were recruited. Evaluation of the UC disease activity index (DAI) was performed using a modified Mayo scoring system. The expression of GC-C, Gn and Ugn in the colonic mucosa was measured by quantitative real-time PCR and Western blot. We found that the UC patients had significantly lower expression of GC-C, Gn and Ugn than the controls. Furthermore, there were significant differences for GC-C, Gn and Ugn expression for the UC groups of Grade 1, 2 and 3 and their expression levels were reduced with increases in their DAI. Taken together, our results demonstrate that GC-C, Gn and Ugn are downregulated in UC and this downregulation is more significant with aggravation of the clinical condition. Therefore, the GC-C signaling pathway may be implicated in the progression of UC.