Background As “the second brain”, the gastrointestinal tract contains an intrinsic neuronal network: the Enteric Nervous System (ENS). The ENS governs motility, fluid homeostasis, and blood flow, and it also works with other parts of the intestine, playing a vital role in the occurrence and development of IBS-D. Methods To assess the effects of different IBS-D rat models (life stress, chemical enema stimulation, and compound stimulation ) on the ENS, we have established three models of BALB/c mice by wrapping restrain stress (WRS), a single administration of trinitro-benzene-sulfonic acid with 50ul (TNBS, 2mg/mouse in 50% ethanol), and WRS + TNBS. We have also determined Cytokine levels, the activity of intestinal neurons, intestinal mucosal barrier function, intestinal neurotransmitters, and structural changes of intestinal nerve cells after inducing IBS-D. Results This research found that the intervention of TNBS + WRS, WRS, and TNBS would induce a similar course of effects on the ENS. Among the three models, the distance at the open-field test decreased with speed, AWR scores (at 0.6ml), and intestinal permeability all increased. The levels of 5- hydroxytryptamine in colon tissue rapidly increased, whereas serum showed no significant changes. Using TEM to observe monocyte cells infiltrating neuronal cells and the structural changes in neurons. According to Western blot, HTR3A, C-fos level increased, and PGP9.5 decreased in TNBS + WRS and WRS modeling groups. Using the LEGENDplex™ detection kit to assess 13 mouse cytokines for colon tissues, we found that some inflammation factors significantly changed in the TNBS + WRS group. Conclusion This study depicts a general description of the major processes through which the tumor itself causes fatigue and renders a standard and reliable animal model for further pharmacological or pharmacodynamic studies.
Irritable bowel syndrome with predominant diarrhea (IBS-D) is characterized by increased intestinal permeability. Previous studies have shown that the microRNA-29 gene is involved in the regulation of intestinal permeability in patients with IBS-D. NF-κB was proved to play a key role in inflammatory response of intestine and resultant disruption of tight junction integrity, whose activity could be inhibited by TNF Receptor-Associated Factor 3 (TRAF3). However, the exact mechanism that induces increased intestinal permeability in IBS-D patients has not been clarified. In this study, we found that microRNA-29b‑3p (miR-29b-3p) was significantly upregulated, while TRAF3 was decreased and the NF-κB-MLCK pathway was activated within the colonic tissue of IBS-D patients. Subsequently, we confirmed the targeting relationship between miR-29b-3p and TRAF3 through a double-luciferase reporter assay. Lentivirus transfection of NCM460 cells with miR-29b-3p-overexpressing and -silencing vectors demonstrated that the expression of TRAF3 was negatively correlated with the level of miR-29b-3p. The NF-κB/MLCK pathway was activated in the miR-29b-3p-overexpressing group and inhibited to some extent in the miR-29b-3p-silencing group. Results in WT and miR-29 knockout mice showed that miR-29b-3p levels were increased, TRAF3 levels were decreased, and the NF-κB/MLCK signaling was activated in the WT IBS-D group as compared with the WT control group. The protein levels of TRAF3 and TJs in the miR-29b-/- IBS-D group were partially recovered and NF-κB/MLCK pathway indicators were, to a certain extent, decreased as compared with the WT IBS-D group. These results suggested that miR-29b-3p deletion enhances the TRAF3 level in IBS-D mice and alleviates the high intestinal permeability. In brief, through the analysis of intestinal tissue samples from IBS-D patients and miR-29b-/- IBS-D mice, we showed that miR-29b-3p is involved in the pathogenesis of intestinal hyperpermeability in IBS-D via targeting TRAF3 to regulate the NF-κB-MLCK signaling pathway.
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