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OBJECTIVES:Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBS patients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies.METHODS:Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN.RESULTS:We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-D patients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant human occludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64.CONCLUSIONS:These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS. [ABSTRACT FROM AUTHOR]

The Simon effect usually refers to the observation that responding to a nonspatial feature of a stimulus is faster when the position of the stimulus (task-irrelevant) matches the position of the to-be-executed response. The Simon effect can disappear when the Simon task is preceded by a spatial compatibility task with an incompatible mapping. In this experiment, during a preliminary phase, 20 children had to decide whether the outline of a colored stimulus was dotted or continuous. Green stimuli were presented exclusively on the right, whereas red stimuli were presented on the left (the color was task-irrelevant). The participants then had to perform a Simon task. When the instructions required them to press either the left or the right button for red or green stimuli, respectively (Group A), the Simon effect on response latencies was not significant. With the opposite instructions (the right or left button for red or green stimuli, respectively; Group B), the Simon effect was significant on response latencies. The Simon effect was significant on movement times for both groups. These results suggest that during the preliminary phase, each color became associated with the manual response automatically activated by that color's position. In the subsequent Simon task, the presentation of the color activated the associated response. This modulated the planning of the to-be-executed response. [ABSTRACT FROM AUTHOR]

Rationale: Intestinal permeability plays an important role in gut-brain axis communication. Recent studies indicate that intestinal permeability increases in neonate pups during maternal separation (MS). Objectives: The present study aims to determine whether pharmacological inhibition of myosin light chain kinase (MLCK), which regulates tight junction contraction and controls intestinal permeability, in stressed neonates, protects against the long-term effects of MS. Methods: Male Wistar rats were exposed to MS (3 h per day from post-natal day (PND)2 to PND14) or left undisturbed and received daily intraperitoneal injection of a MLCK inhibitor (ML-7, 5 mg/kg) or vehicle during the same period. At adulthood, emotional behaviors, corticosterone response to stress, and gut microbiota composition were analyzed. Results: ML-7 restored gut barrier function in MS rats specifically during the neonatal period. Remarkably, ML-7 prevented MS-induced sexual reward–seeking impairment and reversed the alteration of corticosterone response to stress at adulthood. The effects of ML-7 were accompanied by the normalization of the abundance of members of Lachnospiraceae, Clostridiales, Desulfovibrio, Bacteroidales, Enterorhabdus, and Bifidobacterium in the feces of MS rats at adulthood. Conclusions: Altogether, our work suggests that improvement of intestinal barrier defects during development may alleviate some of the long-term effects of early-life stress and provides new insight on brain–gut axis communication in a context of stress. [ABSTRACT FROM AUTHOR]