Dual Role of Endogenous Serotonin in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis

Abstract

Background and Aims: Changes in gut serotonin (5-HT) content have been described in Inflammatory Bowel Disease (IBD) and in different experimental models of colitis: the critical role of this monoamine in the pathogenesis of chronic gastrointestinal inflammation is gradually emerging. Aim of the present study was to evaluate the contribution of endogenous 5-HT through the activation of its specific receptor subtypes to the local and systemic inflammatory responses in an experimental model of IBD.Materials and Methods: Colitis was induced by intrarectal 2,4,6-TriNitroBenzene Sulfonic acid in mice subacutely treated with selective antagonists of 5-HT1A (WAY100135), 5-HT2A (Ketanserin), 5-HT3 (Ondansetron), 5-HT4 (GR125487), 5-HT7 (SB269970) receptors and with 5-HT1A agonist 8-Hydroxy-2-(di-n-propylamino)tetralin.Results: Blockade of 5-HT1A receptors worsened TNBS-induced local and systemic neutrophil recruitment while 5-HT1A agonist delayed and mitigated the severity of colitis, counteracting the increase in colonic 5-HT content. On the contrary, blockade of 5-HT2A receptors improved global health conditions, reduced colonic morphological alterations, down-regulated neutrophil recruitment, inflammatory cytokines levels and colonic apoptosis. Antagonism of 5-HT3, 5-HT4, and 5-HT7 receptor sites did not remarkably affect the progression and outcome of the pathology or only slightly improved it.Conclusion: The prevailing deleterious contribution given by endogenous 5-HT to inflammation in TNBS-induced colitis is seemingly mediated by 5-HT2A and, to a lesser extent, by 5-HT4 receptors and coexists with the weak beneficial effect elicited by 5-HT1A stimulation. These findings suggest how only a selective interference with 5-HT pro-inflammatory actions may represent an additional potential therapeutic option for intestinal inflammatory disorders.

α7 Nicotinic Agonist AR-R17779 Protects Mice against 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in a Spleen-Dependent Way

“…After euthanasia, the colon was explanted, opened longitudinally, flushed with saline solution and MS was immediately evaluated through inspection of the mucosa, executed by two investigators unaware of the treatments applied. MS was determined according to previously published criteria ( Rapalli et al, 2016 ), as the sum of scores (max = 12) attributed as follows: presence of strictures and hypertrophic zones (0, absent; 1, one stricture; 2, two strictures; 3, more than two strictures); mucus (0, absent; 1, present); adhesion areas between the colon and other intra-abdominal organs (0, absent; 1, one adhesion area; 2, two adhesion areas; 3, more than two adhesion areas); intraluminal hemorrhage (0, absent; 1, present); erythema (0, absent; 1, presence of a crimsoned area < 1 cm 2 ; 2, presence of a crimsoned area > 1 cm 2 ); ulcerations and necrotic areas (0, absent; 1, presence of a necrotic area < 1 cm 2 ; 2, presence of a necrotic area > 1 cm 2 ).…”

“…For each sample, at least five transverse 5-μm sections were cut in the distal colon, stained with hematoxylin–eosin and blindly examined in a light microscope (Nikon Eclipse E800). The histological damage was quantified according to Rapalli et al (2016) by an unaware investigator: the grade of mucosal destruction (0, normal; 1, mild; 2, moderate; 3, severe) and the degree of leukocytes infiltration in the lamina propria and submucosa (0, absent; 1, mild; 2, pronounced) were scored (maximum score: 7). Since histological injury produced by TNBS instillation was localized almost exclusively in the distal portion of the colon, the average value of histological score was determined only from sections of distal colon, pooled with those determined for the other animals of the same experimental group and the mean value ± SEM was calculated.…”

Neurotransmitters: The Critical Modulators Regulating Gut–Brain Axis

“…5‐HT 1 has five receptor subclasses namely 5‐HT 1A , 5‐HT 1B , 5‐HT 1D , 5‐HT 1E , and 5‐HT 1F ; 5‐HT 2 has three subclasses, 5‐HT 2A , 5‐HT 2B , and 5‐HT 2C ; whereas 5‐HT 5 has two subclasses, 5‐HT 5A and 5‐HT 5B (Hannon and Hoyer, ). Blockade of 5‐HT 1A receptors has been demonstrated to increase the severity of 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis and exaggerated local and systemic neutrophil recruitment in a mouse model (Rapalli et al, ). On par with these findings, 5‐HT 1A agonist delayed and mitigated the severity of colitis, counteracting the increase in colonic 5‐HT content.…”

Extracts from Hericium erinaceus relieve inflammatory bowel disease by regulating immunity and gut microbiota

“…IBD models are diverse [ 29 , 30 ], and can be broadly categorized into four kinds: chemically induced, biologically induced, genetic (including congenic and genetically modified animals), and cell transfer models. A chemical, 2, 4, 6-trinitrobenzene sulfonic acid (TNBS), is administered rectally in the form of an enema to mice or rats [ 31 ]. It is administered in combination with ethanol, which disrupts the mucous barrier.…”