RESUMO
INTRODUCTION: Disruption of intestinal barrier is a key component to various diseases. Whether barrier dysfunction is the cause or effect in these situations is still unknown, although it is believed that translocation of luminal content may initiate gastrointestinal or systemic inflammatory disorders. Since trauma- or infection-driven epithelial permeability depends on Toll-like receptor (TLR) activity, inhibition of TLR signaling has been proposed as a strategy to protect intestinal barrier integrity after infection or other pathological conditions. Recently, selective serotonin recapture inhibitors including sertraline and citalopram were shown to inhibit TLR-3 activity, but the direct effects of these antidepressant drugs on the gut mucosa barrier remain largely unexplored. MATERIALS AND METHODS: To investigate this, two approaches were used: first, ex vivo studies were performed to evaluate sertraline and citalopram-driven changes in permeability in isolated intestinal tissue. Second, both compounds were tested for their preventive effects in a rat model of disrupted gut barrier, induced by a low protein (LP) diet. RESULTS: Only sertraline was able to increase transepithelial electrical resistance in the rat colon both when used in an ex vivo (0.8 µg/mL, 180 min) or in vivo (30 mg/kg p.o., 20 days) fashion. However, citalopram (20 mg/kg p.o., 20 days), but not sertraline, prevented the increase in phospho-IRF3 protein, a marker of TLR-3 activation, in LP-rat ileum. Neither antidepressant affected locomotion, anxiety-like behaviours or stress-induced defecation. CONCLUSION: Our data provides evidence to support the investigation of sertraline as therapeutic strategy to protect intestinal barrier function under life-threatening situations or chronic conditions associated with gut epithelial disruption.
Assuntos
Citalopram/farmacologia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacologia , Ração Animal , Animais , Dieta , Proteínas Alimentares/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Gut microbiota interventions, including probiotic and prebiotic use can alter behavior in adult animals and healthy volunteers. However, little is known about their effects in younger individuals. To investigate this, male Sprague-Dawley rats (post-natal day 21, PND21) received Lactobacillus casei 54-2-33 (104cfu/ml), inulin as prebiotic (16mg/ml), or both together (synbiotic) via drinking water for 14days. Control rats received water alone. Open field (OF) and elevated plus maze (EPM) behaviors were evaluated at PND34 and 35, respectively. 30min after EPM, brains and trunk blood were collected to evaluate hippocampal 5-HT1A (mRNA and protein) and plasma corticosterone (CORT). Lactobacillus, inulin and synbiotic-treated rats had fewer entries to the OF's center and spent more time in its periphery than controls. Synbiotic-fed rats explored the EPM's open arms longer than probiotic and inulin-fed rats. Synbiotic, but not Lactobacillus nor inulin-fed rats had lower levels of EPM-evoked CORT than controls. Basal CORT levels, evaluated in a naïve cohort, were higher in Lactobacillus- and inulin-fed rats than controls. In naïve synbiotic-fed rats, 5-HT1A mRNA levels were higher in dentate gyrus and cornus ammonis 1 layer (CA1), than in all other naïve groups, while hippocampal 5-HT1A protein levels were lower in bacteria-fed rats than controls. 5-HT1A mRNA changes suggest complex effects of gut microbes on hippocampal gene expression machinery, probably involving endogenous/exogenous bacteria and prebiotics interactions. Importantly, age might also influence their behavioral outcomes. Together, these data suggest that interventions in young rat microbiota evoke early behavioral changes upon stress, apparently in a hypothalamus-pituitary-adrenal axis independent fashion.
Assuntos
Ansiedade/induzido quimicamente , Hipocampo/efeitos dos fármacos , Inulina/administração & dosagem , Lacticaseibacillus casei/fisiologia , Simbióticos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Hipocampo/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismoRESUMO
The gut and the brain communicate bidirectionally through anatomic and humoral pathways, establishing what is known as the gut-brain axis. Therefore, interventions affecting one system will impact on the other, giving the opportunity to investigate and develop future therapeutic strategies that target both systems. Alterations in the gut-brain axis may arise as a consequence of changes in microbiota composition (dysbiosis), modifications in intestinal barrier function, impairment of enteric nervous system, unbalanced local immune response and exaggerated responses to stress, to mention a few. In this review we analyze and discuss several novel pharmacological targets within the gut-brain axis, with potential applications to improve intestinal and mental health.