Toll‐like receptors 2 and 4 exert opposite effects on the contractile response induced by serotonin in mouse colon: role of serotonin receptors

New Findings What is the central question of this study? The action of Toll‐like receptors (TLRs) 2 and 4 on the motor response to serotonin in mouse colon has not previously been reported. What is the main finding and its importance? Toll‐like receptors 2 and 4 modulate the serotonin‐induced contractile response in mouse colon by modifying the expression of serotonin (5‐HT) receptors. Alterations in 5‐HT2A and 5‐HT2C receptors explain the increase of the response to serotonin in TLR2−/− mice. Alterations in 5‐HT2C and 5‐HT4 receptors explain the suppression of the response to serotonin in TLR4−/− mice. The microbiota, through Toll‐like receptors (TLRs), may regulate gastrointestinal motility by activating neuroendocrine mechanisms. We evaluated the influence of TLR2 and TLR4 in spontaneous contractions and in the serotonin (5‐HT)‐induced motor response in mouse colon, and assessed the 5‐HT receptors involved. Muscle contractility studies to evaluate the intestinal spontaneous motility and the response to 5‐HT were performed in the colon from wild‐type (WT), TLR2−/−, TLR4−/− and TLR2/4 double knockout (DKO) mice. The 5‐HT receptor mRNA expression was determined by real‐time PCR. The amplitude and frequency of the spontaneous contractions of the colon were smaller in TLR4−/− and TLR2/4 DKO mice with respect to WT mice. In WT, TLR2−/− and TLR2/4 DKO mice, 100 μm 5‐HT evoked a contractile response. The contractile response induced by 5‐HT was significantly higher in TLR2−/− than in WT mice. In TLR4−/− mice, 5‐HT did not evoke any contractile response. The mRNA expression of 5‐HT2A was increased in TLR2−/− and TLR2/4 DKO mice. The 5‐HT2C and 5‐HT4 mRNA expressions were increased in TLR4−/− and TLR2/4 DKO mice. The 5‐HT2C mRNA expression was diminished in TLR2−/− mice. The 5‐HT3 mRNA expression was increased in TLR2−/−, TLR4−/− and TLR2/4 DKO mice. The 5‐HT7 mRNA expression was diminished in TLR2/4 DKO mice. In WT, TLR2−/− and TLR2/4 DKO mice, 5‐HT2, 5‐HT3, 5‐HT4 and 5‐HT7 receptor antagonists reduced or blocked the contractile response evoked by 5‐HT. We postulate that TLR2 and TLR4 modulate the serotonin contractile motor response in mouse colon in an opposing manner by modifying the expression of several serotonin receptors.