Enteric Nervous System Modulation by Entamoeba histolytica: Role of Serotonin Signaling in Secretory Diarrhea Pathophysiology

Abstract

Entamoeba histolytica causes amebiasis, affecting 50 million people worldwide with symptoms ranging from asymptomatic colonization to severe dysentery. The enteric nervous system (ENS) plays a crucial role in regulating intestinal secretion and motility, yet its involvement in amebic diarrhea pathophysiology remains poorly understood. This study investigates how E. histolytica modulates ENS function through serotonin (5-HT) signaling pathways. Using ex vivo intestinal preparations and in vivo mouse models, we examined the effects of E. histolytica infection on enterochromaffin cell (EC) function and serotonergic neurotransmission. Results demonstrate that E. histolytica induces a 4.2-fold increase in mucosal 5-HT release within 6 hours of infection (P < 0.001). Tryptophan hydroxylase-1 (TPH1) expression in EC cells increased 2.8-fold, while serotonin transporter (SERT) expression decreased by 54%. Ussing chamber experiments revealed that E. histolytica-conditioned medium increased short-circuit current (Isc) by 156 μA/cm², which was blocked by the 5-HT₃ receptor antagonist ondansetron (78% inhibition) and the 5-HT₄ antagonist GR113808 (62% inhibition). Calcium imaging of submucosal neurons demonstrated enhanced neuronal excitability following parasite exposure. Genetic deletion of TPH1 in mice significantly attenuated E. histolytica-induced fluid secretion by 68%. Furthermore, parasite cysteine proteases were identified as key mediators of EC cell degranulation. These findings establish serotonergic signaling as a central mechanism in amebic secretory diarrhea and identify 5-HT receptors as potential therapeutic targets.