Sucralose Alters Gut Microbiota, Intestinal Metabolites, and Epithelial Serotonergic Responses to Visceral Stimulation in Mice Exposed to Chronic Restraint Stress

Background/Objectives: Dietary modifiers of the gut ecosystem may influence intestinal and host responses associated with psychological stress. However, it remains unclear whether sucralose, a widely consumed non-nutritive sweetener, alters host–microbiota interactions following chronic stress exposure. We investigated the effects of short-term experimental sucralose exposure in mice previously subjected to chronic restraint stress (CRS). Methods: Following completion of the CRS protocol, mice received 0.03% or 0.1% sucralose in drinking water for 12 days. Intestinal phenotypes, cecal microbial community structure, microbial metabolites, colonic epithelial gene expression, and epithelial serotonergic responses following allyl isothiocyanate (AITC)-induced visceral stimulation were evaluated. Results: Colon length was significantly reduced in the 0.1% sucralose group, whereas intestinal permeability remained unchanged. Sucralose selectively altered colonic epithelial gene expression and was associated with changes in cecal microbial community structure without marked changes in alpha diversity. The relative abundance of Bacteroides acidifaciens was significantly reduced, particularly in the 0.1% sucralose group. Fecal acetate and cecal tryptophan concentrations were decreased following sucralose exposure. Following AITC-induced visceral stimulation, the CRS + 0.1% sucralose group exhibited reduced immobility behavior together with increased epithelial serotonin and 5-hydroxyindoleacetic acid concentrations. Conclusions: In mice previously exposed to CRS, short-term sucralose exposure was associated with colon shortening, differences in cecal microbial community structure, reduced Bacteroides acidifaciens abundance, decreased fecal acetate and cecal tryptophan concentrations, and altered epithelial serotonergic responsiveness following visceral stimulation. The behavioral and epithelial serotonergic findings suggest that prior stress exposure may influence selected host responses to sucralose. These findings provide a basis for future studies examining how dietary sweeteners modify host–microbiota interactions following chronic stress exposure.