Abstract / Summary
Abstract Gestational diabetes mellitus (GDM) impairs neonatal gut–immune development and increases food allergy risk, yet whether early 2’-fucosyllactose (2’-FL) supplementation can reverse these defects remains unknown. Using a high-fat diet/streptozotocin-induced GDM mouse model, we administered 2’-FL to offspring from postnatal day 7 and evaluated intestinal barrier function, mucosal immunity, regulatory T (Treg) cell responses, gut microbiota (16S rRNA sequencing), and ovalbumin-induced anaphylaxis. Maternal GDM caused sex-biased impairments: male offspring showed greater deficits in intestinal innate immunity (F4/80⁺ macrophages and CD11c⁺ dendritic cells), splenic Treg frequency, and mucosal IgA via downregulated TACI/pIgR, while females primarily exhibited mucus barrier defects (MUC-2 and goblet cell loss). 2’-FL significantly restored these immune parameters in males, with only non-significant trends in females. In the food allergy model, GDM offspring developed severe anaphylaxis, tight junction disruption, sIgA deficiency, Treg/IL-10 loss, and dysbiosis (expansion of Proteobacteria/Epsilonproteobacteria, depletion of Muribaculaceae). 2’-FL alleviated allergic symptoms, repaired ZO-1/Occludin barriers, activated BAFF–TACI signaling to enhance sIgA, restored Treg/IL-10 axis, and reshaped microbiota toward a healthy profile. Notably, 2’-FL only mildly affected OVA-sIgE and Th2 cytokines, suggesting its primary action is tolerance-promoting rather than directly anti-inflammatory. Mechanistically, 2'-FL-mediated expansion of Muribaculaceae and suppression of pro-inflammatory Proteobacteria were correlated with restored tight junction and Treg frequency, implicating microbiota remodeling as an upstream driver of barrier and immune protection. Thus, neonatal 2’-FL exerts sex-dependent protection against GDM-induced gut–immune deficits and reduces food allergy susceptibility, supporting its potential as an early nutritional intervention for GDM-exposed infants, with male offspring showing greater therapeutic responsiveness.