Impact of BECLIN1 haploinsufficiency on goblet cell function and susceptibility to colitis

Abstract BECLIN1 is a central regulator of autophagy and endocytic trafficking essential for epithelial homoeostasis. While complete intestinal epithelial loss of BECLIN1 causes fatal enteritis originating in the small intestine, the consequences of its partial loss in the gut remain unclear. Given that BECLIN1 expression can vary in human disease, we investigated whether reduced BECLIN1 is sufficient to impair gut barrier function. Heterozygous Becn1 deletion ( Becn1 IEC+/− ) in the mouse intestinal epithelium caused subtle but significant defects. These included shortened small intestines and altered epithelial architecture, despite preservation of basal autophagy, implicating trafficking-related functions. Supporting this conclusion, Becn1 IEC+/− small intestinal epithelial cells showed modest increases in RAB5 +ve vesicles, redistribution of E-CADHERIN and F-actin along lateral membranes and altered apico-basal cell morphology. Given the absence of overt small intestinal epithelial disruption or inflammation, as seen with complete loss of BECLIN1, we next addressed whether BECLIN1 insufficiency manifests a phenotype under stress or in other gut regions. Indeed, in the colon, Becn1 IEC+/− mice exhibited reduced colonic crypt length, baseline goblet cell loss and reduced mucin production, particularly in mature goblet cells, indicating vulnerability of the mucus barrier. When challenged with dextran sulfate sodium (DSS), Becn1 IEC+/− mice exhibited greater weight loss, higher disease activity, more severe histological colitis, and disproportionate loss of neutral mucins, with inflammation confined to the mucosa. Together, these findings show that BECLIN1 insufficiency does not trigger spontaneous inflammation but destabilises epithelial organisation and barrier defence, thereby sensitising the gut to inflammatory challenge and further positioning BECLIN1 as a threshold-dependent determinant of intestinal resilience.