Pseudostellaria heterophylla Polysaccharide Increases Colonic Mucus Thickness and Bacterial–Epithelial Distance in HFD/STZ-Induced Diabetic Mice

Pseudostellaria heterophylla is a medicinal plant whose polysaccharides have shown metabolic and intestinal effects in animal studies. Mucus injury and bacterial encroachment are associated with metabolic disease. We evaluated colonic mucus morphology and bacterial spatial localization after PF40 treatment in male mice subjected to a high-fat diet and streptozotocin (HFD/STZ). Mice received PF40 (400 mg/kg/day) or vehicle for 6 weeks under shared dietary conditions. In exploratory comparisons, PF40-treated mice exhibited a thicker retained colonic mucus band, greater mucin 2-positive area and greater bacterial–epithelial distance. Colonic Agr2 expression and occludin-positive area were higher, whereas circulating barrier-related markers and colonic inflammatory mediators were lower. Fasting glucose and homeostasis model assessment of insulin resistance were also lower. Fasting insulin was lower by Welch testing, whereas oral glucose tolerance test area under the curve did not differ significantly in the primary exact rank test; significance for both depended on the method. A separate fluorescein isothiocyanate–dextran pilot (n = 3 per treatment group) was inconclusive and requires validation in a larger cohort. These findings identify colonic mucus morphology and bacterial spatial localization as treatment-responsive phenotypes in this model. These concurrent observations do not establish whether mucus and spatial changes mediate barrier, inflammatory or glucose outcomes.