Zeaxanthin Modulates Early Metabolic and Inflammatory Responses in db/db Mice: Associations with Intestinal Lipid...

Dietary zeaxanthin exhibits low intestinal absorption efficiency, and circulating levels are reduced in individuals with type 2 diabetes, suggesting potential metabolic relevance. However, its role during early-stage diabetes remains incompletely understood. This study examined whether dietary zeaxanthin modulates early metabolic and inflammatory responses and influences host-microbiome interactions during early T2DM progression. Four-week-old male db/db mice and wild-type C57BL/6J mice were fed an AIN-93M diet with or without 0.02% (w/w) zeaxanthin for 4 weeks. Zeaxanthin attenuated body weight gain, adiposity, hyperinsulinemia, and circulating keratinocyte-derived chemokine levels in diabetic mice. These effects were accompanied by reduced ileal membrane localization of Niemann-Pick C1-like protein 1 and decreased hepatic expression of CD36, nuclear factor kappa B p65, and phosphoenolpyruvate carboxykinase 1, without significant improvement in fasting blood glucose or hepatic triglyceride accumulation. Cecal microbiota analysis showed reduced microbial richness in diabetic mice that was not restored by zeaxanthin; however, zeaxanthin induced selective compositional shifts, including enrichment of fermentation-associated taxa (e.g., Ruminococcaceae) and normalization of Clostridium XIVb. Predicted microbial pathways related to fermentation, amino acid biosynthesis, and cofactor metabolism were also altered. Collectively, dietary zeaxanthin modulated early metabolic and inflammatory adaptation and was associated with alterations in intestinal lipid handling, inflammatory signaling, and gut microbiome composition during early T2DM progression.