Bilberry (Vaccinium myrtillus L.) extract alleviates gestational diabetes mellitus by coordinating TGR5/FXR signaling via a gut microbiota–bile acid axis

Abstract

Dietary anthocyanins are associated with a reduced risk of gestational diabetes mellitus (GDM). However, it remains unclear whether their efficacy is mediated through the gut microbiota–bile acid–TGR5/FXR–GLP-1 axis, a mechanism extending beyond the direct antioxidant effects. This study aimed to investigate this hypothesis by examining the protective effects of anthocyanin-rich bilberry (Vaccinium myrtillus L.) extract (VME) in rats with GDM. The GDM model was induced by a high-fat diet. The extract was administered via oral gavage at 400 mg (kg day)⁻¹, starting 6 weeks before mating and continuing throughout the pregnancy. VME supplementation significantly alleviated core metabolic disturbances in GDM rats, including hyperglycemia, insulin resistance, dyslipidemia, inflammation, and oxidative stress. Mechanistically, VME induced substantial gut microbiota remodeling, as characterized by a notable increase in the amount of beneficial Lactobacillus. This shift was accompanied by marked changes in the bile acid (BA) pool, specifically an elevated level of hyodeoxycholic acid (HDCA) and reduced levels of cholic acid (CA) and chenodeoxycholic acid (CDCA). The modification of BAs was simultaneously linked to the activation of TGR5 and the inhibition of FXR, which subsequently correlated with stimulated GLP-1 secretion. Integrated correlation analyses further supported this pathway, linking specific microbial alterations to BA profile shifts and metabolic improvements. Altogether, our findings indicate that the anti-GDM effect of bilberry extract is consistent with action via a coordinated gut microbiota–BA–TGR5/FXR–GLP-1 pathway. This work provides a novel mechanistic basis for the dietary inclusion of anthocyanin-rich foods in GDM management strategies.