Bilberry (Vaccinium myrtillus L.) Extract Alleviates Gestational Diabetes Mellitus by Coordinating TGR5/FXR Signaling via a Gut Microbiota-Bile Acids 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 acids-TGR5/FXR-GLP-1 axis, a mechanism extending beyond direct antioxidant effects. This study aimed to investigate this hypothesis by examining the protective effects of anthocyanins - 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 by oral gavage at 400 mg/(kg·day), starting 6 weeks before mating and continuing throughout 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, characterized by a notable increase in beneficial Lactobacillus. This shift was accompanied by marked changes in the bile acids (BAs) pool, specifically elevated hyodeoxycholic acid (HDCA) and reduced levels of cholic acid (CA) and chenodeoxycholic acid (CDCA). The modified BAs was associated with a coordinated gut signaling response, simultaneously linked to the activation of TGR5 and inhibition of FXR, which subsequently correlated with stimulated GLP-1 secretion. Integrated correlation analyses further supported this pathway, linking specific microbial alterations to BAs profile shifts and metabolic improvements. Our findings indicate that the anti-GDM effect of bilberry extract is consistent with action via a coordinated gut microbiota–bile acids–TGR5/FXR–GLP-1 pathway. This work provides a novel mechanistic basis for the dietary inclusion of anthocyanins-rich foods in GDM management strategies.