Grape Antioxidant Dietary Fibre Modulates Apoptosis-Autophagy Balance via Bcl-2/Beclin-1 Axis in Healthy Colon

¹ Departmental Section of Physiology. Pharmacy School. UCM, 28040 Madrid, Spain.
² Health Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain.
³ Institute of Food Technology CONICET, FIQ–UNL, Santa Fe, Argentina.
⁴ Department of Metabolism and Nutrition, Technology and Nutrition (ICTAN-CSIC), Institute of Food Science, Madrid, 28040 Spain.
⁵ Center for Biomedical Research Network (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ISCIII), 28029 Madrid, Spain.

Academic Editor: Stefano D'errico

Published: 29 October 2025 by MDPI in The 1st International Electronic Conference on Medicinal Chemistry and Pharmaceutics session Natural Products and Biopharmaceuticals

Abstract:

Introduction:

Apoptosis and autophagy are essential for epithelial homeostasis and defense against stress in the colon, with the Bcl-2/Beclin-1 axis acting as a regulatory switch. Dietary bioactives, particularly grape-derived polyphenols and fibers, can modulate these pathways. Grape Antioxidant Dietary Fiber (GADF), derived from red grape pomace (Vitis vinifera, var. Cencibel), combines insoluble fiber with polyphenols, mainly high molecular weight proanthocyanidins. This study evaluated GADF’s effect on apoptosis and autophagy regulation in the proximal colon of healthy rats.

Methods:

Male Wistar rats were fed either a control diet or a GADF diet (5% w/w replacing cellulose in an isoenergetic diet) for four weeks. Following euthanasia, apoptosis and autophagy were evaluated in proximal colonic mucosa by immunohistochemistry, Western blotting, and caspase activity assays.

Results:

GADF reduced intrinsic apoptosis, as shown by lower TUNELlabelling index (−56.1%, p<0.0001) and decreased caspase-9 and caspase-3 activities (−56.5% and −64.5%, respectively, p<0.0001). Caspase-8 was unaffected indicating no effect on the extrinsic pathway. The Bax/Bcl-2 ratio decreased (−22.2%, p<0.001), supporting mitochondrial stability. Concurrently, autophagy was activated with Beclin-1 (+70.2%) and LC3B (+35.3%) upregulated (for both, p<0.001), while p62/SQSTM1 decreased (−44.2%, p<0.01). Beclin-1 and LC3B correlated inversely with apoptosis markers, whereas p62/SQSTM1 showed positive correlation.

Conclusions:

GADF modulates the apoptosis-autophagy balance in the healthy colon through regulation of the Bcl-2/Beclin-1 axis, which suggests enhanced autophagic activity and promotes cellular survival. GADF emerges as a promising dietary component to support gut barrier integrity while offering a sustainable option for functional food innovation.

Spanish patents registered under the numbers 2259258 and 2130092

Funded by Universidad Complutense de Madrid, project PR12/24-31551.

Acknowledgment to Alvinesa Natural Ingredients S.L. for their research support.

Keywords: Grape Antioxidant Dietary Fiber (GADF), Intrinsic caspase-dependent apoptosis pathway, Autophagy, Bcl-2/Beclin-1 axis, Colon homeostasis, Functional foods.

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