Bio-based vitamin B12: bridging biotechnology and sustainability for industrial production.

Vitamin B12 (cobalamin) is a structurally complex, cobalt-containing micronutrient essential for neurological maintenance, cognitive function, and erythropoiesis. Although traditionally obtained from animal-derived foods or via chemical supplementation, the growing demand for sustainable, natural sources has intensified interest in microbial fermentation as an alternative production route. Current knowledge remains fragmented regarding the comparative performance of microbial species, the bottlenecks in de novo corrinoid biosynthesis, and the integration of waste-derived substrates into scalable systems. This review critically integrates recent advances in vitamin B12 bioproduction, focusing on genetic and metabolic engineering strategies that reconfigure the pathways, optimize precursor availability, and redirect metabolic flux toward cobalamin synthesis. Methodological developments in controlled fermentation, downstream purification, and bioavailability assessment, including intestinal uptake mechanisms, are evaluated to identify persistent technological gaps. Particular emphasis is placed on multi-actor approaches that couple microbial biotechnology with food processing and the valorization of agro-industrial by-products, thereby enabling cost-effective production aligned with circular bioeconomy principles. By consolidating mechanistic insights, engineering innovations, and sustainability-driven process integration, this review delineates emerging opportunities for industrial-scale manufacturing of natural vitamin B12 and highlights future research directions needed to enhance yield, functionality, and applicability in health-promoting foods.