An Integrated Engineering Approach to Creating Health‐Modulating Postbiotics

ABSTRACT Postbiotics have emerged as a promising alternative to live probiotics, offering comparable health benefits while overcoming challenges related to safety, stability, and shelf life. This review provides a comprehensive overview of the current state of postbiotic research, beginning with updated definitions and the rationale for transitioning from live microbial formulations to inanimate postbiotics. We examine the diverse mechanisms by which postbiotics modulate host physiology, including enhancement of epithelial barrier function, immunomodulation, systemic metabolic regulation, neuroactive effects, anti‐inflammatory activities, and anticancer properties. Detailed discussions highlight how bioactive components—such as bacteriocins, exopolysaccharides (EPS), short‐chain fatty acids (SCFA), and specific proteins (e.g., Amuc_1100 and P9 from Akkermansia muciniphila )—mediate these effects through complex cellular signaling pathways and host‐microbe interactions. Furthermore, we review the antimicrobial potential of postbiotic formulations, emphasizing their role in controlling pathogenic and spoilage microorganisms. Various methods for microbial inactivation are discussed, ranging from conventional thermal techniques (e.g., pasteurization and ohmic heating) to non‐thermal approaches (e.g., ultrasonication, ionizing radiation, and ultraviolet light), as well as innovative hybrid methods that combine chemical, physical, and enzymatic treatments. These strategies not only ensure the complete inactivation of live microorganisms but also preserve the integrity and bioactivity of postbiotic compounds. Comparative analyses of live probiotics versus postbiotics reveal that inactivated formulations can deliver similar or even enhanced health benefits, with superior safety profiles and improved quality control. The review concludes by addressing current challenges in standardizing postbiotic definitions and production processes and by outlining future research directions necessary to unlock their full potential in clinical, nutritional, and biotechnological applications.