Beyond Gut Modulation: A Critical Review of the Therapeutic Potential, Safety, and Clinical Prospects of Natural Polysaccharides for IBD

ABSTRACT Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a recurrent gastrointestinal condition with a rising global prevalence. Current treatments, such as anti‐inflammatory drugs and biologics, are often limited by severe side effects and drug resistance, driving the search for safer alternatives. Natural polysaccharides (NPs) and their metabolites, particularly short‐chain fatty acids (SCFAs), have garnered significant interest because of their immunomodulatory, antioxidative, and microbiota‐modulating properties, positioning them as promising bioactive agents for IBD management. This review critically examines the structure–activity relationships of NPs and advanced delivery strategies, including nanoformulations, that increase their bioavailability and targeting ability. It also provides a comprehensive evaluation of the existing evidence, an in‐depth analysis of safety profiles, and a critical discussion of clinical translation prospects, addressing complexities in regulatory frameworks. By integrating recent molecular insights with translational challenges, this review aims to inform clinical practice and temper premature expectations, offering a balanced perspective on the journey of NPs from the bench to the bedside.