Macromolecular Organization in <i>Lentinula edodes</i> : Integrating Co‐Occurring Bioactives for Structure–Function Relationships Across Gut Microbiota and Host Metabolism

ABSTRACT Diet–microbe–host interactions are increasingly recognized as properties of complex food matrices rather than the sum of isolated compounds. Lentinula edodes (shiitake) provides a chemically diverse system containing β‐(1→3),(1→6)‐glucans, heteropolysaccharides, phenolics, terpenoids, eritadenine, ergothioneine, and bioactive peptides. Evidence suggests that biological effects attributed to shiitake are better interpreted within the whole matrix rather than through reductionist, single‐compound approaches. Key structural features—including β‐glucan branching, molecular‐weight distribution, conformational stability, and polysaccharide–phenolic interactions— shape microbial accessibility and downstream host responses. Here, macromolecular organization refers to the architecture and co‐occurrence of these components across digestion and microbial transformation. Across experimental systems, shiitake polysaccharides are linked to shifts in gut microbial composition, including enrichment of butyrate‐producing and mucin‐associated taxa such as Faecalibacterium , Roseburia , Akkermansia , and Bifidobacterium . These changes are often accompanied by altered short‐chain fatty acid profiles and related signaling pathways. In parallel, low‐molecular‐weight compounds, particularly eritadenine and ergothioneine, are associated with lipid metabolism and redox‐related processes in preclinical and limited human studies. However, interpretation is constrained by variability in structural characterization, study design, and limited availability of structure‐resolved human data. This review integrates evidence across biosynthesis, processing, microbial fermentation, and host responses, emphasizing context‐dependent associations rather than causal claims. By positioning shiitake as a model system, it highlights the value of structure‐guided frameworks and outlines directions to improve reproducibility and translational relevance in functional food science. These insights extend beyond shiitake and provide a framework for interpreting structure–function relationships in complex food systems.