Reshaping Growth and Metabolic Activity of <i>Akkermansia muciniphila</i> With Natural Prebiotics

ABSTRACT As an important bacterium in the gut microbiota, Akkermansia muciniphila plays crucial roles in regulating metabolism and modulating inflammatory responses. To better understand its growth characteristics and metabolic mechanisms, three classes of natural prebiotics, including polyphenols, oligopeptides, and polysaccharides were evaluated for their ability to promote the growth of A. muciniphila . Among these, Dendrobium‐derived polysaccharide (DP) exhibited superior bioactivity, enhancing bacterial proliferation by 14.77% compared to controls. The prebiotic effect was further reinforced by a 72.39% improvement in carbohydrate utilization when DP was added to the culture system. Metabolic analyses revealed that DP optimized energy metabolism, significantly increasing the production of acetate and propionate by 1.20‐fold and 2.10‐fold, respectively. Untargeted metabolomics demonstrated accelerated consumption of d ‐mannitol and glyceraldehyde‐3‐phosphate, indicating preferential activation of fructose/mannose metabolic pathways and boosted glycolytic flux. Lower levels of lactic, malic, and butanedioic acid (1.48‐ to 1.58‐fold) suggested a shift toward end‐product synthesis rather than merely accumulating intermediates. DP enhances A. muciniphila's activity and short‐chain fatty acid output, especially propionate, which can improve insulin sensitivity and suppress hepatic gluconeogenesis, suggesting DP's prebiotic potential against obesity and type 2 diabetes. Our findings demonstrated DP as a potent metabolic modulator of A. muciniphila , influencing carbohydrate utilization and energy harvesting pathways.