Conjugated 2′‐Fucosyllactose–Potato Protein Hydrolysate as Novel Prebiotics

ABSTRACT While most prebiotics are carbohydrate‐based, probiotics also require amino acids to proliferate. However, approximately 90% of dietary protein is absorbed in the small intestine, leaving gut microbes to compete for limited residual unabsorbed peptides reaching the colon. To address this, we developed protein‐containing prebiotics designed to selectively deliver both proteins and carbohydrates to gut probiotics, boosting their growth more effectively than carbohydrate‐only prebiotics. This novel prebiotic platform utilizes Maillard conjugates of prebiotic oligosaccharides and protein hydrolysates, which self‐assemble into micelles with a protein core and an oligosaccharide shell. This structure retards upper gastrointestinal protein absorption, while enabling oligosaccharide‐mediated, selectively targeted delivery to colonic probiotics. In this study, Maillard conjugates of 2′‐fucosyllactose (2′‐FL) and potato protein hydrolysate (PPH) were formed (pH 8, 80°C, 3 h). These conjugates demonstrated resistance to gastrointestinal digestion, thereby increasing the protein fraction reaching the colon. In a 5‐week murine model, 2′‐FL‐PPH supplementation significantly increased the abundance of Bifidobacteria , short‐chain‐fatty‐acids (SCFAs)‐producing genera, and colonic SCFAs levels compared to saline control, outperforming conventional prebiotics (2′‐FL and the unconjugated components). Notably, no increase in harmful proteolytic fermentation byproducts was observed. Additionally, 2′‐FL‐PPH enhanced gut barrier markers (MUC2 and claudin‐1), increased fecal moisture, and reduced weight gain and hepatic fat accumulation more effectively than the conventional prebiotics. These cumulative findings indicate that protein‐containing prebiotics offer an improved alternative to carbohydrate‐only prebiotics, presenting a promising strategy for enhancing metabolic and gut health. This platform may be extended to additional protein–oligosaccharide combinations to tailor microbiome‐targeted nutritional interventions in health and disease states.