Dietary protein digests regulate the intestinal absorption of lipopolysaccharide by reshaping its physicochemical states and release kinetics during gastrointestinal digestion.

Dietary lipopolysaccharide (LPS) is naturally occurring bacterial toxins found in food. High-fat diet promoted its absorption in the gut, leading to chronic inflammation and being a major cause of metabolic endotoxemia. This study investigated how dietary protein digests regulate the physicochemical state and intestinal absorption of LPS during gastrointestinal digestion. Results showed that protein digests remodel LPS through mechanisms such as electrostatic neutralization, hydrophobic anchoring, and conformational encapsulation. Digest of chicken myofibrillar protein, with its excellent binding affinity (binding constant K = 4.66 × 104 M-1), exhibited the strongest LPS masking effect. Digest of casein, by slowing LPS release kinetics, significantly inhibited transmembrane absorption of LPS in the Caco-2 model, accumulating approximately 78% release, with a 4-h absorption rate of approximately 3.5%, the lowest among all protein groups. Conversely, while soy protein digest induced significant conformational changes in LPS, the resulting complex was unstable, resulting in limited masking. We conclude that dietary proteins and their digests, acting as key gatekeepers, regulate systemic endotoxin exposure by remodeling the bioavailability of LPS. These findings provide a theoretical basis for using specific protein matrices to alleviate diet-induced inflammation.