Marine Peptides from Solenocera crassicornis Are Associated with Improved Metabolic, Hepatic, and Intestinal Markers During Diet Normalization in HFD-Induced Obese Mice

Background/Objectives: Obesity-associated metabolic dysfunction involves oxidative stress, gut barrier impairment, and gut–liver axis disruption. This study evaluated whether enzymatically prepared Solenocera crassicornis peptides (SCPs) provide additional benefits during diet normalization in HFD-induced obese mice and examined associations with antioxidant, microbial, and barrier markers. Methods: SCPs were characterized using UPLC-Q-TOF-MS/MS and amino acid analysis. Peptides underwent bioactivity prediction and Keap1 docking. After 7 weeks of HFD feeding, obese male C57BL/6J mice were switched to a normal diet and administered vehicle, orlistat, or SCPs for 4 weeks. Adipose tissue mass, serum lipid profiles, liver histology, hepatic antioxidant status, barrier-associated histological and biochemical markers, and gut microbiota composition were assessed. A simulated digestion–fecal fermentation model was used to assess the effects of fermentation products generated in the presence of digested SCPs on H2O2-induced oxidative injury and MUC2 secretion in LS174T goblet-like cells. Results: SCPs reduced epididymal and perirenal fat, improved serum lipids, improved hepatic steatosis-related morphology and enhanced hepatic antioxidant status. SCPs were also associated with improved intestinal morphology, increased mucin-associated staining, decreased serum diamine oxidase levels and reduced hepatic lipopolysaccharide accumulation. 16S rRNA sequencing showed SCP-associated microbial shifts, with correlations linking taxa to metabolic and barrier markers. Fermentation products generated in the presence of digested SCPs improved oxidative-stress and MUC2-related readouts in LS174T cells. Conclusions: During diet normalization, SCPs were associated with additional improvements in adiposity, lipid profiles, hepatic antioxidant status, intestinal barrier readouts, and gut microbiota. These findings support further investigation of SCPs as standardized marine protein hydrolysates, but active components, causal mechanisms, long-term efficacy, safety, and human relevance remain to be established.