Konjac Glucomannan–Montmorillonite Hybrids as a Gut-Targeted Therapy for Addressing Diet-Induced Obesity in Mice

Background/Objectives: The growing prevalence of obesity necessitates innovative gut-targeted material strategies to modulate diet-associated metabolic dysfunction. This study investigates a spray-dried konjac glucomannan–montmorillonite (KGM-MMT) hybrid designed to integrate fermentable polysaccharide properties with luminal lipid-adsorptive clay functions within a single micro-engineered formulation. Methods: In HFD-fed mice treated for 42 days with 2% w/w KGM-MMT, cumulative body weight gain was attenuated by 7.6%, with an AUC of 5094 ± 52.95, compared to 5513 ± 81.35 in HFD controls (p < 0.0001). Results: Serum IL-6 concentrations were reduced by 97% (p = 0.0002), while blood glucose decreased by 46% (p < 0.0001); these effects were greater than those observed with MMT (24%, p = 0.0271) and KGM (16%, ns). Gut microbiota profiling demonstrated a significant 6.2-log2-fold increase in Lactobacillaceae (p = 0.023) and a 2.4-log2-fold increase in Enterococcaceae (p = 0.015) following KGM-MMT treatment. Functional shifts inferred from 16S rRNA gene-based prediction indicated a 1.9-fold increase in short-chain fatty acid-related pathways and a 5.4-fold increase in bile acid deconjugation pathways. Conclusions: Although the KGM-MMT hybrid did not consistently outperform its individual components across all endpoints, it consolidated complementary KGM- and MMT-associated effects within a single dosage form. These findings support spray-dried KGM-MMT as a gut-targeted biomaterial strategy that integrates multiple luminal and microbiota-associated functions within a single formulation. Future studies should define dose–response relationships, validate microbiota-derived functional predictions using higher-resolution approaches, and assess durability and safety under longer-term exposure.