Spray dried inulin–montmorillonite hybrids alleviate high-fat diet–induced inflammatory and metabolic dysregulation in rats

Metabolic dysregulation is strongly associated with excessive dietary lipid absorption and gut microbiota imbalances under high-fat diet (HFD) conditions. This study evaluates a spray-dried inulin–montmorillonite (INU-MMT) hybrid designed to simultaneously restrict intestinal lipid digestion and modulate gut microbiota composition. In simulated intestinal digestion, INU–MMT maintained the strong lipid-inhibitory effect of montmorillonite, reducing free fatty acid release by 2.8-fold compared to HFD conditions, while exhibiting improved dispersion stability attributed to INU's ability to reduce clay platelet aggregation. In a 21-day HFD-fed rat model, INU–MMT supplementation (1 g/kg/day) attenuated cumulative weight gain by 4.7% compared to the HFD control, exceeding reductions with INU (2.0%) and MMT (1.5%) alone. 16S rRNA gene sequencing of fecal samples revealed improved gut microbial diversity (Simpson's index, p = 0.0161) and uniquely enriched health-associated taxa including Akkermansiaceae (2.5-fold), Eggerthellaceae (7.7-fold), Ruminococcaceae (3.5-fold), and Peptostreptococcaceae (8-fold). Beta diversity analysis highlighted that INU–MMT induced a distinct microbial composition from INU, suggesting the complimentary effects of the hybrid promote a more widespread microbial change than prebiotic alone. Predictive metagenomic analysis using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) software demonstrated a 98% reduction in microbial triacylglycerol lipase abundance, consistent with the observed in vitro lipolysis suppression. These findings demonstrate that the INU–MMT hybrid preserves MMT's restriction of lipid digestion while delivering INU's prebiotic benefits, producing additive effects in diet-induced weight gain and microbiota modulation. The multifunctional nature of this spray-dried hybrid highlights its potential as a dietary strategy for metabolic dysregulation. • Spray-dried hybrid INU-MMT restricts FFA release 4-fold in intestinal conditions. • Hybrid reduced HFD-induced weight gain in rats more than standalone INU or MMT. • Promotes beneficial microbiota shifts and key SCFA-producing taxa • Suppressed predicted microbial lipase levels by 98% with INU-MMT treatment • INU-MMT offers a multi-mechanistic strategy for future metabolic disease therapies.