Fermented Soy Protein Maillard Product Prevents Bone Loss via TNF-α Suppression and Gut–Bone Axis Modulation in Ovariectomized Mice

This study investigated the bone-protective effects of Maillard reaction products (MRPs) from isolated soy protein and their fermentation product (MRPF) using Lacticaseibacillus rhamnosus IM18. In lipopolysaccharide-induced RAW264.7 cells, MRP showed enhanced antioxidant and anti-inflammatory activities compared to isolated soy protein, which were further improved by MRPF. In ovariectomized mice and RANKL-stimulated RAW264.7 cells, MRPF demonstrated superior anti-osteoclastogenic and bone-protective effects by suppressing osteoclast differentiation and preventing bone resorption. These effects involved downregulation of pro-inflammatory cytokines (Tnfa, Il1b, Il6, and Tnfs11) and upregulation of osteoprotegerin (Tnfrsf11b), along with restoration of intestinal barrier genes (Ocln, Cldn1, and Tjp1). MRPF administration significantly modulated gut microbiota, reducing inflammation-associated taxa (Desulfovibrio) while enriching beneficial genera (Bifidobacterium, Ruminococcus, and Akkermansia). Peptide profiling identified 28 bioactive peptides contributing to observed effects. These findings indicate that MRPF alleviates inflammation and maintains gut homeostasis, supporting its potential as a functional food ingredient for postmenopausal osteoporosis.