Xanthohumol Alleviates Inflammatory Bowel Disease‐Associated Osteoporosis via Regulating Gut Microbial Metabolites

Patients with inflammatory bowel disease (IBD) frequently experience osteoporosis (OP) due to factors such as chronic inflammation, malnutrition, and corticosteroid use. However, there is currently a lack of effective pharmacological interventions for the prevention and treatment of IBD-associated OP. Xanthohumol (XAN), a natural flavonoid compound isolated from hops, has shown beneficial effects on both inflammation and osteoporosis. This study aimed to explore the therapeutic effects and potential mechanisms of XAN from hops on IBD-associated OP based on gut microbiota. The IBD-associated OP model was constructed by free drinking of dextran sulfate sodium (DSS). Therapeutic effects of XAN were investigated through disease activity index (DAI) scoring, colon pathology, mucosal barrier function, inflammatory factors, bone metabolism indicators, and femoral Micro-CT. Mechanisms of XAN regulating gut microbiota were preliminarily elucidated by 16S rDNA sequencing and non-targeted metabolomics. XAN could effectively alleviate colonic tissue inflammation and protect the intestinal mucosal barrier, further improve colonic pathological damage, and reduce the DAI scoring in DSS mice. It also exerted anti-IBD-associated OP effects by reducing serum inflammatory factors IL-6, IL-17A, and TNF-α, inhibiting serum CTX-I expression, promoting serum OPG expression, regulating calcium-phosphorus balance, and improving bone density and morphology. More importantly, 16S rDNA sequencing and untargeted metabolomics showed that XAN increased the abundance and diversity of the gut microbiota in DSS mice. By altering the abundance of specific bacterial taxa such as Turicibacter, norank_f__norank_o__Clostridia_UCG-014, norank_f__Muribaculaceae, and Faecalibaculum, XAN changed the metabolites of gut microbiota, thereby regulating the tryptophan (Trp) metabolism pathway, as well as improving the intestinal mucosal barrier and bone metabolism. XAN can improve the pathological injury of the colon and bone loss caused by IBD. The mechanism is to regulate Trp metabolism by intervening in gut microbiota, thereby protecting intestinal mucosal barrier function and promoting bone formation.