2′‐ Fucosyllactose attenuates estrogen‐deficiency‐associated bone loss and intestinal dysfunction in ovariectomized rats

Abstract

Abstract BACKGROUND Postmenopausal osteoporosis (PMO), driven primarily by estrogen deficiency, is the most prevalent form of osteoporosis and a major global health burden. Estrogen deficiency disrupts gut microbial homeostasis, compromises intestinal barrier integrity and promotes inflammatory bone loss partly through dysregulation of the osteoprotegerin (OPG)/receptor activator of nuclear factor‐κB ligand (RANKL) axis. However, the safety concerns and poor adherence associated with long‐term pharmacotherapy underscore the need for safer nutritional strategies. Here, we evaluated the protective effects of 2′‐fucosyllactose (2′‐FL), a natural milk oligosaccharide, against PMO using chondroitin sulfate (CS) as a comparator. RESULTS The results showed that 2′‐FL restored the balance of the OPG/RANKL axis, improved intestinal integrity and reduced inflammatory cytokine levels. Linear discriminant analysis effect size‐based analysis further indicated that 2′‐FL may reshape the gut microbiota by promoting the enrichment of selected beneficial microbial taxa, including Adlercreutzia , Gordonibacter and Akkermansia , at the same time as reducing the relative abundance of Ruminococcus and Prevotella under estrogen‐deficient conditions. Moreover, 2′‐FL exhibited comparable efficacy to CS in restoring bone homeostasis. CONCLUSION Collectively, these findings demonstrate that 2′‐FL alleviates both bone loss and intestinal dysfunction under estrogen‐deficient conditions. 2′‐FL improved bone microarchitecture, favourably modulated bone‐remodelling and intestinal barrier‐associated markers, reduced inflammation and concurrently altered gut microbial composition. © 2026 Society of Chemical Industry.