摘要Background: Escherichia coli (E. coli) infection in humans and animals usually comes with gut dysbiosis, which is potential culprit to skeletal health, it is still unclear to whether diet interfered gut microbiome changes can be a pro-tective strategy to bone loss development. Here, the effects of resistant starch from raw potato starch (RPS), a type of prebiotic, on E. coli-induced bone loss and gut microbial composition in meat ducks were evaluated. Results: The results showed that dietary 12％ RPS treatment improved bone quality, depressed bone resorption, and attenuated the pro-inflammatory reaction in both ileum and bone marrow. Meanwhile, the 12％ RPS diet also increased the abundance of Firmicutes in E. coli-treated birds, along with higher production of short-chain fatty acids (SCFAs) especially pro-pionate and butyrate. Whereas addition of β-acid, an inhibitor of bacterial SCFAs production, to the drinking water of ducks fed 12％ RPS diet significantly decreased SCFAs level in cecum content and eliminated RPS-induced tibial mass improvement. Further, treatment with MI-2 to abrogate mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) activ-ity replicated the protective role of dietary 12％ RPS in E. coli-induced bone loss including reduced the inhibition on nuclear factor κB (NF-κB) inflammasome activation, decreased bone resorption, and improved bone quality, which were correlated with comparable and higher regulatory T cells (Treg) frequency in MI-2 and 12％ RPS group, respectively. Conclusions: These findings suggested that the diet with 12％ RPS could alleviate E. coli-induced bone loss in meat ducks by changing the gut microbial composition and promoting concomitant SCFAs production, and consequently inhibiting Malt1/NF-κB inflammasome activation and Treg cells expansion.