Lacticaseibacillus casei Zhang modulates iron homeostasis in iron-overloaded mice via an IL-22-dependent pathways

This study elucidated the role of IL-22 in the disruption of iron homeostasis and gut microbiota dysbiosis induced by a high-iron diet (HI) and evaluated the therapeutic potential of the probiotic Lacticaseibacillus casei Zhang (LCZ). In mice fed an HI diet, HI increased serum iron (SI) and IL-22 levels and reduced total iron-binding capacity (TIBC), accompanied by the enrichment of opportunistic taxa, including Parabacteroides goldsteinii , and functional metabolic disturbances, including increased lithocholic acid levels and suppression of lactose degradation pathways. LCZ intervention attenuated these alterations by partially restoring TIBC, reducing IL-22 levels, and increasing the relative abundance of taxa commonly linked to gut health, including Bifidobacterium animalis . In contrast, IL-22 knockout (KO) mice did not exhibit LCZ-associated improvement in iron indices, supporting the requirement for IL-22 to mediate probiotic responsiveness in iron overload. Multi-omics analyses further indicated that LCZ mitigated HI-associated bile acid dysregulation and impaired glucose metabolism, whereas KO mice exhibited more pronounced metabolic disruption. Collectively, these findings identified IL-22 as a key immune node associated with the dietary iron-microbiota-host axis and supported targeting the IL-22-linked pathway as a potential strategy to reduce iron overload-associated risks.