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.