Long -chain unsaturated fatty acids promote trans-kingdom communication during immune responses

Immune responses can significantly influence the gut microbiota by altering its structure and function, leading to rapid transcriptional and metabolic shifts in commensal microbes. However, the specific host mediators involved in this process and their effects on bacteria remain poorly elucidated. Here, using a flagellin injection model, we identified unsaturated long-chain fatty acids (uLCFAs) as broad modulators of bacterial gene expression released in the gut lumen during immune responses. In Blautia, a prominent commensal in humans and mice, uLCFAs triggered the expression of ohyA, encoding oleate hydratase, which produces non-toxic hydroxy-fatty acids with immunomodulatory properties. Remarkably, oral administration of uLCFAs to mice replicated many of the bacterial transcriptional changes induced by flagellin injection, revealing an intriguing parallel between immune responses and dietary habits. This molecular loop underscores the sophisticated interactions between host and microbiota, and sheds light on how immune responses affect gut commensal functions.