Microbiota configuration dictates nutritional immune optimization

Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we demonstrate that DR-induced optimization of immunological memory requires co-operation between memory T cells, the intestinal microbiota, and myeloid cells. Our data indicate that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes expansion of the commensal Bifidobacteria within the large intestine, which supplies the short-chain fatty acid acetate to myeloid cells. Acetate conditioning of the myeloid compartment during DR enhances their capacity to kill pathogens. Enhanced host protection during DR is abolished when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function critically dictates immune responsiveness to this dietary intervention. Altogether, DR induces both memory T cells and the gut microbiota to produce essential, distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings reveal how nutritional cues promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism. Overall design: Examiniation of T cells, monocyts and neutrophils during dietary restriction versus normal condition with RNA-seq and ATAC-seq