Short-term dietary change rapidly remodels microbial community assemblages and reprogrammed systemic immune phenotypes

Diet is a major determinant of the gut microbiome and immune homeostasis, yet the extent to which short-term dietary interventions can remodel established microbial communities and reprogramme immune phenotypes following long-term western diet consumption remains poorly understood. Here, we investigated temporal dynamics of the gut microbiome, microbial metabolites, intestinal barrier function and local and systemic immune responses following diet switching. Mice were fed either a standard chow or a western diet for 8 weeks before remaining on these diets or switching to the alternate diet for 2 or 4 weeks. Long term consumption of chow and western diets resulted in distinct gut microbial communities and differences in intestinal permeability. Diet switching rapidly remodelled microbial community structure within two weeks, with substantial bidirectional changes in community composition. Despite these changes, the relative abundance of several taxa remained influenced by prior dietary exposure. In contrast, faecal SCFA profiles remained largely associated with long-term diet, indicating that microbial metabolic outputs were altered more slowly than microbial community composition. Mass cytometry revealed progressive remodelling of local (MLN) and systemic (PBMC and spleen) immune responses following dietary switching. Activation-associated immune phenotypes, including Ki67+ and PD-1+ B and T cells, inflammatory monocytes and ROR{gamma}t+ regulatory T cells, rapidly responded to diet switching, whereas overall B cells, regulatory T cells and effector memory T cells retained signatures of long-term dietary exposure. Together, these findings demonstrate distinct temporal dynamics across the diet-microbiome-immune axis, whereby gut microbial composition and immune activation states remain highly plastic, while microbial metabolic outputs and several memory and regulatory immune phenotypes exhibit persistent dietary imprinting. These findings highlight the potential utility of short-term dietary interventions to modulate host-microbiome interactions and immune homeostasis.