Diet modulates the gut microbiome, which in turn can impact the immune system. Here, we determined how two microbiota-targeted dietary interventions, plant-based fiber and fermented foods, influence the human microbiome and immune system in healthy adults. Using a 17-week randomized, prospective study (n = 18/arm) combined with -omics measurements of microbiome and host, including extensive immune profiling, we found diet-specific effects. The high-fiber diet increased microbiome-encoded glycan-degrading carbohydrate active enzymes (CAZymes) despite stable microbial community diversity. Although cytokine response score (primary outcome) was unchanged, three distinct immunological trajectories in high-fiber consumers corresponded to baseline microbiota diversity. Alternatively, the high-fermented-food diet steadily increased microbiota diversity and decreased inflammatory markers. The data highlight how coupling dietary interventions to deep and longitudinal immune and microbiome profiling can provide individualized and population-wide insight. Fermented foods may be valuable in countering the decreased microbiome diversity and increased inflammation pervasive in industrialized society. Display omitted •Diet intervention with systems profiling reveals links in diet-microbiome-immune axis•High-fiber diet changes microbiome function and elicits personalized immune responses•Fermented-food diet increases microbiome diversity and decreases markers of inflammation A prospective randomized multiomics study in humans investigating the longitudinal effects of a high-fiber or fermented-food diet shows their differential effects on the diversity of the microbiome, with the latter having a noticeable impact on reducing inflammatory markers and modulating immune responses.