Diet-imprinted IgG constrains microbiome

Background: Both diet and host factors shape the gut microbiome, yet the influence of past dietary history on host-microbiome interactions remains underexplored. Functional contrasts of microbiome provide a powerful approach to detect and compare profile shifts under varying conditions. Here we integrated diet- and time-dependent pathway-level contrasts to dissect gut microbial responses during high-fat diet (HFD) exposure in mice with divergent immune status. Results: Across 20 weeks of feeding, immunodeficient NSG mice showed progressive functional drift, whereas immunocompetent BALB/c mice exhibited stabilization and reversion toward baseline states. Reanalysis of public B6 metagenomes confirmed that prolonged HFD in immunocompetent hosts leads to recovery of specific functions. Cross-strain comparisons highlighted 17 core microbial pathways that were selectively maintained under immune competence. The timing of these divergences suggested adaptive immune effectors as potential mediators. To test this, we performed adoptive transfer of diet-conditioned IgG into HFD-fed SCID mice. Only early transfer of HFD-derived IgG promoted late-phase recovery of several of the 17 core microbial pathways stabilized in immunocompetent hosts, accompanied by improved host metabolic outcomes. Conclusions: Together, these findings highlight diet-imprinted IgG as a mediator of adaptive memory shaping microbiome trajectories, and show how functional contrasts of microbiome across diet and time can be integrated to infer higher-order host factors that organize microbial functional landscapes.