The microbiota and T cells non-genetically modulate inherited phenotypes transgenerationally

The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations. [Display omitted] •Germ-free and T cell-deficient mice show defects in barrier tissue function•Defects persist transgenerationally via non-genetic inheritance•Immune-microbe-influenced inheritance is transmitted by the germlines of both sexes•The microbiome and immune system impact embryonic gene expression of progeny Harris et al. describe phenotypic abnormalities in germ-free and T cell-deficient mice that are not acutely correctable and are non-genetically transmitted to progeny. The parental microbe and immune environment impact gametes to alter early embryonic gene expression, thereby influencing barrier and metabolic tissue of progeny through transgenerational non-genetic inheritance.