Soil-derived microbiota induces T regulatory cells and protect against mouse colitis, metabolic disease, and sepsis.

Recent years have highlighted the profound influence of the gut microbiota not only on local immunity but also on systemic host physiology. However, the translational potential of findings from preclinical animal models remains limited, in part owing to their microbiomes shaped in the absence of natural environmental cues. To address this gap, we developed a scalable, cost-effective, and reproducible preclinical model of environmental exposure (ENV), in which local soil-derived microbiota colonize laboratory mice. Sustained colonization with environmental microbes, particularly Gram-negative bacteria, was associated with a shift toward local and systemic anti-inflammatory immune responses, supporting the expansion of regulatory T cells (Tregs) and IL-10⁺ innate and adaptive populations. These changes confer protection against colitis, obesity, diabetes, and sepsis, ultimately extending both health span and lifespan. Thus, natural microbial exposure lays the foundation for future studies into microbiota‒host interactions, therapeutic resistance, and the development of more physiologically relevant models for human disease.