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This study demonstrates that controlled indoor rewilding modulates microglial states and transcriptional programs relevant to Alzheimer's disease, leading to a more mature immune phenotype and attenuated pro-inflammatory responses. Rewilded mice exhibited systemic shifts in immune networks and alterations in brain immunity, with transcriptional profiles converging with those of wild mice. The findings suggest that natural microbial enrichment may have a positive impact on neurodegenerative diseases.

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Abstract

The diversity of environmental microbial exposure is a key driver of immune maturation and host defense; however, its impact on brain immunity and neurodegenerative diseases remains poorly documented. Here, we show that controlled indoor rewilding, by introducing a natural farm-like environment into laboratory housing, reshapes peripheral and central nervous system (CNS) immune networks in wild-type (WT) and 5xFAD mice, a model of Alzheimer's disease (AD). Compared with traditional specific pathogen-free (SPF) housing, rewilded mice exhibited systemic shifts toward mature immune phenotypes, including increases in effector and memory B and T cells, expansion of plasma cell populations, and alterations in immunoglobulin isotypes. In the brain, indoor rewilding recalibrated microglial and astrocytic activation of SPF-5xFAD mice, attenuating pro-inflammatory transcriptional programs while enhancing homeostatic, complement, and phagocytic signatures. A strong transcriptional convergence was observed between rewilded and wild mice, with rewilded 5xFAD mice exhibiting greater similarity to human AD transcriptional profiles. Morphological and histochemical analyses confirmed that rewilded microglia adopt metabolically adaptable, homeostatic states that influence amyloid-β plaque binding and clearance. Collectively, these findings suggest that microbial diversity through »dirty» mouse modeling could enhance the translational relevance of neuroimmunology and neurodegenerative disease research.

Key findings

  • Rewilded mice exhibited increased effector and memory B and T cells, expansion of plasma cell populations, and alterations in immunoglobulin isotypes
  • Indoor rewilding attenuated pro-inflammatory transcriptional programs in the brain while enhancing homeostatic, complement, and phagocytic signatures
  • Rewilded 5xFAD mice showed greater similarity to human AD transcriptional profiles

Keywords

NeuroimmunologyMicrogliaImmune systemInnate immune systemDiseaseImmunity

Identifiers

DOI
10.64898/2026.02.28.708710
Journal
bioRxiv (Cold Spring Harbor Laboratory)
Year
2026