Baldaro, K. | Search bioRxiv

bioRxiv2025

Epithelium intrinsic zinc sensor controls immune homeostasis with gut microbes via regulation of Tuft cell lineage

Zinc is an essential micronutrient crucial for cell proliferation, differentiation, and apoptosis, yet its precise role in the constantly renewing intestinal epithelium remains unclear. We generated mice lacking the Zn-dependent transcription factor Metal-responsive Transcription Factor 1(MTF1{Delta}IEC) in intestinal epithelial cells. MTF1{Delta}IEC mice exhibited altered metal homeostasis and acute susceptibility to Zn supplementation. Transcriptional and cellular analyses revealed increased inflammatory immune responses to microbes in MTF1{Delta}IEC mice. Mechanistically MTF1 deletion resulted in the loss of Tuft cell lineages compromising barrier function against commensal microbes and pathogens. Ex vivo experiments demonstrated that at a cellular level, Zn treatment skewed the cellular composition from proliferating to differentiated cells. Specifically, we show that Zn sensing via MTF1 is required for IL-13 dependent induction of Tuft cells. Our findings underscore critical role of Zn in maintaining intestinal immune homeostasis through differentiation of specialized cell lineages, highlighting importance nutrient sensing in the constantly remodeling epithelial barrier.

immunology↗

bioRxiv2025

Gut bacteria gatekeep host-specific colonization of a commensal fungus that boosts type 2 immunity

Naturalized, wilded, wildling, and dirty/pet store mouse models represent a spectrum of approaches designed to make laboratory mice more immunologically and physiologically similar to wild or human contexts by increasing their exposure to naturally occurring microbes and pathogens. In this study, we screened the gut mycobiome of pet store mice, and identified Kazachstania pintolopesii as a dominant fungus in pet store mice across various geographical locations. K. pintolopesii strains isolated from mice in geographically distinct pet stores stably colonize the gastrointestinal tract of laboratory mice, independent of gut bacterial composition, maintaining high fungal burdens for extended periods. K. pintolopesii rapidly became the dominant fungus in the mouse gut in conventional, antibiotic, and germ-free settings, outcompeting other non-murine fungal strains. Pet store-derived K. pintolopesii exhibited unique immunological properties distinct from typical anti-fungal responses. Unlike C. albicans colonization, K. pintolopesii did not induce circulating neutrophil expansion or Th17 cell populations in the gut mucosa. When administered systemically, K. pintolopesii-infected mice showed 100% survival with minimal fungal burden in kidneys, contrasting sharply with lethal C. albicans infections. Adaptive immune deficiency (Rag1 knockout mice) did not affect K. pintolopesii colonization or host response, indicating that B and T cell-mediated immunity does not restrain this fungus. K. pintolopesii colonization provided no cross-protection against systemic candidiasis further establishing lack of immune activation. These findings demonstrate that K. pintolopesii establishes a benign host-fungal relationship through neutrophil-independent mechanisms, avoiding classical anti-fungal immune activation while maintaining stable gut colonization. Instead, it selectively induces strong type 2 mucosal immune responses, increasing tuft and goblet cell counts and stimulating Th2 and group 2 innate lymphoid cell (ILC2) populations. This immune profile confers notable protection against intestinal nematode infection, demonstrated by reduced Heligmosomoides polygyrus egg counts. Altogether, K. pintolopesii serves as an exemplary model for commensal mycobiota, revealing distinct mechanisms for host tolerance and immune modulation.

microbiology↗