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bioRxiv · 10.1101/2025.03.19.644259

Early-life gut microbiome and stress-axis perturbations dysregulate systemic, mucosal, and brain immunity

Arrieta, M. C.·Ortega, V. A.·Asbury, M. R.·Mackenzie, C.·Vicentini, F. A.·Hafeez, B.·Duan, H.·Mercer, E. M.·vanTilburg Bernardes, E.·Kalbfleisch, K.·Samara, J.·Pettersen, V. K.·Figeys, D.·Sharkey, K.
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Abstract

BackgroundEarly-life disruptions to the gut microbiome and stress-axis significantly influence the development of immune, neuroendocrine, and other physiological systems. However, the precise microbial species and pathways mediating these effects remain poorly characterized. Using a murine model, we investigated the individual and combined effects of early-life antibiotic exposure and chronic stress on gut microbiota composition, short-chain fatty acid (SCFA) production, hypothalamic-pituitary-adrenal (HPA) axis activity, and systemic, mucosal, and neuroimmune responses. ResultsBroad-spectrum antibiotic treatments severely reduced microbial diversity and SCFA concentrations, with changes persisting into adulthood. Chronic early-life stress exerted more modest but notable effects, reducing key SCFA-producing taxa and impacting microbiome metabolic output. Combined disruptions led to altered microglial active phenotype and cytokine profiles, impaired immune cell populations, and suppressed HPA axis activity. Multi-omic correlational analyses revealed strong associations between SCFAs, specific gut microbes, and immune responses, implicating SCFAs as critical mediators of gut-brain communication. Notably, antibiotic exposure exacerbated susceptibility to allergic airway inflammation, highlighting the systemic consequences of early-life microbiome disturbances. ConclusionsThese findings demonstrate that early microbial perturbations impair neuroimmune maturation, HPA axis regulation, and host resilience to inflammatory diseases. Our study underscores the importance of preserving the early-life microbiome to support long-term immune and neurodevelopmental health, offering insights into potential therapeutic interventions for mitigating the impact of early-life microbiota disruptions.

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Arrieta, M. C., Ortega, V. A., Asbury, M. R., Mackenzie, C., Vicentini, F. A., Hafeez, B., Duan, H., Mercer, E. M., vanTilburg Bernardes, E., Kalbfleisch, K., Samara, J., Pettersen, V. K., Figeys, D., Sharkey, K.. 2025-03-20. Early-life gut microbiome and stress-axis perturbations dysregulate systemic, mucosal, and brain immunity. https://doi.org/10.1101/2025.03.19.644259

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