Critical windows of early-life microbiota disruption on behaviour, neuroimmune function, and neurodevelopment.

Numerous studies have emphasised the importance of the gut microbiota during early life and its role in modulating neurodevelopment and behaviour. Epidemiological studies have shown that early-life antibiotic exposure can increase an individual's risk of developing immune and metabolic diseases. Moreover, preclinical studies have shown that long-term antibiotic-induced microbial disruption in early life can have enduring effects on physiology, brain function and behaviour. However, these studies have not investigated the impact of targeted antibiotic-induced microbiota depletion during critical developmental windows and how this may be related to neurodevelopmental outcomes. Here, we addressed this gap by administering a broad-spectrum oral antibiotic cocktail (ampicillin, gentamicin, vancomycin, and imipenem) to mice during one of three putative critical windows: the postnatal (PN; P2-9), pre-weaning (PreWean; P12-18), or post-weaning (Wean; P21-27) developmental periods and assessed the effects on physiology and behaviour in later life. Our results demonstrate that targeted microbiota disruption during early life has enduring effects into adolescence on the structure and function of the caecal microbiome, especially for antibiotic exposure during the weaning period. Further, we show that microbial disruption in early life selectively alters circulating immune cells and modifies neurophysiology in adolescence, including altered myelin-related gene expression in the prefrontal cortex and altered microglial morphology in the basolateral amygdala. We also observed sex and time-dependent effects of microbiota depletion on anxiety-related behavioural outcomes in adolescence and adulthood. Antibiotic-induced microbial disruption had limited and subtle effects on social behaviour and did not have any significant effects on depressive-like behaviour, short-term working, or recognition memory. Overall, this study highlights the importance of the gut microbiota during critical windows of development and the subtle but long-term effects that microbiota-targeted perturbations can have on brain physiology and behaviour.

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Declaration of Competing Interest APC Microbiome Ireland is a research centre funded by Science Foundation Ireland (SFI/12/RC/2273_P2). J.F.C is funded by the Science Foundation Ireland (SFI/12/RC/2273_P2), Saks Kavanaugh Foundation and Swiss National Science Foundation project CRSII5_186346/NMS2068, and has received research funding from Cremo, Dupont/IFF, Reckitt, Nutricia, and Pharmavite. J.F.C has also been an invited speaker at meetings organized by Alimentary Health, Alkermes, Ordesa, and Yakult; and has served as a consultant for Nestle. G.C. has received honoraria from Janssen, Probi, and Apsen as an invited speaker; is in receipt of research funding from Pharmavite and Fonterra; and is a paid consultant for Yakult, Zentiva and Heel pharmaceuticals. C.S.M.C. was supported by a European Union H2020 Marie Skłodowska-Curie Individual Fellowship (grant no. 797592). C.M.K.L was also funded by the HEA Covid-19 Cost Extension Fund. All other authors report no potential conflicts of interest. This support neither influenced nor constrained the contents of this article.