Antibiotic cocktail-induced gut microbiota depletion in different stages could cause host cognitive impairment and emotional disorders in adulthood in different manners.

Gut microbiota depletion may result in cognitive impairment and emotional disorder. This study aimed to determine the possible association between host gut microbiota, cognitive function, and emotion in various life stages and its related underlying mechanisms. Seventy-five neonatal mice were randomly divided into five groups (n = 15 per group). Mice in the vehicle group were administered distilled water from birth to death, and those in the last four groups were administered antibiotic cocktail from birth to death, from birth to postnatal day (PND) 21 (infancy), from PND 21 to 56 (adolescence), and from PND 57 to 84 (adulthood), respectively. Antibiotic exposure consistently altered the gut microbiota composition and decreased the diversity of gut microbiota. Proteobacteria were the predominant bacteria instead of Firmicutes and Bacteroidetes after antibiotic exposure in different life stages. Long-term and infant gut microbiota depletion resulted in anxiety- and depression-like behaviors, memory impairments, and increased expression of γ-aminobutyric acid type A receptor α1 of adult mice. Long-term antibiotic exposure also significantly decreased serum interleukin (IL)-1β, IL-10, and corticosterone of adult mice. Gut microbiota depletion in adolescence resulted in anxiety-like behaviors, short-term memory decline, decreased serum interferon-γ (IFN-γ), mRNA expression of 5-hydroxytryptamine receptor 1A, and neuropeptide Y receptor Y2 in the prefrontal cortex of adult mice. Antibiotic exposure in adulthood damaged short-term memory and decreased serum IL-10, IFN-γ, and increased γ-aminobutyric acid type B receptor 1 mRNA expression of adult mice. These results suggest that antibiotic-induced gut microbiota depletion in the long term and infancy resulted in the most severe cognitive and emotional disorders followed by depletion in adolescence and adulthood. These results also suggest that gut microbes could influence host cognitive function and emotion in a life stage-dependent manner by affecting the function of the immune system, hypothalamic-pituitary-adrenal axis, and the expression of neurochemicals in the brain.