The role of the gut microbiota in the effects of early-life stress and dietary fatty acids on later-life central and metabolic outcomes in mice

Early-life stress (ELS) leads to increased vulnerability for mental and metabolic disorders. We have previously shown that dietary low {omega}-6/{omega}-3 polyunsaturated fatty acid (PUFA) ratio is able to protect against ELS-induced cognitive impairments. Due to the importance of the gut microbiota as determinants of long-term health, we here study the impact of ELS and dietary PUFAs on the gut microbiota, and how this relates to the previously described cognitive, metabolic and fatty acid profiles. Male mice were exposed to ELS via the limited bedding and nesting paradigm (postnatal day (P)2 - P9) and to an early diet (P2 - P42) with either high (15) or low (1) {omega}-6 linoleic acid to {omega}-3 alpha-linolenic acid ratio. 16S ribosomal RNA was sequenced and analyzed from fecal samples at P21, P42 and P180. ELS increased {beta}-diversity at P42, which persisted into adulthood. The low {omega}-6/{omega}-3 diet prevented the ELS-induced increase in {beta}-diversity, at P42. At the level of taxa abundance, for example, the abundance of the phyla Bacteroidetes increased while Actinobacteria and Verrucomicrobia decreased with age; ELS reduced the relative abundance of the genera RC9 gut group and Rikenella into adulthood and the low {omega}-6/{omega}-3 diet reduced the abundance of the Firmicutes Erysipelotrichia. At P42, species abundance correlated with body fat mass and circulating leptin (e.g. Bacteroidetes and Proteobacteria taxa) and fatty acid profiles (e.g. Firmicutes taxa). This study gives novel insights into the impact of age, ELS and dietary PUFAs on microbiota composition, providing potential targets for non-invasive (nutritional) modulation of the ELS-induced deficits. ImportanceEarly-life stress (ELS) leads to increased vulnerability to develop mental and metabolic disorders, however the biological mechanisms leading to such programming are not fully clear. Increased attention has been given to the importance of the gut microbiota as determinant of long term health and as potential target for non-invasive nutritional strategies to protect against the negative impact of ELS. Here we give novel insights in the complex interaction between ELS, early dietary {omega}-3 availability and the gut microbiota across ages and provides new potential targets for (nutritional) modulation of the long-term effects of the early-life environment via the microbiota.