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 a low dietary omega-6/omega-3 polyunsaturated fatty acid (PUFA) ratio protects against ELS-induced cognitive impairments. Due to the importance of the gut microbiota as a determinant 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 to P9 and to an early diet (P2 to P42) with an either high (15) or low (1) omega-6 linoleic acid to omega-3 alpha-linolenic acid ratio. 16S rRNA was sequenced and analyzed from fecal samples at P21, P42, and P180. Age impacted alpha- and beta-diversity. ELS and diet together predicted variance in microbiota composition and affected the relative abundance of bacterial groups at several taxonomic levels in the short and long term. For example, age increased the abundance of the phyla Bacteroidetes, while it decreased Actinobacteria and Verrucomicrobia; ELS reduced the genera RC9 gut group and Rikenella, 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 noninvasive (nutritional) modulation of ELS-induced deficits. IMPORTANCE Early-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 a determinant of long-term health and as a potential target for noninvasive nutritional strategies to protect against the negative impact of ELS. Here, we give novel insights into the complex interaction between ELS, early dietary omega-3 availability, and the gut microbiota across ages and provide new potential targets for (nutritional) modulation of the long-term effects of the early-life environment via the microbiota.