Effects of a highly simplified microbiota on postnatal intestinal, immune, and brain development

Abstract

At birth, the newborn mammal enters a highly microbial world, leading to colonization of the gut by trillions of microorganisms, known as the microbiota. We previously reported that germ-free (GF) mice have altered brain development in the first days of life, suggesting that the arrival of microbes at birth is essential for normal brain development. However, GF mice are a highly artificial model system, with known deficits in immune and intestinal development. To determine the effects of a more realistic curtailment of microbial exposure, we utilized a reduced, defined microbiota. Specifically, GF mouse dams were colonized with the altered Schaedler flora (ASF), a community of eight bacterial species, which supports relatively normal immune and intestinal function in adulthood. Measures in the periphery (colon histology and gene expression, plasma cytokines) and brain (neuronal cell death, microglial density, forebrain expression of cytokine and blood–brain barrier protein genes) were then compared among offspring born to ASF, GF, and conventionally colonized (CC; i.e., control) mice at postnatal day (P)3 or P23, focusing on those measures previously reported to differ between CC and GF conditions. We observed that ASF newborns have a higher bacterial load in the colon than CC mice but are essentially monocolonized. For some measures (e.g., plasma cytokines, neuronal cell death), ASF newborns at P3 are similar to controls, whereas for others they are GF-like or intermediate. The ASF microbiota grows to comprise 5 bacterial species by weaning age, compared to explosive diversification in CC offspring. Analyses at P23 demonstrate that microglia density is like that of controls in ASF weanlings but several peripheral measures remain GF-like. Thus, effects of an absent microbiota are evident within a few days of life, and colonization with a highly simplified, defined microbiota normalizes some, but not all, measures in the developing periphery and brain.