Microbiota induced immune system maturation plays a key role in development of normal behaviour

Abstract

Gut microbiota has been shown to regulate the growth and development of the central and enteric nervous systems (CNS and ENS) after birth. There is ample evidence to suggest that intestinal bacteria can influence behavior of the host through both immune and immune-independent mechanisms. Gut-microbiota-regulated CNS structural changes are focused in the limbic system, at centres associated with memory, social and emotional behaviour. Several studies using germ-free (GF) and specific pathogen free (SPF) mice demonstrated microbial influence on behaviour development accompanied by neurochemical changes in the brain. Higher exploratory and lower anxiety-like behavior was found in GF mice compared to SPF mice with lower central expression of neurotrophins, such as nerve growth factor and BDNF. The mechanisms by which the microbiota influences behavior are unknown but could be immune-mediated, neural, or humoral in origin. In this study I investigated the role of immune system maturation on mouse behaviour after bacterial colonization. I showed that mono-colonization of GF mice with E. coli normalizes behaviour similar to colonization with complex microbiota (SPF and ASF) and the continuous presence of bacteria is not required to maintain this normal behaviour. I also showed that innate immunity through the MyD88/Ticam pathway is crucial for the development of normal behaviour and that multiple innate immunity and neuronal genes are involved in this process. Together these results suggest that bacterial colonization primes and matures the innate immunity and development of the central nervous system ultimately leading to normal behaviour. I believe that bacterial colonization at birth is not only important for the epithelial barrier function, gut homeostasis, and immune functions, but also for the development of normal behaviour. Altered immune priming during the postnatal period due to abnormal microbial colonization may have wider implications when considering psychiatric disorders in humans.