Gut feelings: from gut to brain and back again

Cross-talk between the immune system and the brain is essential to neuronal development, brain health, and behaviour. Gut microbiota are essential to immune system development and immune function; hence, it is essential to consider more broadly the microbiota-immune-brain axis in brain health. Our recent work examined the impact of loss of functional T cells on development of the gut-brain axis. A longitudinal design was used to map the temporal gut microbial and gut/brain metabolomic trajectory during postnatal development spanning from early-life to adulthood in wild type B6 and T cell receptor deficient mice (TCR β–/–δ–/–, due to genetic knockout of both beta and delta chains of the T-cell receptor). TCR β–/–δ–/– mice had an altered trajectory of microbiome maturation, reduced alpha diversity, several differences in microbial composition, including increased abundance of Akkermansia and reduced abundance of Rosburia, and changes in gut and brain metabolite profiles. Using integrated analytical approaches, our data showed that reduced cecal and fecal butyrate levels were associated with Muribaculaceae taxa in TCR β–/–δ–/– mice. Moreover, T-cell related changes in gut microbiota and metabolome were paralled by changes in neuroactive metabolites in the brain. This work shows that bidirectional T-cell-microbe communication is a component of normal microbiota-immune development, and highlights specific bacteria and metabolites that are key to this crosstalk. The key findings here have important translational value as researchers move to consider how microbiota-immune relationships influence the trajectory of development of the microbiome and impact human brain development. Moreover, a more mechanistic understanding of the molecular entities on the microbe side and on the host side of this crosstalk in animal models and in people has the potential to provide novel biomarkers and new targets for microbiota-based therapies that can foster healthy microbiome maturation, in parallel with healthy brain development.