The Role of Gut-Brain Signalling in Functional Responses to Chronic Social Stress

Abstract

Chronic stress has a cumulative physiological impact, causing dysregulation of multiple systems due to allostatic overload. There is growing evidence that one such system, the microbiota, is engaged in persistent bidirectional interplay with the brain—a phenomenon that influences neural function and behaviour. However, the functional role of the microbiota in stress-associated changes and the underlying pathways of communication are unknown. Using a murine model of depression, we demonstrate that chronic stress has top-down effects on the structure of the microbiota community, reducing its richness and diversity, altering its profile, and causing differential abundance of various bacterial genera. These structural changes have functional consequences, including in metabolic pathways responsible for the synthesis of short chain fatty acids, tryptophan, and tyrosine. Using a physiologically active bacteria, Lactobacillus rhamnosus (JB-1), we probed for bottom-up signalling in chronic stress. JB-1 attenuated deficits in anxiety-like and social behaviours, and induced systemic immunoregulatory effects, independent of affecting stress-induced changes in the microbiota. In examining possible mechanisms of gut-brain brain signalling, we observed that in unstressed mice, a single dose of JB-1 causes rapid expression of c-Fos—a marker of neuronal activation—in distributed areas of the brain within 165 minutes, absent behavioural changes. No such effects were observed with heat-killed JB-1, despite that both live and heat-killed preparations facilitated vagal activity. Sub-diaphragmatic vagotomy prevented neuronal activation in most but not all brain regions, suggesting that vagal signalling is critical but indicating the presence of additional independent pathways. Finally, only chronic JB-1 treatment increased ΔFosB expression in the brain, which is indicative of long-term neuronal adaptations, in association with behavioural changes. These studies demonstrate a role for bidirectional gut-brain signalling in chronic stress, and highlight the signalling pathways and brain regions through which gut bacteria exert their influence on host behaviour.