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. / Thesis / Candidate in Philosophy / Stress, which is a leading risk factor for mental illnesses such as depression,
drastically affects the microbiota—the community of intestinal bacteria. However, this
influence is bidirectional as gut bacteria can also influence the brain. Thus, we sought to
understand the role of the microbiota in the negative effects of stress and how these
microorganisms interact with the brain. We observed that behavioural changes in mice
after chronic stress were associated with inflammation and community-wide changes in
the microbiota. Treatment with a bacterial strain, Lactobacillus rhamnosus (JB-1),
attenuated changes in behaviour and inflammation, but had no effect on the microbiota
composition. We observed that the brain rapidly responded to JB-1 via the vagus nerve,
and that chronic treatment caused long-term changes in brain regions. This work will
allow us to discover novel pathways that can be targeted with greater specificity in
clinical settings, providing an innovative approach to treatment of psychiatric conditions.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24855 |
| Date | January 2019 |
| Creators | Bharwani, Aadil |
| Contributors | Bienenstock, John, Forsythe, Paul, Medical Sciences (Neurosciences) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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