The gut and the brain are in constant communication through pathways that include the immune system, the nervous system, neurotransmitters, and hormones. Modifications in the gut, especially the gut microbiome, have the potential to cause changes in the brain resulting in behavioral and cognitive changes. A healthy and diverse microbiome, which may be achieved by a high fiber diet or probiotic or prebiotic treatments, is associated with improvements in cognition. Gut dysbiosis and a decrease in diversity of the microbiota, which may be caused by a western diet or antibiotic treatments, is associated with cognitive decline and decreased memory. There are many possible pathways through which these changes in the gut act to change cognition, including the immune system, the expression of brain derived neurotropic factor, metabolites such as short chain fatty acids, gut hormones, and neurotransmitters. If researchers can decipher which pathways are involved in modifying cognition, they may be able to identify treatments that can help improve memory and specifically decrease age-related cognitive decline.

Depression and anxiety disorders affect upwards of one in six individuals at some point in their life making them the most prevalent mental illnesses today. Recent evidence has suggested a possible correlation between the human gut microbiota and the development of depressive and anxiety-like symptoms through a signaling pathway termed the microbiota-gut-brain axis. In both animals and individuals suffering from depression and anxiety-like symptoms, alterations in their gut microbial composition seem to compromise the function of this pathway. In addition to this microbiota-gut-brain axis, other microbiota-derived molecules have been linked to symptoms of depression and anxiety. Given this emerging role of the gut microbiome and gut–brain axis, it is crucial to understand the factors shaping our gut microbiome in order to determine potential therapeutic strategies to treat depression and anxiety. Following a concise review of the human microbiome, depression/anxiety, and the gut-brain axis, I will examine the gut microbiota role as a regulator of depression and anxiety. In addition, other biological markers associated with both the gut microbiome and these disorders will be reviewed. Lastly, I will evaluate the gut microbiome as a prospective therapeutic target for mental illnesses such as depression and anxiety.

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Bacteria, especially symbiotic species in the gastrointestinal tract, have lived with human for long time and are involved in many aspects of host physiology. There is growing evidence that microbiota-gut-brain axis plays an important role in modulating the response to stress in both human and animals. Alterations in the gut microbiota can change the central nervous system function through effects on the endocrine, immune and nervous systems. Recent studies suggest that probiotic treatment may help to maintain resistance against the detrimental effects of stress though the microbiota-gut-brain axis. However, how potentially beneficial bacteria interact with specific immune and neural components, to mediate beneficial effects on behavior remain unclear. Using chronic social defeat stress, a model often used in post-traumatic stress disorder research, we found that administration of Lactobacillus rhamnosus JB-1 beginning 48 hours following chronic social defeat led to persistence of fear memory and social deficits. These effects were associated with changes in gene expression related to emotion and memory in the hippocampus. This was in contrast to previous studies showing that probiotic intervention during social defeat prevents stress induced deficits in social behavior. This indicates that timing of L. rhamnosus treatment in relation to stress exposure has important implications for effects of the bacteria on behavior. In relation to the mechanism of action of L. rhamnosus on behavior, we demonstrate through depletion and adoptive transfer experiments that CD4+CD25+ T cells in mice treated with JB-1 were necessary and sufficient for JB-1 induced anxiolytic and antidepressant-like effects. Evidence also suggested that Ly6Chi monocytes may be a downstream target inhibited by Tregs involved in the behavioral effects of the bacteria. We observed that JB-1 could also reduce the number of activated microglia in the hippocampus, and attenuate hypothalamic-pituitary-adrenal axis reactivity with the integrity of vagus nerve. Crucially we demonstrated that JB-1 induced promotion of peripheral Tregs, reduction in microglia activation in the hippocampus, and attenuation of HPA axis reactivity, were all inhibited following vagotomy indicating that vagus nerve integrity is required to maintain immune and endocrine linkages from gut microbes to the brain. These studies demonstrate prerequisites for beneficial probiotic effects on stress related behaviours including a specific time window in relation to stress exposure, the activation of regulatory immune cells, and undisrupted vagal nerve signalling. These findings highlight the inter-systemic communication of the microbiota-gut-brain axis in the stress response, and might help to unveil more therapeutic opportunities in relation to stress-related mood disorders. / Thesis / Doctor of Philosophy (PhD) / Excessive exposure or dysregulated responses to stress in human and animals induces behavioral changes and the development of mood disorders. The Microbiota-gut-brain axis plays an important role in maintenance of homeostasis. However, crosstalk between the different components of microbiota-gut-brain axis, and how specific microbes can modulate these interactions, remains unclear. Thus, we sought to understand the mechanism of inter-systemic communication linking a specific gut microbe to changes in stress response and behavior. We observed immunoregulation by regulatory T cells were essential in Lactobacillus rhamnosus JB-1 induced anxiolytic and antidepressant-like effects. We also found the integrity of vagus nerve was necessary for JB-1 induced promotion of regulatory T cells and decrease in microglial activation and attenuation of hypothalamic-pituitary-adrenal axis that are associated with the anxiolytic effects of the bacteria. We also identified that the temporal relationship between exposures to stress and the bacteria is important as ingestion of JB-1 directly after chronic social defeat lead to persistence of fear memory and social deficits. This work will help us to understand mechanisms underlying the microbiota-gut-brain axis, which may allow for the development of novel microbe based therapeutic intervention against mood disorders.

Introduction: Irritable bowel syndrome (IBS) is characterized by gastrointestinal (GI) symptoms, and as a consequence of dysregulated communication via the gut-brain axis, is highly comorbid with mental illnesses such as anxiety and depression. With no known cure, IBS patients must manage their symptoms through lifestyle factors. Physical activity is one such lifestyle factor that reduces GI symptoms and improves mental health; however, it remains unclear whether physical activity buffers against the acute worsening of IBS symptoms following a stressor. Method: To investigate this, we evaluated the stress reactivity and recovery of 9 IBS patients and 13 healthy controls following exposure to acute stress. We exposed participants to an electronic Trier Social Stress Test (e-TSST) and measured changes in psychological stress (state anxiety), physiological stress (sympathovagal balance, where higher LF/HF ratio indicates greater stress system activation), and GI symptom severity before, during and every 20 minutes for one hour after. Physical activity was measured using the Stanford Seven-Day Physical Activity Recall questionnaire and quantified as weekly energy expenditure. Results: IBS patients had higher state anxiety (p = .05), LF/HF ratio (p = .01) and GI symptom severity (p = .01) than healthy controls. Although the e-TSST did not exacerbate these group differences, higher state anxiety at baseline (p = .03) and higher LF/HF ratio in response to an acute stressor (p < .001) were associated with more severe GI symptoms within the first 20 minutes following the e-TSST. Importantly, IBS patients who were more physically active experienced less severe GI symptoms during that same timeframe (p = .03). Conclusion: Physical activity may be a promising lifestyle factor for lessening GI symptom severity in response to an acute stressor. / Thesis / Master of Science in Kinesiology

Evidence suggests that the gut-brain axis can influence stress-related behaviour, mood and neuropsychological disorders, including anxiety. Stress exposure can increase anxiety-related symptoms such as muscle tension &amp; worrying. Medical treatment has low success and a range of side effects on anxiety. This review aimed to see if probiotics can reduce anxiety symptoms in humans. Where relevant articles on people with anxiety disorders are lacking, the review evaluates articles addressing healthy participants in stressful situations such as exams or public speeches via anxiety questionnaires. I hypothesized that probiotics could be an effective anxiolytic treatment in combination with therapy. Most articles demonstrated reduced subjective and objective results in anxiety and stress measurements after a daily intake of probioticstrains. Findings demonstrate potential anxiolytic benefits with a daily probiotic intake. However, future research on participants with an anxiety disorder is needed to conclude the hypothesis.

Microbiota-released extracellular vesicles (MEVs) have emerged as key players in intercellular signaling in host-microbiome communications. However, their role in gut-brain axis signaling has been poorly investigated. Here, we performed deep multi-omics profiling of MEVs generated ex-vivo and from stool samples to gain insight into their role in gut-brain-axis signaling. Metabolomics unveiled a wide array of metabolites embedded in MEVs, including many neurotransmitter-related compounds such as arachidonyl-dopamine (NADA), gabapentin, glutamate, and N-acylethanolamines. To test the biodistribution of MEVs from the gut to other parts of the body, Caco-2, RIN-14B, and hCMEC/D3 cells showed the capacity to internalize labeled MEVs through an endocytic mechanism. Additionally, MEVs exhibited dose-dependent paracellular transport through Caco-2 intestinal cells and hCMEC/D3 brain endothelial cells. Overall, our results revealed the capabilities of MEVs to cross the intestinal and blood-brain barriers to delivering their cargo to distant parts of the body.

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Research has shown that our gut microbiota confers many beneficial functions, including aiding the development of the immune system, metabolism, modulating stress reactivity and behaviour. The diverse population of the gut microbiota has been shown to be heterogeneous between individuals, with host genetic factors emerging as a contributor to gut microbiota composition. Recent work suggests that microRNA may act as a mediator of communication between the host and resident gut microbiota. Here we explore host genetic differences in gut microbiota composition and fecal miRNA profiles in two inbred mouse strains BALB/C and C57BL/6, in relation to gastrointestinal homeostasis. Furthermore, we evaluate the role of host genetics in response to perturbation of the gut microbiota using broad-spectrum antibiotic treatment. Distinct differences in the gut microbiota composition evaluated by fecal 16s rRNA gene sequencing between BALB/c and C57BL/6 mice were found with notable significant differences in genera Prevotella, Alistipes, Akkermansia and Ruminococcus. Significant host genetic differences were also observed in fecal miRNA profiles evaluated using the nCounter Nanostring platform. A BLASTn analysis was used to identify conserved fecal miRNA target regions in bacterial metagenomes, which identified numerous bacterial gene targets. Of those miRNA targets that were conserved in our dataset, 14 significant correlations were found between fecal miRNA and predicted taxa relative abundance. Treatment with broad-spectrum antibiotics for a period of 2 weeks resulted in BALB/c mice exhibiting a decrease in barrier permeability while C56BL/6 barrier permeability remained unchanged, demonstrating a host-specific physiological response to antibiotics at the gastrointestinal barrier. Differential response to antibiotics was also observed in the expression of barrier regulating genes in both host strains. Individual taxa were found to respond differentially by host strain, with Parabacteroides and Bacteroides associating with changes in barrier function. Together these findings suggest that host genetics play a role in determining the host-microbe relationship in both healthy homeostatic conditions and altered microbial conditions. / Thesis / Master of Science (MSc)

The human gut and brain have a bidirectional communication that has shown to play a pivotal role in our health and disease. Literature has shown that microbiota composition and diversity can be influenced by both genetic and environmental factors, contributing to shaping an individual’s microbial composition. The current work includes analysis of the microbiome of several mouse models to better understand how gene-environmental interactions during early development can influence the composition of microbiota within the gut. Here, male and female mice from several strains (C57BL/6, Balb/C, FVB, CD1) and genetically modified mice including T-cell receptor knock out mice (TCRβ-/-δ-/-) and Fragile-X-mice (FMR1-KO) were exposed to early life stressors including lipopolysaccharide (LPS) injection on postnatal day 3 (P3) and/or overnight maternal separation on P9. Fecal samples were collected at P24 and microbiota composition was determined by amplifying the 16s rRNA gene variable 3(v3) region and sequenced using the MiSeq Illumina platform. DADA2, was used to analyze this data in R software. Among the group, strain was found to be significant among alpha and beta diversity metrics while sex and stress were found to contribute to within strain variation, which demonstrated that both genetic and environmental factors are important in shaping an individual’s microbial composition. Secondly, we also explored the role of gut microbiota on the development of the immune system in TCRβ-/-δ-/- and C57BL/6 mice. Mice that lack T-lymphocytes were found to have a lower alpha diversity, as well as separated from their wild-type controls by beta diversity. Several bacterial taxa were found to be influenced by the immune system, demonstrating a bidirectional communication between the gut and T-cells. Lastly, the influence of litter, an environmental factor on microbial composition was explored within inbred mouse strains, C57BL/6 and Balb/C. Litter was found to influence alpha diversity, in which litters among C57BL/6 exhibited the greatest variation in such diversity. Beta diversity was also found to be influenced by litter, as related litters were found to cluster together. Differences in bacterial taxa between the inbred strains were observed and a subset of those taxa were found to be influenced by litter. Hierarchical clustering and co-occurrence analysis revealed different clusters of co-occurring taxa between both strains. These findings demonstrate that environmental factors can contribute to influence the composition of microbiota. / Thesis / Master of Science (MSc)