Vagal afferents in the gut are polymodal for a multitude of chemical mediators, including beneficial and noxious sensory stimuli, and therefore must encode sensory information for the brain about the luminal environment. This sensory information has profound influence on related reflex pathways, gut function, and mood and behaviour via the gut-brain axis. Using an established mesenteric nerve recording protocol, we investigated how vagal afferents from the small intestine signal and encode information about luminal stimuli and somatic age to the brain. We investigated the role of an intramural sensory synapse between intrinsic primary afferent neurons (IPANs) of the enteric nervous system (ENS) and extrinsic vagal afferents in the gut wall in the excitatory response to luminal application of the vagus-dependent selective serotonin reuptake inhibitor (SSRI) sertraline. Vagal afferent excitation by sertraline was inhibited by intramural sensory synaptic blockade, indicating a potential role of IPAN to vagal crosstalk in the vagal response to sertraline. We examined patterns of vagal afferent firing produced by stimuli with opposing effects on behaviour to determine how the vagus encodes information pertaining to antidepressant stimuli. A distinct temporal pattern code of antidepressant vagal afferent signaling was identified that was different from the pattern code produced by non- antidepressant stimuli. Lastly, we examined how vagal afferent signaling to the brain differed in aged mice and in an aged Parkinson’s disease (PD) model. There was a significant reduction in vagal afferent firing in old and PD model mice, but this reduction was partially reversed by treatment with the excitatory aminosterol squalamine. These studies demonstrate that vagal afferent firing is critical to the communication of sensory information from the gut lumen to the brain and that this information is encoded in specific patterns of firing that are influenced by the type of stimulus and the welfare of the signalling pathway. / Thesis / Candidate in Philosophy / The vagus nerve connects the brain and gut enabling the transfer of bidirectional nervous signals, of which 80-90% transmit towards the brain. Some of these vagal signals that travel from the gut to the brain can modify behaviour or mood. We investigated a potential mechanism by which vagal afferents change firing in response to stimuli inside the gut to communicate mood-altering information to the brain and explored whether vagal signaling is vulnerable to aging. We presented evidence that the antidepressant sertraline increased vagal firing by synaptic signaling between neurons in the gut wall and vagal afferents. We demonstrated that antidepressant agents produced a specific pattern of action potential firing that might encode mood-altering information to the brain. Lastly, we found that aging and Parkinson’s disease decreased vagal afferent firing, but not insurmountably. This work identifies novel mechanisms by which intestinal vagal afferents signal the brain, which may have therapeutic applications.

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.

No description available.

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

Molecular profiling of blood for several purposes, 1) To identify prostate cancer biomarkers, 2) to identify commonalities between asthma and mood disorders, and 3) to identify mRNAs that may be involved in psychobiotic changes to behaviour. / Every cell of the body has the opportunity to secrete molecules into the blood. These molecules: proteins, RNAs, and DNAs, can be secreted freely, or within extracellular vesicles (EV). The complement of specific molecules secreted by cells can vary in accordance with changes to their immediate environment, such as disease in a particular organ. Cells of the immune system which circulate in the blood may also change the rates at which they produce these molecules in response to a disease or unusual event occurring somewhere within the body. The full complement of proteins, RNAs, or DNAs from all sources within the blood can therefore be measured to garner information about disease states and communication between every tissue of the body. In this body of work, we leveraged this to address three separate challenges within medical science. First, we utilized blood as a source of biomarkers for disease and disease severity; isolating EVs from the blood of prostate cancer patients and healthy subjects and characterized their proteins with mass spectrometry to identify potential biomarkers for prostate cancer and its stages. Next, we explored the ability of blood to identify commonalities between distinct but often comorbid diseases; here we utilized publicly available datasets to identify transcripts or gene sets potentially facilitating the relationship between PTSD, MDD, and asthma. Finally, we utilized differential gene and gene sets expression to gain mechanistic insight into microbiota-gut-brain axis; investigating the hippocampus and blood of mice fed one of two psychobiotic bacteria: Lactobacillus rhamnosus JB1, Lactobacillus reuteri 6475. The analysis identified several mRNA expression differences potentially responsible for the mood-altering characteristics of these psychobiotic bacteria. This body of work illustrates the utility of blood omics data for addressing many problems within medical science, and highlights the large scale of information stored within the blood. / Thesis / Doctor of Philosophy (Medical Science) / Every cell of the body has the opportunity to secrete molecules into the blood. These molecules: proteins, ribonucleic acids (RNAs), and deoxyribonucleic acids (DNAs), can be secreted freely, or within small membrane compartments called extracellular vesicles (EV). Specific molecules are secreted more or less by cells depending on changes to their immediate environment, such as disease in a particular organ. We leveraged this to the benefit of medical science in three separate scenarios: 1) using the molecular contents of EVs to determine when someone has prostate cancer, and at what stage; 2) examining RNAs of the blood to determine why so many with asthma also have depression or PTSD; 3) measuring RNAs in the blood and hippocampus of mice to better understand how certain bacteria in the gut can alleviate depression. This work illustrates the utility of blood in tackling many challenging problems within medical science.

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.

No description available.