Major depressive disorder (MDD) is a highly heterogeneous disorder, with some patients displaying immune activation and altered intestinal microbiota composition when compared to healthy controls. In recent years, the transfer of fecal microbiota pooled from several MDD patients has been used to model depression in recipient rodents. However, we have previously observed the induction of donor-specific phenotypes in mice receiving microbiota from individual irritable bowel syndrome and generalized anxiety disorder patients. Therefore, we assessed the efficacy of fecal microbiota transplant (FMT) using individual versus pooled MDD patient microbiota to induce depressive-like behaviour in recipient rodents. We observed that pooling microbiota from several patients abrogated microbial features unique to individual donors. Mice that received pooled microbiota displayed different behavioural and immune phenotypes when compared to mice that received individual patient microbiota. Two individual MDD microbiota donors, patients MDD1 and MDD5, altered the behaviour of recipient mice when compared to controls. We identified several microbial species that may underlie the anxiety- and depressive-like behaviours observed in MDD1 and MDD5 mice. Additionally, altered expression of neural and immune genes was observed along the gut-brain axis of mice colonized with MDD1 microbiota. As microglia activation may play a role in our model, we developed a protocol for the isolation and phenotyping of adult mouse microglia that will facilitate future research efforts. Overall, our results demonstrate the heterogeneity of the microbial underpinnings of MDD and support the use of individual patient microbiota in future FMT experiments. / Thesis / Master of Science (MSc)

Neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder, are a heterogeneous set of developmental disorders affecting the central nervous system. Studies into their etiology remain challenging, as neurodevelopmental disorders frequently present with a wide range of biological, behavioral, and comorbid symptomologies. Increasing epidemiological reports of antibiotic use during pregnancy as a significant correlate of subsequent mental disorder diagnosis in children suggest a mechanism of influence via the maternal gut-fetal brain axis. Importantly, antibiotics cause dysbiosis of the gut microbiome and disrupt the delicate composition of the microbial inoculum transferred from mother to child, which is critical for development of the immune system and holds implications for long-term health outcomes. The research objective of this dissertation is to reveal a causal mechanism of maternal microbial influence on neurodevelopment by examining the brain's resident immune cells, microglia, and corresponding behavioral outcomes in a mouse model of antibiotics-driven maternal microbiome dysbiosis (MMD). We identify early gross motor deficits and social behavior impairments in offspring born to MMD dams, which paralleled hyperactivated microglia in brain regions specific to cognition and social reward. The MMD microglia also exhibited altered transcriptomic signatures reflective of premature cellular senescence that support evidence of impaired synaptic modeling found in MMD brains. We report that these deficits are rescued in the absence of Cx3cr1, a chemokine receptor expressed ubiquitously on microglia, to highlight a pathway in which maternal microbiota may signal to neonatal microglia to undergo appropriate neurodevelopmental actions. Finally, we characterize Lactobacillus murinus HU-1, a novel strain of an important gut bacterium found in native rodent microbiota, and demonstrate its use as a probiotic to restore microglial and behavioral dysfunction in MMD offspring. / Ph. D. / Population studies on neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder, highlight antibiotic use during pregnancy as a major correlate of subsequent diagnoses in children. These findings support a growing body of evidence from animal and human studies that the microbial ecosystems (“microbiome”) found in and on our bodies play significant roles in mental health, including mood, cognition, and brain function. Importantly, antibiotics during pregnancy create an imbalance of the gut microbiome (“dysbiosis”) and disrupt the microbial inoculum transferred from mother to child, which is critical for maturation of the infant immune system and holds implications for long-term health outcomes. Thus, the research objective of this dissertation is to identify a mechanism of influence from the mother’s gut to the neonate’s brain by examining the brain’s resident immune cells (“microglia”) in a mouse model of antibiotics-driven maternal microbiome dysbiosis (MMD). We uncover autism-like behavioral deficits and dysfunctional microglia in MMD offspring, and characterize signaling cues specific to microglia by which improper neurodevelopment may be taking place. We also reveal that the detrimental effects of MMD are reversed in mice born to mothers pretreated with a probiotic candidate, Lactobacillus murinus HU-1, to suggest maternally-derived Lactobacillus may help to mediate proper neurodevelopment.

The gut-brain axis describes a paradigm wherein the trillions of microorganisms inhabiting the gastrointestinal tract engage in bidirectional communication with the host central nervous system. Adaptive immunity represents an important intermediate in this dynamic crosstalk; previous work in our lab has demonstrated that T-lymphocytes, a main class of immune effector cells, contribute to neurodevelopmental processes and behavioral outcomes across the lifespan. Parallels between the phenotype of T-cell deficient and germ free mice led us to hypothesize that bidirectional T-cell-microbe communication is critical for normal neurodevelopment, and that T-cell deficiency impacts the neural circuitry underpinning behavior via disruption of the gut-brain axis. The main objective of this thesis was to elucidate the mechanisms by which T-cells mediate developmental gut-brain signalling. The first installation examined the gut microbiome, gut metabolome, and neurochemical profile in wild-type and T-cell deficient mice from adolescence to adulthood, demonstrating that absence of T-cells impacts the developmental trajectory of functional microbiome output and levels of neuroactive molecules in the brain. Experiment two investigated the impact of T-cell deficiency on gut-brain communication through the lens of host gene expression in the parenchyma and the intestine. T-cell deficient mice showed significant changes in genes related to intestinal immunity and barrier function, in addition to decreases in microglia-related genes in the prefrontal cortex during early life. The final experiment transitioned into a wild-type model to measure the co-evolution of T-cell subsets in mucosal and central immune compartments with composition and diversity of the microbiota. We demonstrated a parallel diversification of the gut microbiome and the functional T-cell repertoire, whereby emergence and proliferation of specific T-cell subsets is linked to compositional shifts in dominant microbial communities across development. Together, our results demonstrate the importance of T-cells for normal development of the holo-organism, with implications for the developmental wiring of functional brain circuitry. / Thesis / Doctor of Philosophy (PhD) / Modern medicine has increasingly placed emphasis on the mind-body connection. This has been exemplified by a series of recent discoveries surrounding the importance of the gut microbiome in maintaining our physical and mental health. One of the key channels through which the microbiome communicates with the host is through the immune system, an equally complex network of cells and proteins that protect the body against invading pathogens. Indeed, these systems evolve alongside each other and engage in constant crosstalk throughout the lifespan, with downstream impacts on the developing brain. This thesis sought to further explore the role of T-cells, a key component of the adaptive immune system, in coordinating gut-microbiome-brain interactions across development. The first experiment examined the microbiome as well as small molecules in the gut and brain of normal mice and mice lacking T-cells. The second experiment built on this work to examine how T-cells influence the expression of different genes in the gut and brain. Finally, the third experiment mapped different populations of T-cells and microbiome composition from the first week of life to adulthood, to better understand how they interact at different stages of development. This work will offer insight into how T-cells talk to the microbiome and how they transmit signals from the gut to the brain, with implications for understanding neurodevelopmental disorders and how they arise.

Tidigare forskning har visat ett samband mellan vår tarmflora och vår fysiska hälsa, och idag görs även mycket forskning på om den även kan påverka vår mentala hälsa. Idag lider över fyra procent av världens befolkning av depression, och den här litteraturstudien har, genom att analysera sju studier och deras resultat, försökt få svar på frågan om probiotika kan lindra depression. Antingen som primär behandling eller som komplement till annan behandling. Den här litteraturstudien gav inga konkreta svar på den frågan, annat än att alla inblandade forskare är överens om att det behövs göra fler, längre och större studier innan man kan dra några slutsatser. / Previous research has shown a connection between our microbiota and physical health, and today a lot of research is also being done on whether it also can affect our mental health. Today, over four percent of the world's population suffers from depression, and this literature study has, by analysing seven studies and their results, attempted to answer the question of whether probiotics can alleviate depression. Either as primary treatment or as a supplement to other treatment. This literature study did not provide any definite answers to that question, other than that all the researchers involved in the studies analysed agree that more, longer and larger studies are needed before one can draw any conclusions.

Alzheimer’s disease (AD) is the most common form of dementia and a growing disease burden that has seen pharmacological interventions primarily fail. Instead, it has been suggested that preventative measures such as a healthy diet may be the best way in preventing AD. Prebiotics are one such potential measure and are fermented into metabolites by the gut microbiota and acting as gut-brain axis components, beneficially impact the brain. However, the impact of prebiotics in AD prevention is unknown. Here we show that the prebiotic inulin increased multiple gut-brain axis components such as scyllo-inositol and short chain fatty acids in the gut, periphery, and in the case of scyllo-inositol, the brain. We found in E3FAD and E4FAD mice fed either a prebiotic or control diet for 4-months, that the consumption of the prebiotic inulin can beneficially alter the gut microbiota, modulate metabolic function, and dramatically increase scyllo-inositol in the brain. This suggests that the consumption of prebiotics can beneficially impact the brain by enhancing metabolism, helping to decrease AD risk factors.

The Mediterranean diet (Medi) has been highlighted as the golden diet rich in protective properties associated with cognitive- and emotional health. The foundation of the Medi comprises vegetables, fruits, nuts and seeds, legumes, and extra virgin olive oil. Research has been conducted in both holistic dietary approach and single nutrient approach regarding the impact of nutrition and diet, in this case, the Medi‟s effect on brain health. This review aims to give an up to date overview of the Mediterranean diet, outline some of the diet's abundant nutrients, and discuss studies linking the nutrient's potential effect on depression, cognitive decline, dementia, and brain structure and function. In addition, this review will attempt to assess whether the Medi as a whole or if a single nutrient approach is accountable for the health-promoting findings. Furthermore, the gut-brain axis, and other potential underlying mechanisms involved in the modulation of food- and nutrient intake and their effects on the brain, will be outlined. A diet high in fruit-, vegetable-, polyunsaturated fatty acid-, and monounsaturated fatty acid content has great power for health-maintenance and decreases the risk of suffering cognitive decline, dementia, and potentially depression. More randomized controlled trials are however eagerly awaited to give more substance to previous findings.

As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

(EN) Research in interactions between the nervous and immune systems is focused mainly on mammals, while in other vertebrates, including birds, it remains neglected. Two types of cannabinoid receptors interconnect the nervous and immune systems: CB1, which is in mammals involved in regulation of neural processes, and CB2, which is in mammals involved in regulation of immune processes. However, little is presently known about the roles of these receptors in nervous and especially immune processes in birds. Therefore, in this work I focus on the expression of cannabinoid receptors in cognitively advanced bird species (parrots, passerines) during induced sterile peritoneal inflammation. Unlike passerines, parrots appear to lack the gene for CB2, which may affect the inflammation regulation. I have revealed no changes in the expression of these receptors during peritoneal inflammation neither in parrots, nor in songbirds. Nevertheless, the increase in expression of the proinflammatory cytokine IL- 1β in the brain in parrots confirms the importance of neuroimmune interaction and mutual influences along the gut-brain axis. This work suggests that even in birds, the central nervous system is affected by inflammation through the gut-brain axis. The expression of cannabinoid receptors does not change much...

Abstract: Alzheimer’s Disease (AD) is a complex neurodegenerative disease that requires interprofessional collaboration. Pharmacological options are currently ineffective, increasing the need for preventative strategies to combat the rise of AD. Considerations of gut-targeted interventions have increased as a key component in the prevention of AD, based on the understanding that the state of the gut microbiome can impact cognitive function through the pathway known as the gut-brain axis. Methods: This scoping review explored information on the gut-brain axis in persons with AD. A comprehensive search was conducted in November 2023. Forty reviews and 13 human studies were analyzed. Results: There is an abundance of information supporting the role of the gut-brain axis in the development and prevention of AD. This information is complex and may deter healthcare professionals outside of neuroscience, medicine, and nutrition from engaging in the literature. Further research is needed from within the SLP’s scope of practice.

Flera miljoner människor världen över är idag drabbade av depression vilket skapar ett stort lidande. Depression leder även många gånger till självmord. Känt är att tarmmikrobiotan är en viktig del i sjukdomsförloppet [MB1] och att kunna karakterisera tarmmikrobiota som är av psykobiotisk karaktär blir därför viktigt i ett behandlande syfte men också för att kunna ställa diagnos mer objektivt. Syftet med den här litteraturstudien är att genom artikelgranskning i PubMed undersöka vad senaste forskningen säger om tarmmikrobiotans roll i tryptofanmetabolismen med efterföljande effekt på depression. Skiljer sig tarmmikrobiotan och tryptofanmetabolismen mellan individer med och utan depression och kan tarmmikrobiotan och tryptofanmetaboliter användas som biomarkörer för att diagnostisera depression? Resultatet visar att tarmmikrobiotan och vissa tryptofanmetaboliter skiljer sig signifikant åt mellan friska individer och individer med depression. Studiens slutsats är att tarmmikrobiota och tryptofans metaboliter skulle kunna användas som biomarkörer för att kunna diagnostisera depression mer objektivt. Dock förekommer flera olika potentiella confounders som bör tas i beaktning. / Several million people worldwide are today affected by depression, which creates a lot of suffering. Depression also often leads to suicide. It is known that the gut microbiota is an important part of the course of the disease and being able to characterize gut microbiota that is of a psychobiotic nature therefore becomes important for a treatment purpose but also to be able to make a diagnosis more objectively. The aim of this literature study is to examine, through article review in PubMed, what the latest research says about the role of gut microbiota in tryptophan metabolism with subsequent effect on depression. Do gut microbiota and tryptophan metabolism differ between individuals with and without depression and can gut microbiota and tryptophan metabolites be used as biomarkers to diagnose depression? The results show that the gut microbiota and certain tryptophan metabolites differ significantly between healthy individuals and individuals with depression. The study's conclusion is that gut microbiota and tryptophan metabolites could be used as biomarkers to diagnose depression more objectively. However, there are several different potential confounders that should be taken into account.