Microbiota and the Brain

May 11-18, 2024

Director: John Cryan

University College, Cork, Ireland

Faculty:

Jane Foster, UT Southwestern, Dallas, USA

Rochellys Diaz Heijtz, Karolinska Institute, Stockholm, Sweden

Mauro Costa-Mattioli, Altos, San Francisco, USA

Aletta Kraneveld, Vrije Universiteit Amsterdam, The Netherlands

Christoph Thaiss, University of Pennsylvania, Philadelphia, USA

Carlos Ribeiro, Champalimaud Centre for the Unknown, Lisbon, Portugal

Premysl Bercik, McMaster University, Hamilton, Canada

Mireia Valles-Colomer, Pompeu Febre University, Barcelona, Spain 

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past two decades have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders.

This Advanced Course brings together international leaders to discuss the mechanisms underpinning microbiota to brain communication and address key questions around directionality and causality. Many factors that can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics, will be discussed. At the other extreme of life, microbial diversity diminishes with ageing. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions, including autism, anxiety, obesity, schizophrenia, visceral pain, Parkinson’s disease, and Alzheimer’s disease. The Advanced Course will also address how animal models -from flies to rodents- have been paramount in linking the regulation of fundamental neural processes. Moreover, translational human studies are ongoing and will greatly enhance the field, and attempts to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders will be elaborated.

Dedicated attention will be devoted to the tools and strategies used to understand the effects of the microbiome on brain function and behaviour. Its Faculty will focus on all aspects of microbiome science from basic science, clinical medicine and population-based perspectives and how it interfaces with neuroimmunology, neuroendocrinology, nutrition, neurology & psychiatry. No advanced knowledge of the microbiome is required. Finally, it will highlight the hopes (and hype) surrounding nutritional and microbial-based intervention strategies for various brain disorders. It will be of interest to a wide range of basic and clinical scientists. During all sessions, a strong emphasis will be placed on open, interactive discussions and a strong encouragement for participants to interact as much as possible with the Faculty.

John Cryan

Gut Feelings: A Primer on the Microbiome as a Key Regulator of Brain & Behaviour Across the Lifespan 

The microbiota-gut-brain axis is emerging as a research area of increasing interest for those investigating the biological and physiological basis of neurodevelopmental, age-related and neuropsychiatric disorders. The routes of communication between the gut and brain include the vagus nerve, the immune system, tryptophan metabolism, via the enteric nervous system or via  microbial metabolites such as short chain fatty acids. Studies in animal models have been key in delineating that neurodevelopment and the programming of an appropriate stress response is dependent on the microbiota. Developmentally, a variety of factors can impact the microbiota in early life including mode of birth delivery, antibiotic exposure, mode of nutritional provision, infection, stress as well as host genetics.   Stress can significantly impact the microbiota-gut-brain axis at all stages across the lifespan. Moreover, animal models have been key in linking  the regulation of fundamental brain processes ranging from adult hippocampal neurogenesis to myelination to microglia activation by the microbiome. Finally, studies examining the translation of these effects from animals to humans are currently ongoing. Further studies will focus on understanding the mechanisms underlying such brain effects and developing nutritional and microbial-based psychobiotic intervention strategies and how these interact with various systems in the body across the lifespan.

Jane Foster

Host Genetic-Microbiome Interactions

As researchers attempt to understand how the microbiome influences brain function, understanding how nature (gene) and nurture (environment) contribute to differences in the microbiome in healthy individuals and in disease is an important consideration. While it is common for the media, the public, key stakeholders, and researchers to suggest that diet it the most important factor influencing our microbiome, this is an overstatement, and the importance of an individual’s genetic make-up is underestimated. Host genetics is a key factor in shaping the human microbiome composition. Studies in monozygotic and dizygotic twins have demonstrated that microbiota composition was more similar (but not identical) in monzygotic compared to dizygotic twins, suggesting in fact that genetics can explain some of the variance in microbiome composition. In addition genome wide analyses have identified genes and pathways that are associated with microbiome composition and identified heritable bacterial taxa.

Research targeted at determining what constitutes a healthy microbiome has revealed significant individual differences in composition and diversity. Each individual’s microbiome is their own. Several factors influence the composition, diversity, and function of the microbiome including host genetics, environment, and lifestyle. As more researchers integrate the microbiome into animal and clinical studies, a solid understanding of how these different factors influence the microbiome and microbiota-brain communication is needed. Further, there is a gap in our understanding of how gene, environment, and lifestyle factors interact to influence health and disease. This session will examine 1) individual differences in the microbiome, 2) factors that influence individual differences in the microbiome, 3) recent evidence from preclinical and clinical research examining the contribution of host genetics to microbiota-brain communication and function, and 4) novel approaches and future considerations

Aletta D. Kraneveld

Gut4Brain: microbiome, neuroimmunology & neurodegeneration

Changes in the composition and activity of intestinal bacteria, the compromised intestinal barrier and mucosal, as well as low-grade systemic inflammation in patients, point to the relevance of the microbiome-gut-immune-brain axis in neurodegeneration. Based on (pre)clinical data the talk will shed light on the possible mechanism of the crosstalk between gut bacteria, immune system and brain in Parkinson’s disease (PD) with a focus on neuroimmunological mechanisms. In addition, our recent findings on the role of neuroimmune interactions in the enteric nervous system – a potential gateway to the brain – will be presented.

There is a great need for additional therapies for PD that reduce both motor and non-motor symptoms. Recently, we demonstrated that pharmaceutical targeting of toll-like receptor 4 has a beneficial effect in a pesticide-induced mouse model for PD. In addition, we have demonstrated that a diet containing nutritional precursors and cofactors shown to improve synapse function, as well as prebiotic fibres, had therapeutic effects in the same mouse model for PD and improved the effect of oral L-DOPA therapy. These and other reports indicate important diet-microbiota-pharma interactions in PD.

A poor gut function leads to a poor brain function and vice versa; therefore, targeting the microbiome-gut-immune-brain axis with nutritional interventions and/or pharmaceutical compounds can be a new approach for the (additional) therapy of PD for the treatment of both motor and non-motor dysfunctions.

Mireia Valles Colomer

The neuroactive potential of the human gut microbiome

Advances in high-throughput sequencing technologies enabled the exploration of the composition of the gut microbiota in a broad range of neurological and psychiatric disorders and diseases. As the microbiome displays high phenotypic variation at the strain level, strain tracking methods allow to better understand the association between members of the gut microbiota and mental health. Recent developments in microbiota-gut-brain axis (MGB) research also make it possible to assess the potential of gut microorganisms to metabolize neuroactive compounds, with beneficial, neutral, or detrimental effects on the host.

 This session will go through the necessary steps to 1) design, 2) process, and 3) analyze microbiome studies, and the advantages and limitations of the existing tools and strategies will be addressed. In addition, examples on the application of functional profiling and strain tracking tools in the MGB context will be discussed.

Carlos Ribeiro

Nutrition, Metabolism and the Microbiome: Lessons from model organisms

Multicellular organisms have long been known to live in a community with microorganisms. Many of these microbiota have co-evolved mutualistic or commensal relationships with their host. These relationships manifest themselves in microbiota and have a strong influence on the host, ranging from physiology and metabolism to growth and immune system function. Most remarkable is the finding that the microbiome’s effect can profoundly affect brain function and behaviour. Current evidence suggests that a large fraction of the effects of the microbiome on the host can be attributed to the interaction of diet and microbiota. While a major effort in the field is still dedicated to identifying the host traits shaped by the microbiome as well as the microbes which shape these phenotypes, progress in this field requires identifying the cellular and molecular mechanisms by which commensal bacteria act on the host. Doing so in humans remains extremely challenging. Gnotobiotic animal models have, therefore, proven to be essential to causally pinpoint the contribution of specific microbes to specific phenotypes and elucidating molecular and cellular mechanisms by which they do so. I will discuss how model organism studies have advanced the field by providing mechanistic insights into how the microbiome affects host brain function. I will discuss how the powerful combination of neurogenetics, automated, quantitative behavioural analyses, nutritional and microbial genetic manipulations, metabolomics, functional genomics, and in vivo neuronal activity imaging approaches is allowing us to achieve a mechanistic understanding of how the microbiome affects whole animal physiology and neuronal circuit functions to regulate diverse behavioural traits.

Mauro Costa-Mattioli

Unraveling gut-microbiome-brain interactions

 When we think of behaviour and neurological disorders, we think about the brain. Traditional research on the biology of neurological disorders has focused on the brain, aiming to identify key brain regions and circuits, relevant molecular mechanisms, and/or new genetic variants associated with brain disorders. Consequently, current therapeutic approaches for neurological disorders aim to target the brain directly.

However, we are the bearers of not only our own genomes but also the genomes of the microbes living with us in symbiosis. As we now appreciate, symbiotic microbes are fundamental to nearly every aspect of host function and fitness. In my lab, we serendipitously discovered that specific microbes in the gut could modulate brain function and behaviours in an amazingly powerful way. In this presentation, I will focus on our more recent work that aims to dissect the signals, structures and mechanisms that regulate gut-microbiome-brain interactions. In addition, I will discuss how a selective, non-invasive, microbial-based approach is beneficial in preclinical animal models or neurological dysfunction and, more recently, in humans. Our findings could provide a new holistic dimension of how gut microbes control behaviours and the brain and lead to the development of new non-invasive microbial-based therapies for neurological disorders.