Scientific progress on the Microbiota-Gut-Brain axis at Mind, Mood & Microbes conference 2023

Keynote presentations

The diet-mental health connection 

The conference’s two keynote presentations exemplified the breadth of disciplines that tackle problems related to the microbiota-gut-brain axis. Felice Jacka of Deakin University (Australia), a prominent name in the growing field of ‘nutritional psychiatry’, opened the conference on May 10th. She oriented the audience toward the diet-mental health connection and the possible roles of the gut microbiota in mediating this connection. Jacka covered evidence that shows an ‘unhealthy’ diet is a risk factor for poor mental health. On the other hand, adhering to a Mediterranean diet pattern is associated with reduced depression scores and a lower inflammatory index. One trial showed a pronounced reduction in depressive symptoms after improving diet quality (i.e., reducing unhealthy and ultra processed foods). Given this, Jacka emphasized the urgency of looking at gut-focused therapies for mental health. 

Communication-mode between the CNS and peripheral immunity unraveled 

Neuroimmunologist Jonathan Kipnis of Washington University School of Medicine (USA) has spent many years elucidating how the immune system is key to the communication between the brain and the periphery. He addressed the question of how microbiota-derived molecules successfully reach the brain. He explained that the central nervous system (CNS) borders, the meninges that cover the brain, serve as an interface for neuroimmune interactions. His group discovered that meningeal lymphatic vessels drain CNS molecules and immune cells to the deep cervical lymph nodes. This mode of communication between the CNS and the peripheral immunity may play a role in several neurological and psychiatric disorders. 

The microbiota-gut-brain axis and neurodevelopment

Early life gut microbiota supports neurodevelopment 

Maria Rodriguez Aburto of University College Cork (Ireland) spoke on the significance of the gut microbiota in the development of the brain, glial cells, and blood vessels during early life. This development is important for supporting neurons and maintaining their environment. In postnatal germ-free mice the lood-brain-barrier (BBB) function is impaired and becomes more permeable. However, short-chain fatty acids (SCFAs) actually reduce BBB permeability. This shows the crucial role of the microbiota in maintaining BBB integrity.  

Maternal microbiota may program brain development  

Alexandra Castillo-Ruiz from Georgia State University (USA) showed a way in which the maternal microbiota seems to program aspects of brain development in newborn mammals. Rapid development occurs in the mouse brain around the time of birth. Herwork showed that the lack of a microbiota leads to increased microglial labeling, indicating an increased activation of microglial cells. Additionally, it reduced expression of pro-inflammatory cytokines, as well as region-specific changes in cell death. Even when the microbial community of the young mice was normalized after birth, the brain changes persisted. This leads to the notion that the maternal microbiota programs certain aspects of neurodevelopment either in utero or during the first week after birth. 

New brain imaging signature of preterm birth  

In an “emerging topics” presentation, Kadi Vaher from University of Edinburgh (UK) showed a new brain imaging signature of preterm birth. MRI features of cerebral impaired maturation in cerebral white matter and deep and cortical grey matter are linked to the richness and composition of the neonatal microbiota. Different bacteria may be correlated with different features of brain development. 

Fecal transplantation from humans with ASD to mice increases repetitive behaviour  

Two talks focused on autism spectrum disorders (ASDs). Sylvie Rabot from INRAE (France) said that despite there being no ASD-specific microbiota signature in humans, fecal microbiota transplantation from humans with ASD to germ-free mice increases repetitive behaviour and impairs spatial memory in mice.  This is accompanied by increased inflammatory markers. However, it may be necessary to consider multiple factors such as genomics, proteomics, and metabolomics in order to guide the development of future treatments and clinical trials.    

New therapeutics for ASD on the way 

Stewart Campbell, CEO of Axial Therapeutics (USA) then described a therapeutic currently being developed for individuals with ASDs. The scientists identified a specific metabolite called 4 -ethylphenyl sulfate (4-EPS) that is elevated in a human ASD cohort; in preclinical models, 4-EPS inhibits oligodendrocyte (a type of glial cell in the central nervous system)- maturation. This   is associated with altered behaviors. A therapeutic called AB-2004 removes this metabolite from the gut without impacting the microbial community. As a result, autism-associated irritability and anxiety are reduced. A Phase 2B trial is ongoing.
Discussing emerging therapies for autism, after several years of preclinical studies, Winclove Probiotics is now finalizing a premium probiotic formula for children with autism. To verify that this formula yields expected benefits, world renowned pediatrician Prof. Hania Szajewska is now preparing a clinical trial focusing on children with ASD.  

Fecal microbiota shows associations with ADHD diagnosis  

Miranda Stiernborg of Karolinska Institute showed evidence from the largest fecal microbiota whole genome sequencing study in children and adults with attention deficit hyperactivity disorder (ADHD). Children clustered together, with adults clustering separately. The fecal microbiota was associated with ADHD diagnosis in adults; in children, certain patterns were associated with the use of psychostimulant medication or probiotics. Psychostimulant medication co-occurred with decreased abundance of a strain of Bacteroides stercoris, as well as a decrease in bacterial genes encoding enzymes for vitamin B12 synthesis.  

The microbiota-gut-brain axis and neurological disorders

Two main neurological conditions were of interest in this session: multiple sclerosis (MS) and Parkinson’s disease (PD).   

Link between diet, microbiome and immune response in MS 

Jon Laman, an immunologist from University Medical Center Groningen (the Netherlands), talked about the latest work on diet and MS. Chronic inflammation and an altered host response to the microbiota are observed in MS. He combines analysis of patients’ brain tissue with animal models (marmosets and mice). As a result, he has found that bacterial peptidoglycan appears to be a mediator in the gut-brain axis and drive chronic inflammation. The access to the distinct human brain regions is varying.  In the animal models, a dietary intervention is successful in ameliorating disease symptoms. This shows the potential links between diet components, microbiome composition, and altered immune responses.  

Short chain fatty acids may modulate pathogenesis of MS 

Jessica Perego from San Raffaele Vita-Salute University (Italy) focused in on the role that SCFAs play in neural homeostasis. Working across a variety of models, her work has shown that SCFAs act on the nervous system at multiple levels and create a tolerogenic effect on peripheral immunity while also acting as mediators of CNS homeostasis. Ultimately, they have beneficial effects on neuroinflammation, and may modulate the pathogenesis of MS. 

New research categorizes PD in biological subtypes 

Jacob Horsager from Aarhus University Hospital (Denmark) presented advanced research on categorizing Parkinson’s disease (PD) into different biological subtypes. These subtypes are determined based on the origin of the alpha-synuclein pathology, a key characteristic of PD. Horsager shared neuroimaging evidence suggesting two distinct types of PD: ‘brain-first’, where the pathology originates in the brain (olfactory bulb, amygdala) and spreads to the peripheral autonomic nervous system; and ‘body-first’, where the pathology begins in the body in the enteric or peripheral autonomic nervous system and later spreads to the brain. These patterns were observed in mild, moderate, severe, and very severe PD, and correlated with distinct symptoms: individuals with body-first PD more frequently show autonomic dysfunction, especially constipation and orthostatic hypotension. The gut microbiota may be especially important in body-first PD. 

Potential for therapeutically targeting gut microbiota in PD 

Adding to the information on PD, Ted Dinan, Medical Director at Atlantia Clinical Trials (Ireland) noted some proofs of concept that the gut microbiota can be therapeutically targeted in PD: one  showed the potential of fecal microbiota transplantation to improve motor and non-motor symptoms, and another  showed a probiotic intervention for 12 weeks in individuals with PD was associated with better scores on the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). 

Biological pathways and molecular mechanisms

This session went in detail into the molecular mechanisms involved in microbiota-gut-brain axis communication.  

How do bacteria transgress the blood-brain barrier?

Roos Vandenbroucke from Ghent University (Belgium) talked about how bacteria transgress the BBB: through a loss of barrier integrity or through leukocyte trafficking. Extracellular vesicles are important in transferring signals from one cell to another.  

Microbiota-derived GABA relates to mental health   

Benoit Pugin of ETH Zurich (Switzerland) later talked about how microbiota-derived GABA is regulated within the human gut ecosystem and how it relates to mental health. GABA is a signaling molecule with a range of functions throughout the CNS, immune system, and enteric nervous system. His group uses a bottom-up approach to study microbiota-derived GABA. They found that most Bacteroides strains produced GABA in vitro, with a low pH environment being necessary. The work confirmed that gut bacteria contribute to levels of GABA in the gut, and that physiochemical conditions of the gut are influential.  

Microbiome derived toxin may be linked to depression 

In a short talk later in the program, Elene Zhuravliova of Ilia State University (Georgia) described a microbiome derived toxin (p-cresol) that can induce different types of neurotoxicity and may be linked to depression. She found that the Sigma-1 receptor is a possible regulator of p-cresol-induced depression. 

Amino-acids and enteric viruses linked with resp. depression and cognition 

Jordi Mayneris Perxachs from Girona Biomedical Research Institute (Spain) covered gut microbiota contributions to both depression and cognition. Bacterial pathways related to metabolism of amino acids arginine, proline, and histidine were reduced in depression. Overall, the work showed a possible causal role of the microbiome in depression through altered proline metabolism. This induces disruption of glutamatergic and GABAergic homeostasis in the gut. Here’s a role for dietary means of addressing depression. Next, Mayneris Perxachs highlighted the role of enteric viruses in cognition. Individuals with higher levels of two major bacteriophage families (Caudovirales and Siphoviridae) in the gut microbiome showed better performance on executive processing and verbal memory tasks. Those with increased Microviridae had greater impairment in executive abilities. The contribution of the viruses to these cognitive parameters was confirmed using animal models. 

Probiotic formula has benefits to mood, anxiety, sleep quality and perceived stress 

Umar Haris Iqbal from Lallemand talked about a probiotic intervention with psychological benefits and evidence for how it achieves its effects. The translational approach for the ‘Cerebiome’ formulation consists of phenotypic and genetic characterization, mechanistic studies, and clinical trials. Clinical cohorts receiving the intervention showed improvement of psychological stress, with benefits to mood, anxiety, sleep quality, and perceived stress. Mechanisms involve a decrease in neuroinflammation and protection against intestinal inflammation and permeability. 

Microbiota-gut-brain axis and psychiatric/cognitive disorders

Probiotics reduce stress reactivity in PTSD 

Christopher A. Lowry from University of Colorado Boulder (USA) covered microbiota-gut-brain axis signaling in post-traumatic stress disorder (PTSD). He wondered whether it is possible to alter this signaling to prevent PTSD. Lowry noted the close connection between inflammation and PTSD, since biomarkers of inflammation are among the top-ranking features predicting future diagnosis of PTSD. After PTSD is established, the gut microbiome is altered. Moreover, affected individuals have difficulty suppressing inappropriate inflammation and develop a risk of autoimmune disorders. In a pilot study using probiotics with anti-inflammatory effects, those with PTSD show less stress reactivity after the intervention. Further, a probiotic strain (Mycobacterium vaccae NCTC 11659) isolated from soil shows promise in promoting stress resilience, having been shown to prevent stress-induced gastrointestinal inflammation in animal models. 

Gut microbiota can trigger abnormalities in endocannabinoid system 

Amadeo Minichino from University of Oxford (UK) talked about anhedonia – i.e., the inability to feel pleasure—in psychotic illness, and how the gut-microbiome-endocannabinoid axis contributes. Minichino argued that the endocannabinoid system is abnormally active in psychotic illness. The levels of endocannabinoids are associated with severity of negative symptoms and cognitive deficits. These changes parallel alterations in the gut microbiota. Causality is challenging to determine, but one study in mice showed that an anhedonic state can be triggered by modifying the endocannabinoid system in the brain. Minichino said current evidence supports a “mediation” model whereby gut microbiota changes trigger abnormalities in the endocannabinoid system, which have an impact on mental health. 

Depleted microbiome induces increased drug-seeking behaviors 

Drew Kiraly from Wake Forest University (USA) shared some valuable insights into drug seeking behaviors in substance use disorders, gained from working with animal models. Across all of the models, some patterns emerged: when the gut microbial community was depleted with broad-spectrum antibiotics, animals increased intake of low-dose drug, exerted more effort to obtain drug, and increased drug-seeking behaviors when the drug was scarce. Transcriptomics analyses highlight the microbiome’s effects on gene expression in the brain in response to multiple drugs of abuse, resulting in Kiraly’s theory that a depleted microbiome leads to dysregulated gene expression, with abnormal behavioral and synaptic plasticity. 

Probiotic formula reduces cognitive reactivity to sad mood 

Jessica Eastwood of University of Reading (UK) turned to healthy individuals, describing a clinical trial on a probiotic aimed at improving cognitive function and mood in older adults. A multi-species probiotic (“Ecologic Barrier”) consisting of 9 strains at a dose of 5×10^9 CFU/day, or placebo, was given to individuals aged 65-80 in a double-blind cross-over randomized controlled trial. The supplementation reduced cognitive reactivity to sad mood, and also appeared to increase executive function in conditions of higher cognitive demand. These effects may occur through increased growth of Lactoccocus species in the gut microbiota of healthy older adults, impacting immune pathways involved in cognitive function. 

Strain selection for psychobiotic activity  

An emerging topic later covered by Melania Casertano of University of Naples (Italy) and University of Wageningen (the Netherlands) concerned the selection of probiotic microorganisms with potential psychobiotic activity. Casertano screened probiotic strains for neurotransmitter synthesis (production of GABA), then undertook a clinical study with two of the selected strains. In vivo, the strains did not have a beneficial effect on cognitive performance or mood, but it did improve cognitive reactivity to sad mood. Strain selection for desired brain effects deserves further consideration. 

New technologies for studying the gut-brain axis

According to some participants, the session on new technologies was among the most useful and applicable to their scientific work. Indeed, many cutting-edge science and scientific techniques were presented. 

Non-invasive tool to module gut microbiota  

Sylvia Arboleya of Instituto de Productos Lácteos de Asturias (Spain) described ‘photobiomodulation’, a non-invasive tool (transcranial low-light-level therapy) with the potential to modulate the gut microbiota.  

Microfluidic device to model multi-organ interaction

Lena Sophie Koch from University of Twente (the Netherlands) explained a model of the gut, brain, and vagus nerve on a microfluidic chip. Individual components of the microbiota-gut-brain axis were recreated from induced pluripotent stem cells and integrated on a custom microfluidic device. This organ-on-a-chip technology can be used to model multi-organ interactions in the microbiota-gut-brain axis. 

Tool that analyses the circadian rhythms of the microbiome 

Thomasz Bastiaanssen from University College Cork (Ireland) argued that the temporal dynamics of the microbiome are under-investigated. He noted that circadian rhythms play an important role in the functioning of the microbiota-gut-brain axis. He described an easy-to-use R-based tool called ‘Kronos’ that can be used for analysis of circadian rhythms. This novel tool offers the ability to handle time for either independent or repeated measures data, as well as datasets ranging from single variables to multiple omics.  

Regarding probiotics, delivery matrix matters 

Finally, Olaf Larsen of Yakult Netherlands and VU Amsterdam highlighted some future hot topics for interventional strategies targeting the gut microbiota. Regarding probiotics, he noted that the delivery matrix likely matters and that scientists need to further elucidate the factors that separate responders from nonresponders. Further, scientists may attempt to replicate the effects of fecal microbiota transplantation (with microbial “guilds” that function as units), and multi-strain preparations might be a first step toward supplying these guilds.