Mind, Mood & Microbes Pre-Conference Webinar Summary

Studying the microbiota-gut-brain axis

The first half of the virtual event focused on the latest tools and technologies that limit or expand how scientists approach their research questions in the complex field of the microbiota-gut-brain axis.

Dr. Olaf Larsen from Free University of Amsterdam, the Netherlands, and Yakult started off by emphasizing the complexity inherent in studying the microbiota-gut-brain axis. He described it as a ‘system of systems’ that includes neural modes of communication such as the vagus nerve and sympathetic nervous system, as well as systemic means of communication such as hormones and metabolites. The observed interpersonal variation in the gut microbiota, as well as the changes over time in the same individual, create challenges for clinical trial design. And when it comes to measuring brain structure and function, researchers are still working toward establishing robust neuroimaging indicators by making use of machine learning. Mathematical modeling of microbial ecosystems is also promising, since this could be used for the creation of rational microbiota interventions, but choosing the appropriate tools and selecting communities to model remain very challenging.

Prof. Aletta Kraneveld from Utrecht University, the Netherlands, covered how preclinical research allows researchers to go beyond associations and investigate causality in brain-related disorders. Humanized rodents (i.e. rodents that receive a fecal microbiota transfer from a human donor) are important for this type of work. Kraneveld raised some factors to consider to ensure good results. Fecal donor controls must be sex- and age-matched, with sibling controls if possible to minimize differences in dietary exposures. As for the mouse recipients, it is known that adult germ-free rodents develop significantly different physiology from normal ones, so in some cases it may be worth considering the use of microbiota-depleted adult rodents. She also cautioned that in acceptor rodents it may be difficult to separate the graft-host immune response from the brain disorder-associated immune response.

Prof. Jonathan Swann from University of Southampton and Imperial College London, UK, communicated how the metabolic output of the microbiome is a key aspect of communication between microbes and the brain. Metabolomics allows researchers to study this metabolic exchange. A common method is to combine in vitro bacterial cultures with metabolomic analysis to assess which molecules individual microbes might be producing or consuming, and whether these might include neuro-modulatory compounds. This information can then be used in more complex systems to find out whether the same patterns emerge in situations with complex bacterial cross-feeding. When it comes to in vivo models such as rodents, data on brain-related metabolites can be analyzed alongside information on brain tissues to find out the ‘metabolic landscape’ of certain brain regions. And finally, these findings can be tested in human cohorts. Once metabolites provide the targets, researchers can interrogate ways to modify these metabolites.

Dr. Ted Dinan from Atlantia Clinical Trials made the point that more well-designed human intervention studies are needed in the field. One crucial thing to decide before designing a trial is the target of the intervention – brain or gut microbiota? Further, the population must be defined adequately. If the intervention you are studying is a live biotherapeutic product (LBP), pharmacokinetic and dose-ranging studies are needed. These types of studies are common in the pharmaceutical industry, but need to be adapted for probiotic or LBP studies. Ultimately, however, clinical trials do not have to be prohibitively expensive because a well-designed study should be able to provide the required information in an economical manner.

Progressing toward gut-brain axis interventions

As the field advances, certain brain-related disorders are coming out ahead in the race to achieve clinically-relevant interventions. The second part of the virtual event focused on the specific states or indications that are promising for microbiota-focused gut-brain axis interventions.

Dr. Eldin Jašarević from University of Pittsburgh, USA, says we are currently seeing major advances in what we know about the gut microbiota’s role in women’s health and offspring development. First, there is high variation in early life microbial composition and assembly, and various configurations are linked to disease susceptibility later on. Furthermore, researchers have identified some of the key epigenetic/metabolic/immune signals from the mother (some of which derive from the metabolic activities of gut microbes) that cross the placental barrier, shaping the fetal development in complex ways.

Jašarević said by the number of ongoing studies related to women’s preconception, pregnancy, and postpartum health, we are poised to learn a lot in this area in the years to come—including how to develop microbiota-directed interventions during key windows of time. He added that pregnancy provides a rich opportunity for novel product identification because of the rapid changes that can be observed in microbial structure and function alongside the continuum of physical changes. Future work will likely focus on identifying gut microbiota-derived functional targets—and importantly, an equity-oriented approach to the research is needed.

Prof. Jane Foster from UT Southwestern Medical Center, USA, covered progress related to the gut-brain axis in neurodevelopment. She says the past decade of rodent work in this area has built the foundation for researchers’ ability to understand how these systems work, both in healthy individuals and in neurodevelopmental disorders. This has led to more recent work showing case- control differences in the gut microbiome and metabolites between typically-developing children and those with autism, for example. Given the higher rates of gastrointestinal symptoms in children with autism spectrum disorders, researchers need to be cautious of this possible confounder. Research on functional outcomes of microbial communities in autism is especially promising.

Prof. John Cryan from University College Cork and APC Microbiome Ireland emphasized the need to move towards a more causal understanding of the microbiota-gut-brain as it relates to psychiatric disorders. His lab is focused on elucidating mechanisms at key windows across the lifespan. Across the animal kingdom, from honey bees to baboons, researchers observe that the social brain is sensitive to microbial signals. This is the motivation for investigating disorders such as social anxiety as well as stress-related psychiatric disorders (anxiety and depression, which impact an individual’s social life). Large-scale translational and longitudinal studies are needed to establish whether the gut microbiome can be a target for ameliorating symptoms.

Dr. Filip Scheperjans from Helsinki University Hospital and Neurobiome gave an update on neurological disorders, focusing primarily on Parkinson’s Disease (PD), which is one of the leading areas of research interest. He says gut-brain research has expanded how we view PD: whereas it was once seen as a ‘dopamine deficit disorder’, it is now viewed as a multi-system disease with various motor and non-motor symptoms, especially gastrointestinal dysfunction. An emerging theory proposes two sub-types of PD – ‘body first’, with pathological proteins starting in the gut and spreading toward the brainstem via the vagus nerve, and ‘brain first’, in which pathology starts in one brain hemisphere and spreads downward. Scientists have a shortlist of potential mechanisms for these processes, such as butyrate-linked modification of DNA methylation patterns, which need to be investigated further.

Beyong PD, multiple sclerosis (MS) is also an active area of research. Scheperjans noted the convincing animal work linking gut microbiota to MS symptoms. The influence of the gut microbiota is also seen in epilepsy, although the heterogeneity of the disorder makes it challenging to study.

Overall, this relatively young field continues to see remarkable progress as information from different types of studies is put together to yield new insights. Many of these concepts will be explored in more detail at the upcoming Mind, Mood & Microbes in-person event.