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Unlocking New Potential in the Gut-Brain Axis

Our Gut-Brain Development Program will translate breakthrough research for a new class of probiotics targeting the gut-brain pathway. Plus a Q&A with gut-brain pioneer Dr. Sarkis Mazmanian.

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Unlocking New Potential in the Gut-Brain Axis
Contents
Our Gut-Brain Program A New Frontier in Mental Health Unlocking the Potential of BacteriaBeyond #GutMania In Conversation with Dr. MazmanianCitations

Building on over a decade of discoveries from the Caltech lab of gut-brain pioneer (and Seed Health Board Member), Dr. Sarkis Mazmanian, we’ve partnered with Axial Therapeutics (co-founded by Dr. Mazmanian) to develop probiotic innovations for areas like anxiety, depression, stress, and overall mental well-being. 

Breakthroughs in microbiome research continue to inform almost every aspect of our health, and this new program extends our work, translating microbiome science into novel applications of probiotics. Axial’s expertise in the gut-brain axis, combined with our platform to enable rapid, efficient advancement of microbial research from discovery through application is an extraordinary opportunity to transform current treatment paradigms in mental health. 

In the past decade, research has unveiled an internal, bidirectional “superhighway” between the gut and the brain, termed the gut-brain axis (or, more specifically, the microbiome-gut-brain axis). This axis describes the complex network of physiological pathways that connect the gut and the brain via the vagus nerve. Insights into this gut-brain crosstalk have revealed a dynamic communication system that not only influences intestinal activities like digestion and motility, but also regulates immune and pain response, metabolism, mood, social behavior, and cognition. 

More recent research has focused on elucidating the role of the gut-brain axis in human health and disease, such as a growing number of psychological and neurological diseases, including Autism Spectrum Disorder, depression and anxiety1, Parkinson’s2, Alzheimer’s disease3, and Irritable Bowel Syndrome (IBS). 

These advances not only evolve our understanding of neurology, gastroenterology, and associated pathologies, but also unlock a novel framework to reimagine treatment. 

 

The gut and brain use various forms of communication to converse, the most prominent physical connection and pathway being via the vagus nerve, one of the longest nerves in the human body. Other messages are sent in the form of microbial metabolites such as organic acids (like short-chain fatty acids), proteins, fats, and neurotransmitters, which reach the brain by hitching a ride through blood vessels or stimulating the vagus nerve.

One particularly compelling area of gut-brain research explores how specific microbial metabolites influence neuropsychiatric health, and how probiotic treatments may be used to control these metabolites for mental health outcomes. Dr. Mazmanian’s Caltech lab was the first to discover the critical contributions of intestinal microbes and microbial metabolites in neuropsychiatric conditions, as well as the molecular signals from gut bacteria that can influence anxiety behavior. 

More recently, his lab published a study in Nature4, which demonstrated that specific microbes alone could activate neuronal activity in the hypothalamus to reduce levels of corticosterone, a stress hormone in mice, known in humans as cortisol. After first confirming the link between increased levels of corticosterone and reduced microbiome diversity in mice, his team identified a bacterial species (Enterococcus faecalis), which promotes social activity and reduces corticosterone levels following social stress.

His latest paper, published earlier this year in Nature Medicine5, found that manipulating levels of microbial metabolite in the gut, 4-ethylphenyl sulfate (4EPS), has profound effects on social behavior—first in mice, then translating to an open-label clinical study in humans. Building on previous Nature6 findings linking heightened levels of 4EPS with anxious behaviors in mice, the results imply that modulation of the gut microbiome—through the introduction of the probiotic Bacteroides fragilis, previously shown7 to reduce levels of this metabolite—could reduce anxious behaviors, with implications for human anxiety or other mood conditions. 

“The work of Dr. Mazmanian and the Axial team has brought us to a critical inflection point in gut-brain research, unlocking insights that allow movement beyond correlation to causation. We now have human-centric data from Dr. Mazmanian’s research, which defines how the gut can influence behavior. At the same time, we reveal the potential to harness specific bacterial strains to repress the metabolites implicated in a range of neurological applications.” – Dr. Dirk Gevers, Chief Scientific Officer, Seed Health

We talk a lot about #GutMania at Seed, AKA the meteoric rise of buzzwords like gut health, probiotics, the microbiome, and yes, even the gut-brain axis, across conversation, headlines, and hashtags. This new frontier is certainly buzzworthy—but with this excitement comes an overload of information (and misinformation) that can feel confusing and overwhelming to navigate.

The gut-brain connection and the resulting commercialization is an area where, to date, evangelism has largely outpaced the evidence. The emergence of “psychobiotics,” for example, while often not evidence-based, is evidence of a growing willingness and hope for alternative treatments. At the same time, anxiety disorders impact over 40 million adults8 in the United States, and rates of anxiety and depression have spiked by more than 25% over the course of the ongoing pandemic9, and existing treatment options do not consider nor target the underlying role of the gut microbiome. 

Until recently, we’ve lacked clarity into how the gut microbiome regulates emotions and impacts complex behaviors. These advancements in gut-brain research—particularly those out of Dr. Mazmanian’s lab—reveal the potential for microbial innovations to maintain or even improve mental well-being. Now, our program will translate this breakthrough research for a new class of probiotics that could modulate the gut microbiome and target the gut-brain pathway for neuropsychiatric health. 

From the Seed-verse: Investigating the axis
We sat down with Dr. Sarkis Mazmanian to discus his work, what inspired him to pursue this field, and what we can do to support a healthy gut-brain connection.

 

The gut-brain axis is a very hot topic right now. What do you think is being mischaracterized about the field that you’d like to clear up?

Emerging fields of science often generate a lot of hype—and oftentimes, evangelism can tend to get ahead of evidence. This is not necessarily a new concept—it has happened with the Human Genome Project, gene therapies, novel cancer treatments, to name just a few. There’s often a desire for one new discovery to explain everything, to answer all of our questions. In reality, it is a lot more complex than that. 

This in mind, it’s valuable to reframe how we think about the gut-brain axis—it does not have to be the be-all, end-all of neuropsychiatric outcomes. While it is certainly a promising component to consider, we’ll still want to be conservative in our expectations of how (and when) this research may impact human health, and to what extent other factors (such as genetics, the environment or personal experiences, perceived or actual stress) also influence mental well-being.

 

What inspired you to explore the gut-brain connection?

It was quite serendipitous. My entry into gut-brain came after I’d already been working on the microbiome for more than a decade, and my decision to explore this area really came as the result of a singular event. 

I was speaking with my late colleague Paul Patterson, a neuroscientist at Caltech, and he mentioned that there was emerging literature showing that children with Autism had gastrointestinal issues. The research in this area was very anecdotal at the time, but it struck me as extremely interesting that a classic neurodevelopmental disorder would have any GI component. And I thought, could there be a possibility that those two events were biologically related? 

So this conversation led me to do some experiments in mice, which then generated some positive results and got me very motivated and encouraged me to move forward with this research. Now, my lab works almost exclusively in gut-brain research. 

 

What can we do to support a healthy gut-brain connection?

Diet and nutrition are one of the foremost ways we can support the gut microbiome, and in turn, the gut-brain pathway. Just as there is no one universally healthy microbiome, there is no one-size-fits-all, “perfect” diet. Generally, however, a plant-rich diet, low in sugar, preservative agents, processed foods, food additives and saturated fats, tends to correlate with a “healthy” microbiome. 

Sleep is also important for your microbiome, as microbes follow their own circadian rhythms and require rest to stay in balance. Evidence shows that sleep patterns can affect the microbiome and the gut-brain connection, so it’s valuable to prioritize rest. 

Additionally, regular exercise is significant for the gut-brain connection. Movement is helpful in stress management, and research has shown that moderate physical exercise positively modulates the relationship between the gut and brain.

 

What are some factors that can disrupt this connection? How do you know when this connection is disrupted? 

Both chronic and acute stressors can shift both composition of the gut microbiome and contribute to intestinal permeability. The heightened inflammation that frequently accompanies high levels of stress triggers blooms of pathogenic bacteria that promote dysbiosis and a leaky gut.10 Poor diet and nutrition can also negatively impact the gut microbiome, and in turn, the gut-brain connection. 

That said, it is actually very hard to know when the connection itself is disrupted in humans. There’s no doubt that there is a connection between the gut and the brain, but what exactly to measure for the “health” of this connection is still being understood. Most of the research to date has been done in mice and other laboratory animals, and we can only infer the same is happening in people. There are, for instance, a lot of molecular signals and immune cells trafficking between the two organs—to what degree do changes in any of these processes lead to a change in mood or behavior? That is still something we as a biomedical community are unraveling through research. 

 

What are some of the developments in the gut-brain space you’re most excited about in your own work? In other work you’re tracking? 

Out of my lab, I’m particularly excited about our research into the impact of the gut microbiome in anxiety-like behaviors and in Parkinson’s disease. The robustness of the effect of microbiome disruption in mice has been incredibly profound in both of those areas. Based on the data we have, I’m hopeful—especially for Parkinson’s—that these new discoveries in mice will be applicable to human health, as well. 

Outside of my lab, I’ve seen really tantalizing pieces of evidence showing that the microbiome of those with depression is disrupted in a very specific way. In general, I’m really optimistic about the potential of microbiome-based intervention, particularly in neuropsychiatric health where there’s no physical damage to the brain. 

 

What kind of potential do probiotics have for mental health? 

It really comes down to making sure not just that the product is high quality, but that we know what the effects are in a general population. The potential, in that case, lies in clinical research, and in having the physical data to demonstrate that probiotics are a viable intervention. Overall, I’m very bullish on the potential of improving day-to-day mental health issues through the gut microbiome. There’s a lot of anecdotal evidence on the impact of the microbiome on mental health, but the most significant opportunities will come through continued research.

  1. Foster, J. A., & McVey Neufeld, K. A. (2013). Gut-brain axis: how the microbiome influences anxiety and depression. Trends in neurosciences, 36(5), 305–312. https://doi.org/10.1016/j.tins.2013.01.005
  2. Keshavarzian, A., Green, S. J., Engen, P. A., Voigt, R. M., Naqib, A., Forsyth, C. B., Mutlu, E., & Shannon, K. M. (2015). Colonic bacterial composition in Parkinson’s disease. Movement disorders : official journal of the Movement Disorder Society, 30(10), 1351–1360. https://doi.org/10.1002/mds.26307
  3. Kowalski, K., & Mulak, A. (2019). Brain-Gut-Microbiota Axis in Alzheimer’s Disease. Journal of neurogastroenterology and motility, 25(1), 48–60. https://doi.org/10.5056/jnm18087
  4. Wu, W. L., Adame, M. D., Liou, C. W., Barlow, J. T., Lai, T. T., Sharon, G., Schretter, C. E., Needham, B. D., Wang, M. I., Tang, W., Ousey, J., Lin, Y. Y., Yao, T. H., Abdel-Haq, R., Beadle, K., Gradinaru, V., Ismagilov, R. F., & Mazmanian, S. K. (2021). Microbiota regulate social behaviour via stress response neurons in the brain. Nature, 595(7867), 409–414. https://doi.org/10.1038/s41586-021-03669-y
  5. Stewart Campbell, A., Needham, B. D., Meyer, C. R., Tan, J., Conrad, M., Preston, G. M., Bolognani, F., Rao, S. G., Heussler, H., Griffith, R., Guastella, A. J., Janes, A. C., Frederick, B., Donabedian, D. H., & Mazmanian, S. K. (2022). Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial. Nature medicine, 28(3), 528–534. https://doi.org/10.1038/s41591-022-01683-9
  6. Needham, B. D., Funabashi, M., Adame, M. D., Wang, Z., Boktor, J. C., Haney, J., Wu, W. L., Rabut, C., Ladinsky, M. S., Hwang, S. J., Guo, Y., Zhu, Q., Griffiths, J. A., Knight, R., Bjorkman, P. J., Shapiro, M. G., Geschwind, D. H., Holschneider, D. P., Fischbach, M. A., & Mazmanian, S. K. (2022). A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature, 602(7898), 647–653. https://doi.org/10.1038/s41586-022-04396-8
  7. Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T., Codelli, J. A., Chow, J., Reisman, S. E., Petrosino, J. F., Patterson, P. H., & Mazmanian, S. K. (2013). Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 155(7), 1451–1463. https://doi.org/10.1016/j.cell.2013.11.024
  8. COVID-19 pandemic triggers 25% increase in prevalence of anxiety and depression worldwide. (2022, March 2). World Health Organization (WHO). https://www.who.int/news/item/02-03-2022-covid-19-pandemic-triggers-25-increase-in-prevalence-of-anxiety-and-depression-worldwide
  9. Depression Facts & Statistics (2022). Anxiety & Depression Association of America. https://adaa.org/understanding-anxiety/depression/facts-statistics
  10. Zeng, M. Y., Inohara, N., & Nuñez, G. (2017). Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal immunology, 10(1), 18–26. https://doi.org/10.1038/mi.2016.75