We sat down for a conversation with Nikole Kimes, Ph.D., Co-Founder and CEO of Siolta. The company’s name, which is pronounced sheel-ta, is a Gaelic word for “seeds” and speaks to the company’s microbial therapeutics that are created to reseed the depleted gut microbiome with naturally occurring bacteria, which are essential for a healthy immune system.

Nikole.jpgDr. Kimes’ interest in science resulted from two passions: human health and environmental ecosystems. Her intrinsic understanding that these two concepts are inevitably linked fueled her interest in science and eventually converged at an understanding of how the world around us impacts our biological ecosystem.

1.      Tell us about your background and how Siolta came to be.

As a student I studied holistic health and microbial ecology at different points in my training, and both underscored the complex interactions of dynamic biological systems. Through my interest in health, I learned the ecological concepts of systems biology and applied the latest microbial genomic tools to different ecosystems, such as coral reefs and the Gulf of Mexico following the Deepwater Horizon oil spill. Subsequently, I transferred these skills and concepts to the realm of the human microbiome when I joined the laboratory of Dr. Susan Lynch, Professor of Medicine at the University of California San Francisco (UCSF), Director of the Benioff Center for Microbiome Medicine, and Co-founder of Siolta Therapeutics. Dr. Lynch’s focus on the human microbiome in human health from an ecological perspective was a perfect fit for my particular interests, background, and skill set. It is there that we worked on rationally designing microbial medicines for the prevention of disease based on years of work performed by Dr. Lynch and her collaborators.      

The decision to translate our academic findings into a clinical application resulted at yet another convergence point, one in which the science, interest in the field, and a compelling sense of necessity all aligned. It was at this point that Dr. Lynch and I co-founded Siolta in partnership with Samir Kaul, Founding Partner and Managing Director at Khosla Ventures, in order to translate this ground-breaking research into innovative clinical applications.  

2.      Why has Siolta chosen to focus on pediatric/early life microbial networks?

The answer is simple, our approach is science-driven. We are focusing on early life because this is where the science is telling us we could have the most transformative impact. There is now substantial evidence that the developing microbiome is instrumental in establishing and maintaining healthy immune responses. Moreover, disruption to this process is thought to underlie a myriad of chronic diseases, including allergic, metabolic, and neurodevelopmental diseases; all of which are increasing in incidence at alarming rates in our children. This unique early-life window has the potential to be instrumental in approaching disease from an innovative prevention standpoint. We are developing a method where the underlying causes of chronic disease are addressed through early intervention, rather than treating downstream symptoms later in disease development. This has a lot of positive outcomes – lower costs, fewer side-effects and the potential to eliminate the long-term treatment modalities used for asthma and allergy sufferers today.

3.      How does understanding of the microbiome support your work around therapeutic interventions?

What we have learned over the last decade is that the human microbiome, like any other ecosystem, begins as a relatively naïve system. Early “founder” microorganisms play an important role in shaping the local environment in a way that subsequently impacts the additional accumulation of diversity. This is important not only from a perspective of what microbes are present, but more importantly for what functionality the community represents. Notably, the science suggests that different founding communities impact the trajectory of immune development in different ways, and likely microbial metabolism is one of the mechanisms by which they do this. Thus, our growing understanding of the human microbiome and its interconnectedness to our health has both identified potential mechanisms of action and novel strategies for addressing disease.

4.      What role does metabolomics play in understanding the complex associations between microbial activity in the gut and human health?

Metabolomics provides another layer of analyses that allows us to more directly address the functional contribution of the microbiome to human physiology. It adds to the tool box that we have available to better characterize both general phenomena, through untargeted metabolomics, and more specific mechanisms of action, through targeted metabolite analysis. Both of which are important drivers of research and development in this emerging field.

5.      How has Metabolon’s untargeted approach to metabolomics provided benefit in uncovering what the microbiome is doing to impact human health?

You can refer to the published work from Dr. Lynch’s lab to see how untargeted metabolomics has helped characterize early-life signatures of infants at risk for developing allergy and asthma. Their work establishes that different microbial profiles are associated with different metabolic signatures, immunological impacts, and disease outcomes1,2. Furthermore, they use this approach to identify specific metabolites associated with high risk infants for allergy and asthma, as well as the associated microbial genes capable of producing such metabolites, that are capable of impeding immune tolerance3. Thus, Dr. Lynch’s work established a potential mechanistic link between early life microbiome perturbations and disease development later in life, while also identifying a potential biomarker for high risk infants.

6.      How will Metabolon’s untargeted approach to metabolomics provide benefit in uncovering what the microbiome is doing among the subjects in your studies?

At Siolta, we are also utilizing both untargeted and targeted metabolomic approaches to help characterize the overall metabolic signatures associated with treatment and response and potentially provide insight into patient stratification for more precise therapeutic approaches moving forward. We start with untargeted metabolomics, casting a wide net to characterize general metabolic shifts across different pathways and to identify the biomarkers that we may not know are there yet. Once the analysis is complete and we have pinpointed the biomarkers we want to focus on, we work to develop a targeted assay. In this way, Metabolon has the capacity to support our work through the complete research continuum.

7.      How does metabolomics help make genomics smarter?

The genomic revolution that has occurred over the past few decades is fundamental to our current understanding of complex microbial communities, including the human microbiome. The resulting advancements in technology have led to increased awareness of the role microbial communities play in environmental and human health, including the vast functional potential harbored by these complex systems. Metabolomics, generally speaking, allows us to investigate a step further, moving from what potential is present to what functions are being fulfilled. This is a critical step in pushing the boundaries of our knowledge beyond who and what is present and moving towards functional characterization and finer resolution of metabolic networks.

 

View for our webinar – to hear more from Dr. Kimes and other researchers who are successfully applying metabolomics to their microbiome research.

References:

1. Fujimura KE, Sitarik AR, Havstad S, Lin DL, Levan S, Fadrosh D, et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nature Medicine. 2016Dec;22(10):1187–91.

2. Durack J, Kimes NE, Lin DL, Rauch M, Mckean M, Mccauley K, et al. Delayed gut microbiota development in high-risk for asthma infants is temporarily modifiable by Lactobacillus supplementation. Nature Communications. 2018;9(1).

3. Levan SR, Stamnes KA, Lin DL, Panzer AR, Fukui Eundefined, McCauley K, et al. Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance. Nature Microbiology. 2019Jul22;4:1851–61.