Recently, Kerensa Broersen, head of the advanced analytics team at NIZO and associate professor at the University of Twente, has been awarded an NWO (Dutch Research Council) Vici grant. This personal grant, worth 1.5 M€, leverages Broersen’s research activities at the University of Twente to investigate interactions between the intestinal tract and the brain at a molecular level.
Naturally, this field of research has promising parallels and avenues in line with many of the current NIZO research activities: think of in vitro digestion assays, health benefits of various compounds including plant proteins and polyphenols and amino acid availability. While NIZO projects currently focus primarily on the intestinal system using 2-dimensional cell layers, Broersen’s Vici project enables exploration of nutritional effects of food products beyond the gut, toward brain and heart in a 3-dimensional manner. The NIZO approach to simulation of the microbiome is currently primarily addressed by 96-well culture of fecal-isolated strains which is a powerful, yet limited approach to investigate the formation of metabolites upon exposure to specific food products.
Many health claims are currently based on epidemiological observations and animal studies. While these approaches traditionally led to highly valuable and insightful information on the impact of nutrition on health, limitations in animal studies and ethical considerations hamper direct translation of findings to human subjects. On the other hand, human studies are limited in resolution, as they fail to provide unequivocal insight into molecular mechanisms of certain health effects. Two-dimensional cell layers of intestinal origin provide a simplified approach to study the impact of nutrition on gut health at a more mechanistic level but lack the complex 3-dimensional interaction between different cell types within organs.
Broersen’s Vici project will make use of pluripotent stem cells which have the ability to differentiate into many different cell types by exposure to various growth factors inspired by insights obtained from human embryology. In this way, differentiation of stem cells can be directed towards an intestinal, vagus nerve, brain or cardiac phenotype. Differentiated cells will then assemble into small cellular clusters termed organoids, or mini-organs that show physiologically relevant features such as electrophysiological activity, selective permeability, secretion of factors and expression of specific receptors. While many organ systems have in the past been re-created using stem cell technology, the Vici project broadly extends on this topic by investigating inter-organ communication pathways. For example, we already know that the state of the gut and nutritional intake are largely connected to brain and cardiac health. We also are largely aware that many processes, pathologic or physiological, are driven by such complex communication with no organ in our body known to operate in isolation. In this way, epidemiological and clinical studies have strongly suggested that disorders such as Parkinson’s disease, Alzheimer’s disease, schizophrenia, depression and autism spectrum disorders, traditionally though to originate from the brain, go hand-in-hand with gastro-intestinal problems.
In the human body, the gastro-intestinal tract is the first anatomical stage of interaction between the human body and ingested food. From there, signals mediated by food intake are relayed towards peripheral sites in the human body, including heart and brain, substantially affecting their functioning. One of the routes employed to direct such signals involves the vagus nerve, a major nervous tract connecting the gastro-intestinal tract with the brain, among other organs and tissues. The interplay between food intake and composition of the gut microbiota, also termed microbiome, is thought to affect the nature of these molecular signals. In this project therefore the stem cell-derived mini-gut will be co-cultured with a range of strains representing the microbiome. Anatomically, the brain, gut and heart are separated from each other by some defined distance such that they are unable to communicate directly by physical interaction. Culturing the various organoids within one single culture reservoir would therefore not do justice to their physiological and anatomical organization. The Vici project addresses this issue by culturing these different organ systems onto a microfluidically controlled chip the system with spatially separated reservoirs connected by a long channel housing the stem cell-derived vagus nerve closely mimicking the anatomical organization of these organ systems.
Most of this 5-year Vici project will address the development of this system, such that a validated, fully functional and genetically tractable model is generated. For example, secretion of a mucus layer will need to be optimized, which is a critical feature to house a viable microbiome. The susceptibility of stem cells to genetic engineering provides targeted insight into molecular features of relevance to gut/brain/heart communication. Moreover, stem cells may be extracted from skin or urine provided by different donors enabling investigation of the impact of genetic background to personalized response to nutritional composition or specific food components.
Overall, the outcomes of this Vici project are envisaged to greatly extend upon NIZO’s current microbiome and intestinal models to study health aspects, provide molecular insights into this process, and investigate the impact of food composition on tissues peripheral from the gastro-intestinal tract.