Microbiome-gut-brain axis-on-chip
The gut-brain axis (GBA) is a bi-directional communication system that connects the central nervous system and the gastrointestinal tract. This interaction can involve immune, endocrine or metabolic pathways, or the Vagus nerve as the most direct route. The functioning of the GBA is also significantly affected by the bacteria in the intestine, which form the gut microbiome. Dysregulation of the gut-brain axis is implicated in a large number of neurodegenerative diseases and conditions (NDs). For an improved fundamental understanding of the microbiome-gut-brain axis and its functioning in health and disease, we are recreating the GBA using pluripotent stem cells (PSCs). Using PSCs we recreated hippocampal brain organoids, Vagus nerve-like neurons and human intestinal organoids. These organoids will be integrated in a custom microfluidic chip. To model the microbiome, we will introduce intestine-specific bacterial strains to the multi-organ culture on chip.
Microbiome-Gut-Brain Axis on a Chip
The brain is connected to the gastrointestinal tract through bidirectional signaling pathways which are largely regulated by the composition of the microbiota. The goal of this study is to translate the gut-brain axis (GBA) to a microfluidic chip and thus study the complex relationship between the gut microbiome and brain health. We use human pluripotent stem-cell technology combined with relevant on-chip readouts to model the impact of microbiota variation on neuronal functioning in health and disease.
Focused ultrasound treatment on hiPSC derived blood brain barrier model
280.000 patients have Alzheimer’s disease in the Netherlands, however, there is currently no treatment available. Two problems for developing a cure are that therapeutics cannot pass the blood-brain barrier and that current research mainly uses animal models that have different pathophysiological processes. We want to tackle these problems by developing a method for astrocyte differentiation in suspension and applying these cells to a blood-brain barrier model. Using this model, we test and validate focused ultrasound treatment, a technique to temporarily increase barrier permeability using resonating microbubbles. This barrier function is measured by integrating a TEER measuring device.
Funding
EFRO – REACT EU
Implementing an immune system in brain organoids
The exact mechanisms of communication between gut and brain are not yet fully understood, but it is believed that the immune pathway plays an important role. Stem cell-derived astrocytes and microglia will be incorporated into brain organoids. This model aims to gain insights in the role of immune-mediated crosstalk between the intestine and the brain. Electrophysiological approaches are applied to determine functioning of the brain.
Funding
NWO Talent Programme Vici – Applied and Engineering Sciences (AES) 2022
Investigating gut-microbiome communication on a chip
To improve our understanding of the complex interactions across the microbiome-gut-brain axis it is necessary to have better models. Focusing on the intestinal compartment, the use of hiPSCs-derived intestinal organoids generated in the lab, allow us to mimic the intestinal epithelium within a microfluidic chip.
Study of the impact of the microbiota on the gut, will be achieved with co-culture procedures of bacteria from the human microbiota
Funding
NWO Talent Programme Vici – Applied and Engineering Sciences (AES) 2022
Unravelling the gut-brain cross-talk
Neurotransmitters like acetylcholine may play an important role in the regulation of both the brain and intestines’ physiology and inflammation. As such, the goal of the brain-gut axis on a chip is to recapitulate parts of this cross-talk with the focus on the acetylcholinergic pathway.
Furthermore, novel sensors and electrodes can be incorporated into the chip model to monitor the changes in neurotransmitters and electrical activity, as a correlation to the gut-brain axis physiological function.
Lastly, organ-specific resident immune cells will be incorporated into the models with the goal to better recapitulate the in-vivo scenario of gut-brain axis with a present innate immune system.
Synaptic Connectivity Tracing in Gut-Brain Axis
Communication between the gut and the brain, known as the gut-brain axis, is primarily mediated by the vagus nerve. To explore the elusive communication pathways and the pathologies related to disruptions in this system, we have recently developed a gut-brain model using a microfluidic device and utilized stem cell-derived organoids and tissues cultured on a custom-made microfluidic device for this study. Electrophysiological signaling is a key method for transmitting signals between the gut and the brain. Although biomarker analysis has confirmed that the organoids exhibit organ-specific characteristics, functional connectivity has yet to be demonstrated. To demonstrate functional synaptic connectivity between the stem cell-derived gut and brain axis on a microfluidic chip, neurotropic virus based synaptic tracing strategy that will allow for the identification of such connectivity between the tissues on the chip will be utilized.
Funding
NWO Talent Programme Vici – Applied and Engineering Sciences (AES) 2022