Getting closer to modeling the gut-brain axis using induced pluripotent stem cells

Abstract

The gut microbiome (GM), the gut barrier, and the blood-brain barrier (BBB) are key elements of the gut-brain axis (GBA). The advances in organ-on-a-chip and induced pluripotent stem cell (iPSCs) technology might enable more physiological gut-brain-axis-on-a-chip models. The ability to mimic complex physiological functions of the GBA is needed in basic mechanistic research as well as disease research of psychiatric, neurodevelopmental, functional, and neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. These brain disorders have been associated with GM dysbiosis, which may affect the brain via the GBA. Although animal models have paved the way for the breakthroughs and progression in the understanding of the GBA, the fundamental questions of exactly when, how, and why still remain unanswered. The research of the complex GBA have relied on equally complex animal models, but today’s ethical knowledge and responsibilities demand interdisciplinary development of non-animal models to study such systems. In this review we briefly describe the gut barrier and BBB, provide an overview of current cell models, and discuss the use of iPSCs in these GBA elements. We highlight the perspectives of producing GBA chips using iPSCs and the challenges that remain in the field.

Stress and the gut-brain axis: an inflammatory perspective

“…The lumen of gastrointestinal tract is separated from the blood circuitry by an intestinal barrier (IB) and the transport into blood vessels is controlled by the gut-vascular barrier (GVB) (Di Tommaso et al, 2023 ). The CNS is covered by two barriers interconnecting the blood and the brain, the BBB, and the blood-cerebrospinal fluid barrier, which involves choroid plexus epithelium (Kim et al, 2021 ; Hall and Bendtsen, 2023 ). Starting from the gut lumen surface, the IB is composed of the mucus-producing goblet cells, positioned between the epithelial cells (Suzuki, 2020 ).…”

Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models

“…More recently, the impact of the gut microbiome on the CNS and BBB has been extensively investigated and reviewed [ 239 , 240 , 241 , 242 ]. In line with the “endotoxin hypothesis,” developing multi-organs-on-a-chip platforms could assist in filling in the knowledge gap concerning how the microbiome may contribute to neurodegeneration [ 243 , 244 , 245 ].…”

Leveraging iPSC technology to assess neuro-immune interactions in neurological and psychiatric disorders

“…The upcoming years will likely also see innovative solutions to model other environmental risk factors with iPSC such as the exposure to heavy metals or pollution (Figure 2). Models to investigate the gut-brain-immune axis in psychiatric disorders will also be of interest (183,184).…”