Effect of gut microbiota-derived metabolites and extracellular vesicles on neurodegenerative disease in a gut-brain axis chip

TLDR

The microbiome‑gut‑brain axis is a dynamic bidirectional communication system linking gut microbes to the CNS, influencing brain health and neurodegenerative diseases, yet its precise mechanisms remain unclear. This study aimed to develop a controllable in‑vitro gut‑brain axis chip to causally assess the effects of microbe‑derived metabolites and extracellular vesicles on neurodevelopment and neurodegeneration using human iPSC‑derived neurons. Metabolites and exosomes from gut microbes can cross the intestinal epithelium or blood–brain barrier into circulation, and the chip co‑cultures these substances with iPSC‑derived neurons to evaluate their impact. Strain‑specific microbial metabolites and exosomes significantly promoted neural growth, maturation, and synaptic plasticity, indicating their promise as therapeutic strategies for neurodevelopmental and neurodegenerative disorders.

Abstract

Abstract A new perspective suggests that a dynamic bidirectional communication system, often referred to as the microbiome-gut-brain axis, exists among the gut, its microbiome, and the central nervous system (CNS). This system may influence brain health and various brain-related diseases, especially in the realms of neurodevelopmental and neurodegenerative conditions. However, the exact mechanism is not yet understood. Metabolites or extracellular vesicles derived from microbes in the gut have the capacity to traverse the intestinal epithelial barrier or blood–brain barrier, gaining access to the systemic circulation. This phenomenon can initiate the physiological responses that directly or indirectly impact the CNS and its function. However, reliable and controllable tools are required to demonstrate the causal effects of gut microbial-derived substances on neurogenesis and neurodegenerative diseases. The integration of microfluidics enhances scientific research by providing advanced in vitro engineering models. In this study, we investigated the impact of microbe-derived metabolites and exosomes on neurodevelopment and neurodegenerative disorders using human induced pluripotent stem cells (iPSCs)-derived neurons in a gut-brain axis chip. While strain-specific, our findings indicate that both microbial-derived metabolites and exosomes exert the significant effects on neural growth, maturation, and synaptic plasticity. Therefore, our results suggest that metabolites and exosomes derived from microbes hold promise as potential candidates and strategies for addressing neurodevelopmental and neurodegenerative disorders.