Short-chain fatty acids mitigate inflammation and associated metabolic programming of human stem cell-derived enteric glial cells

The enteric nervous system (ENS) plays a pivotal role not only in gastrointestinal function but also in neurodegenerative diseases through bidirectional communication with the central nervous system along the gut-brain axis. Enteric glial cells are central to ENS function, acting as key regulators of neuroimmune interactions. Enteric glial cell metabolism likely plays an important role in these functions. However, how pro- or anti-inflammatory stimuli influence enteric glial cell metabolism remains largely unexplored. Here, we established a human embryonic stem cell (hESC)-derived ENS model, incorporating both enteric neurons and glial cells, to investigate pro-inflammatory cytokine-induced metabolic adaptations in enteric glial cells. Cytokine exposure triggered a pro-inflammatory response associated with a metabolic shift towards glycolysis, TCA cycle and glutathione metabolism. Short-chain fatty acids (SCFAs) exhibited strong anti-inflammatory properties and reversed the observed metabolic shift. Tracer-based metabolomics further revealed that both pro-inflammatory cytokine and SCFA treatment alter glucose metabolism in hESC-derived enteric glial cells, driving them into distinct flux phenotypes. By integrating immune and metabolic perspectives, our findings identify condition-dependent glucose metabolism programs and reveal pathways that may be exploited to modulate glial activity, providing new insights into enteric glial cell biology, under homeostatic, pro-inflammatory and SCFA-rescued conditions. Overall, our findings enhance our understanding of ENS pathophysiology and lay the groundwork for identifying novel therapeutic strategies aimed at mitigating ENS inflammation in gastrointestinal and neurodegenerative disease.