Neural Activation of Human Primary Intestinal Enteroendocrine L-cells
- 1Wyss Institute
Abstract
Intestinal enteroendocrine L-cells play a central role in metabolic homeostasis by secreting the gut hormones GLP-1 and PYY, but whether and how neural signals regulate human L-cell function remains poorly understood. This gap reflects the limited availability of human model systems enriched for mature L-cells. Here, we establish a differentiation strategy that generates human donor-derived ileal organoids with markedly increased L-cell abundance, enabling functional interrogation of L-cell physiology in their basal state. Using this system, we show that cholinergic and adrenergic stimuli activate L-cells, triggering calcium influx and secretion of GLP-1 and PYY. Pharmacological analysis reveals that cholinergic regulation of human L-cells is mediated predominantly through M3 muscarinic receptors, while adrenergic regulation is mediated through the {beta}1 adrenergic receptor. Neurotransmitter-evoked activation also initiates gap junction-dependent calcium waves that propagate across the intestinal epithelium; however, disruption of epithelial coupling by abolishing calcium propagation does not impair hormone secretion. Together, these findings identify L-cells as integrative hubs that couple neural signals to gut hormone secretion and epithelial calcium waves, providing mechanistic insight into the gut-brain axis and how the nervous system regulates intestinal endocrine function in human intestine.
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BibTeX
@misc{lindsay2026neural,
title = {{Neural Activation of Human Primary Intestinal Enteroendocrine L-cells}},
author = {J. Lindsay and D. Zeve and S. Rudolph and A. Shepherd and A. Grossberg and D. Breault and M. Levin and D. Ingber},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.763680},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763680v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Neural Activation of Human Primary Intestinal Enteroendocrine L-cells
AU - J. Lindsay
AU - D. Zeve
AU - S. Rudolph
AU - A. Shepherd
AU - A. Grossberg
AU - D. Breault
AU - M. Levin
AU - D. Ingber
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.763680
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.763680v1
AB - Intestinal enteroendocrine L-cells play a central role in metabolic homeostasis by secreting the gut hormones GLP-1 and PYY, but whether and how neural signals regulate human L-cell function remains poorly understood. This gap reflects the limited availability of human model systems enriched for mature L-cells. Here, we establish a differentiation strategy that generates human donor-derived ileal organoids with markedly increased L-cell abundance, enabling functional interrogation of L-cell physiology in their basal state. Using this system, we show that cholinergic and adrenergic stimuli activate L-cells, triggering calcium influx and secretion of GLP-1 and PYY. Pharmacological analysis reveals that cholinergic regulation of human L-cells is mediated predominantly through M3 muscarinic receptors, while adrenergic regulation is mediated through the {beta}1 adrenergic receptor. Neurotransmitter-evoked activation also initiates gap junction-dependent calcium waves that propagate across the intestinal epithelium; however, disruption of epithelial coupling by abolishing calcium propagation does not impair hormone secretion. Together, these findings identify L-cells as integrative hubs that couple neural signals to gut hormone secretion and epithelial calcium waves, providing mechanistic insight into the gut-brain axis and how the nervous system regulates intestinal endocrine function in human intestine.
ER -