Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells

Abstract

The intestinal microbiota closely interacts with the neuroendocrine system and exerts profound effects on host physiology. Many of the molecular mechanisms underlying these interactions await discovery. Here we report that Nod1 ligand derived from intestinal bacteria directly modulates catecholamine storage and secretion in mouse adrenal chromaffin cells. The cytosolic peptidoglycan receptor Nod1 is involved in chromogranin A (CHGA) retention in dense core granules (DCGs) in chromaffin cells in a cell-autonomous manner. Mechanistically, upon recognizing its cognate ligands, Nod1 localizes to DCGs, and recruits Rab2a, which is critical for CHGA retention in DCGs. Loss of Nod1 ligands leads to a profound defect in epinephrine storage in chromaffin cells, and subsequently, less secretion upon stimulation. The intestine-adrenal medulla crosstalk bridged by Nod1 ligands modulates adrenal medullary responses during the immobilization-induced stress response in mice. Thus, our study uncovers a mechanism by which intestinal microbes directly modulate a major pathway in response to stress, which may provide further understanding of the gut-brain axis.