Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells

The intestinal microbiota closely interacts with the neuroendocrine system and exerts profound effects on host physiology. Here, we report that nucleotide-binding oligomerization domain 1 (Nod1) ligand derived from intestinal bacteria 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. Mechanistically, upon recognizing its ligand, Nod1 localizes to DCGs, and recruits Rab2a, which is critical for Chga and epinephrine retention in DCGs. Depletion of Nod1 ligand or deficiency of Nod1 leads to a profound defect in epinephrine storage in chromaffin cells and subsequently less secretion upon stimulation. The intestine-adrenal medulla cross talk bridged by Nod1 ligand modulates adrenal medullary responses during the immobilization-induced stress response in mice. Thus, our study uncovers a mechanism by which intestinal microbes modulate epinephrine secretion in response to stress, which may provide further understanding of the gut-brain axis.