A gut-brain axis mediates sodium homeostasis via the gastrointestinal peptide regulation on brain stem neural circuits

Abstract

Water and salt homeostasis is one of the three fundamental homeostasis for mammals to maintain body metabolism. Sophisticated neural and endocrine pathways are closely involved in regulating water and sodium balance. Water and sodium intake is the primary source of water and salt homeostasis. Previous studies indicated that angiotensin II (ANGII) and aldosterone play vital roles in mediating water and sodium solution drinking behavior via neuron signaling pathways from the subfornical organ (SFO) or the nucleus of the solitary tracts (NTS). Both ANGII and aldosterone are secret in the brain after detecting osmolality changes. However, only a few studies focus on whether peripheral organs modulate water and sodium intake.

In the human body, the gastrointestinal tracts (GI tracts) take responsibility for water and sodium absorption. The expression of sodium channels increases in intestinal tracts to respond to water and sodium deficiency. Previous studies from our lab showed that the gastrointestinal peptide Secretin (SCT) and its receptor play an essential role in modulating ANG1alpha function in SFO to induce water intake and trigger vasopressin (VP) release in the hypothalamus to compensate for water loss. We further found the reduction of sodium desire during sodium deficiency conditions in both SCT and SCTR functional knock-down mice models. In contrast, the mechanism of SCT to sodium desire remains unknown. Thus, we hypothesis whether SCT released from GI tracts can modulate water and sodium desire.

This study reports that colon mesenchymal cells can release SCT to face sodium deficiency. The releasing SCT enters the blood and penetrates the blood-brain barrier (BBB) to the ventricles. Furthermore, we confirmed that the highest expression level of SCTR in the brain is the nucleus of the solitary tracts (NTS), a critical nucleus that can induce sodium intake behavior. NTS SCTR+ neurons were activated under SCT concentration increased conditions. To test whether SCTR+ neurons can drive sodium appetite. We generated SCTR-Cre mice to manually activate SCTR+ cells, which triggered sodium intake in sodium satisfied conditions while inhibiting them under sodium depletion reduces sodium drinking behavior. Finally, we found a new signal pathway from NTS SCTR+ neurons to the paraventricular nucleus of the hypothalamus (PVH) that takes responsibility for SCT-derived sodium metabolism.