Stomach at the crossroads: nuclear receptor signaling at the interface between what we are and what we eat

The stomach is home to numerous nuclear receptor transcription factors (NRs) that can respond to food, toxins, and other ingested agents. Conversely, signals secreted from other organs (e.g., hormones) can engage gastric NRs to modulate gastric physiology. Thus, there is a rich potential interface between external and internal signals that gastric NRs might respond to and interpret. Here, we seek to comprehensively review the role of NRs in gastric homeostasis and disease pathogenesis. NRs are evolutionarily conserved proteins that regulate gene transcription by interpreting hormonal and environmental signals. We explore NR roles in normal stomach development, cell fate determination, and responses to dietary compounds and xenobiotics. The last topic is of particular recent importance 1) because NRs stimulated by ingested agents might directly regulate gastric physiology like the relative activity of acid-secreting and stem cells and 2) because the stomach is one of the first organs to encounter dietary compounds and pollutants. Additionally, we review the emerging yet understudied field of gastro-endocrinology, exploring how systemic endocrine circuits influence the stomach's function. We also discuss how NRs contribute to pathological conditions like precancerous lesions and cancer. Additionally, we summarize known agonists, antagonists, and coregulatory proteins, highlighting potential therapeutic targets. Understanding NR roles could pave the way for a better understanding of dietary and environmental toxin exposure and also lead to innovative treatments for gastric disorders, including gastritis, gastric intestinal metaplasia, and gastric cancer.