The Enterarchon: An ancient visceral brain

The gastrointestinal (GI) tract is innervated by intrinsic neurites and extrinsic pathways linking it bidirectionally to the central nervous system. These circuits regulate digestion, metabolism, and homeostasis across metazoans. Comparative evidence from early-diverging animals to Drosophila and vertebrates suggests gut-embedded circuits arose on an epithelial/peptidergic scaffold and evolved in parallel across lineages, coordinating motility and secretion before centralised brains emerged. While vertebrates offer detailed molecular atlases of enteric nervous system (ENS) cell types, flies allow linking molecular identity with physiological function at cellular resolution. We highlight how the intestine-ENS axis integrates endocrine and immune signals and undergoes remodelling along three axes: sex as a constitutive dimorphism, reproduction as a reversible plasticity, and ageing as a biphasic trajectory. This comparative view challenges brain-centric models of systemic regulation. We propose instead that the intestine, through its neuronal, epithelial, and immune components, acts as an Enterarchon : an ancient visceral brain shaping organismal homeostasis. • The ENS is an ancient, semi-autonomous regulator of gut physiology. • Sex shapes ingestion and gut plasticity via enteric circuits and hormones. • Across animals, gut-embedded circuits scaffold pre-brain centralisation. • In Drosophila , enteric neurons link internal state to gut function. • Ageing trajectories are sex-biased; internal barrier permeability predicts mortality.