Enteroendocrine cell types that drive food reward and aversion

Abstract

Animals must learn through experience which foods are nutritious and should be consumed, and which are toxic and should be avoided. Enteroendocrine cells (EECs) are the principal chemosensors in the GI tract, but investigation of their role in behavior has been limited by the difficulty of selectively targeting these cells in vivo. Here we describe an intersectional genetic approach for manipulating EEC subtypes in behaving mice. We show that multiple EEC subtypes inhibit food intake but have different effects on learning. Conditioned flavor preference is driven by release of cholecystokinin whereas conditioned taste aversion is mediated by serotonin and substance P. These positive and negative valence signals are transmitted by vagal and spinal afferents, respectively. These findings establish a cellular basis for how chemosensing in the gut drives learning about food.

Gut–brain circuits for fat preference

“…Interestingly, examination of single-cell RNA atlases from both rodent and human gut tissue suggests this is likely the case 33,49 . Future studies should help define this…”

“…Given that CCK functions as the signalling molecule in the gut for the sugar and nutrient-sensing pathway, we anticipate that there is a unique subset of intestinal CCK-positive EECs that co-express the sugar (SGLT1) and fat (GPR40 and GPR120) preference receptors (the nature of the amino acid receptor is not yet known). Notably, examination of single-cell RNA atlases from both rodent and human gut tissue suggests that this is probably the case 33 , 49 . Future studies should help to define this subtype of CCK-expressing EEC that uses CCK as a transmitter (rather than as a gut neuromodulator or hormone) to activate the gut–brain axis and report the presence of intestinal sugar, fat and amino acid nutrients.…”

“…the sugar/nutrient sensors) also responded to CCK, the vast majority of vagal neurons that respond to CCK do not respond to nutrient stimuli (bottom heat maps, n = 136 neurons). This is expected since only a small fraction would be mediating sugar/nutrient preference, versus other roles of CCK signaling [31][32][33]…”

“…Thus, we explored how CCK can function both as a satiety hormone and as a nutrient preference signal in the gut. We reasoned that this conundrum could be easily resolved if a genetically distinct 33 subset of CCKAR-expressing vagal neurons mediates nutrient preference.…”

Nutrient-Based Appetite Regulation

“…65 As such, fast signal conductivity is critical within the GBA, which is why enteroendocrine cells in the gut are now known as neuropod cells. 66,67 Therefore, the GBA not only relies on adequate gut hormonal release to regulate appetite, but also in the sensing of nutrients and subsequent signaling to the VN afferent fibers.…”