Nutrient Sensing and Lipid Handling by Enteroendocrine Cells in Adult Mice

Enteroendocrine cells are specialized secretory cells found in the lining of the intestinal tract and represent the largest endocrine system in the human body. Enteroendocrine cells play a critical role in nutrient sensing and are responsible for releasing hormones, such as glucagon-like peptide-1, which regulates digestion, absorption, and energy metabolism. Mice born without enteroendocrine cells die shortly after birth^1,2 and, similarly, human newborns with NEUROG3 mutations present with severe malabsorptive diarrhea requiring parenteral nutrition.³ Because of these challenges, enteroendocrine cell–mediated intestinal metabolism is not well characterized in adult humans or mice. Despite the importance of diet and microbiome in regulating intestinal metabolism,^4,5 few studies have provided direct evidence into how enteroendocrine cells relay nutritional information from the environment to neighboring cells, such as intestinal stem cells and Paneth cells. In this issue of Cellular and Molecular Gastroenterology and Hepatology, 2 independent groups^6,7 reported on the role of enteroendocrine cells in modulating intestinal metabolism in adult mice. Both studies built their observations with the use of tamoxifen-inducible VillinCreERT2 mouse model to delete Neurog3, a master regulator of secretory cell lineage,^8,9 in adult mice, resulting in enteroendocrine cells depletion. Consistently, ablation of enteroendocrine cells had no immediate effects on the viability of the affected animals; however, both groups found significant changes in intestinal energy and lipid metabolism.

On close examination of enteroendocrine cells deficient mice, McCauley et al⁶ found a significant reduction of ATP and ADP in intestinal crypts compared with those of control mice in the fasted state. Because mitochondrial activity is spatially correlated with the crypt-villus axis, with villus cells having higher levels,¹⁰ the authors used Seahorse bioanalyzer to assay mitochondrial activities and found increased levels of energy expenditure and fatty acid oxidation in the crypts of enteroendocrine cell–deficient mice relative to control crypts. Consistent with these metabolic changes, single-cell RNA sequencing analysis of enteroendocrine cell–deficient human intestinal organoids displayed increases in lipid metabolizing genes in stem cells, progenitor cells, and Paneth cells. Lastly, crypts of enteroendocrine cell–deficient mice displayed reduced nutrient sensing as suggested by the decreased phospho-S6 levels, a readout of the mTOR complex 1 (mTORC1) signaling activity. Taken together, these results suggest that in the absence of enteroendocrine cells, relay of nutritional information is abolished, inducing a metabolically reprogrammed state similar to fasted condition.

Blot et al⁷ showed that deletion of enteroendocrine cells in adult mice did not impact their viability under standard chow diet; however, feeding these enteroendocrine cell–deficient mice with a high-fat diet induced lethality within 5 weeks of tamoxifen administration. In addition to increased expression of lipid metabolism genes in the intestinal tissue of enteroendocrine cell–deficient mice, lipid malabsorption was identified by decreased lipid profiles in blood samples, whereas those of fecal samples were increased. In line with this observation, differential gene expression analysis of sorted enteroendocrine cells from mice on standard and high-fat diets revealed increased activation of lipid metabolism genes in high-fat diet conditions, and interestingly identified elevated levels of transcripts for hormones, such as NTS, CCK, and SCT, which have been associated with lipid absorption. Prompted by an observed increase of antimicrobial peptide gene expression in enteroendocrine cell–deficient mice, the authors examined fecal microbial composition 15 and 30 days after induction of enteroendocrine cell ablation. They found that enteroendocrine cells–deficient mice exhibited a microbiome with reduced α-diversity and increased representation of genes in pathways for infection and carbohydrate metabolism. Thus, ablation enteroendocrine cells led to defects in lipid absorption and changes in the microbiome composition.

These complimentary studies offer much needed insight on how enteroendocrine cells regulate intestinal energy metabolism in adult organisms by describing the effects of these critical cells on shaping the microbiome⁶ and dissecting the metabolic and noncell autonomous impact on intestinal stem cell functions.⁷ Although McCauley et al⁶ concluded that enteroendocrine cell–deficiency increased stem cell activity from their transplanted human intestinal organoids, Blot et al⁷ observed no changes in Lgr5 levels and decreases in Olfm4 expression by reverse-transcriptase qualitative polymerase chain reaction of intestinal tissue. Differences in these observations may implicate a microbiome-related effect. Further work may be needed to delineate the specific dietary cues and enteroendocrine cell–specific receptors controlling intestinal nutrient sensing and lipid handling processes. The transcriptomic analysis of Blot et al⁷ offered some potential target hormones that may relay nutritional information by enteroendocrine cells. In line with this, it would be interesting to test if an interplay exists between hormone and mTORC1 signaling in intestinal stem cells as observed by McCauley et al.⁶ Elucidating the mechanisms of nutrient sensing mediated by enteroendocrine cells will certainly benefit the development of therapeutics for intestinal metabolic disorders.