Functional loss of myosin Vb (MYO5B) induces a variety of deficits in intestinal epithelial cell function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). The impact of MYO5B loss on differentiated cell lineage choice has not been investigated. We quantified the populations of differentiated epithelial cells in tamoxifen-induced, epithelial cell–specific MYO5B-knockout ( VilCre ^ERT2 Myo5b ^{fl / fl} ) mice utilizing digital image analysis. Consistent with our RNA-sequencing data, MYO5B loss induced a reduction in tuft cells in vivo and in organoid cultures. Paneth cells were significantly increased by MYO5B deficiency along with expansion of the progenitor cell zone. We further investigated the effect of lysophosphatidic acid (LPA) signaling on epithelial cell differentiation. Intraperitoneal LPA significantly increased tuft cell populations in both control and MYO5B-knockout mice. Transcripts for Wnt ligands were significantly downregulated by MYO5B loss in intestinal epithelial cells, whereas Notch signaling molecules were unchanged. Additionally, treatment with the Notch inhibitor dibenzazepine (DBZ) restored the populations of secretory cells, suggesting that the Notch pathway is maintained in MYO5B-deficient intestine. MYO5B loss likely impairs progenitor cell differentiation in the small intestine in vivo and in vitro, partially mediated by Wnt/Notch imbalance. Notch inhibition and/or LPA treatment may represent an effective therapeutic approach for treatment of MVID.

In addition to the small intestine’s well-known function of nutrient absorption, the small intestine also plays a major role in nutrient sensing. Similar to taste sensors seen on the tongue, GPCR-coupled nutrient sensors are expressed throughout the intestinal epithelium and respond to nutrients found in the lumen. These taste receptors respond to specific ligands, such as digested carbohydrates, fats, and proteins. The activation of nutrient sensors in the intestine allows for the induction of signaling pathways needed for the digestive system to process an influx of nutrients. Such processes include those related to glucose homeostasis and satiety. Defects in intestinal nutrient sensing have been linked to a variety of metabolic disorders, such as type 2 diabetes and obesity. Here, we review recent updates in the mechanisms related to intestinal nutrient sensors, particularly in enteroendocrine cells, and their pathological roles in disease. Additionally, we highlight the emerging nutrient sensing role of tuft cells and recent work using enteroids as a sensory organ model.