The small intestine (SI) plays a crucial role in nutrient absorption, ensuring systemic energy homeostasis while serving as a protective barrier against pathogens and external insults. The SI epithelium is organized into crypt-villus units, where crypt-resident stem cells give rise to differentiated cell types along the villus. Among all differentiated cells, enterocytes are the most abundant and primarily responsible for nutrient sensing and uptake. However, the molecular mechanisms governing enterocyte differentiation and functional specialization remain poorly understood. Here, we identify the transcription factor c-Maf, a member of the AP-1 family, as a key regulator in enterocyte differentiation and functional zonation along the intestinal crypt-villus axis. We demonstrate that c-Maf is specifically expressed in small intestinal enterocytes, and exhibits a zonated expression pattern, confined to the mid-villus region. We show that this spatial restriction is regulated by the increasing BMP signaling throughout the villus and overlaps with the expression region of most nutrient transporters. To investigate the role of c-Maf in enterocyte biology, we used a constitutive intestinal epithelial cell (IEC)-specific c-Maf knockout mouse model (MafΔIEC). These mice were viable and born in normal Mendelian ratios but exhibited impaired enterocyte maturation, reduced nutrient uptake, weight loss and decreased body temperature. Transcriptomic and functional analyses revealed reduced expression of nutrient transporters involved in carbohydrate and protein absorption, as well as reduced absorptive capacity as shown by in vitro and ex vivo uptake assays. Furthermore, c-Maf-deficient enterocytes showed defects in the adaptation to increased carbohydrate availability. Besides its role in nutrient absorption, c-Maf deletion also impacted immune and microbial homeostasis, leading to a reduction of intraepithelial lymphocytes (IELs) and an expansion of segmented filamentous bacteria (SFB). Our ongoing work explores the role of c-Maf in dynamic states of intestinal epithelial and nutritional remodeling, such as during maternal lactation or chronic intestinal inflammation. Collectively, our findings establish c-Maf as a critical transcriptional regulator of enterocyte differentiation and function, essential for intestinal homeostasis, nutrient uptake and host-microbiota interactions.
