c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs

c-MAF, highly expressed in villus small intestinal enterocytes, coordinates transcriptional programs for nutrient absorption. Enterocyte-specific c-MAF inactivation impairs dietary lipid handling but also leads to tuft cell expansion and adaptive gut lengthening, revealing crosstalk between enterocytes and tuft cells during intestinal adaptation. Small intestinal villi are structural and functional units present in higher vertebrates and uniquely adapted to nutrient absorption. Villus enterocytes are organized in transcriptional zones dedicated to specialized tasks such as absorption of specific nutrients. We report that the transcription factor c-MAF is expressed in differentiated lower and mid-villus enterocytes and is a target of BMP signaling. Maf inactivation perturbed the villus zonation program by increasing carbohydrate-related transcripts while suppressing transcripts linked to amino-acid and lipid absorption. The formation of cytoplasmic lipid droplets, shuttling dietary fat to chylomicrons, was impaired upon Maf loss indicating its role in dietary lipid handling. Maf inactivation under homeostatic conditions expanded tuft cells and led to compensatory gut lengthening, preventing weight loss. However, delayed Maf(-/-) enterocyte maturation impaired weight recovery after acute intestinal injury, resulting in reduced survival. Our results identify c-MAF as a regulator of the intestinal villus zonation program, while highlighting the importance of coordination between stem/progenitor and differentiation programs for intestinal regeneration.

Automated summary

The transcription factor c-MAF plays a crucial role in regulating the differentiation and nutrient absorption in intestinal epithelial cells. Inactivation of c-MAF affects lipid handling, tuft cell expansion, and adaptive gut lengthening. These findings highlight the importance of the crosstalk between enterocytes and tuft cells in intestinal adaptation.