Impaired nutrient absorption and alterations in gut microbiome contribute to reduced postnatal growth in Zeb2+/- mice

As a member of the ZFH1 family of two-handed zinc finger/homeodomain transcription factors, ZEB2 plays a pivotal role in regulating cell differentiation and early fetal development. Loss-of-function mutations lead to Mowat-Wilson syndrome (MWS), a rare genetic disorder associated with significant growth retardation for reasons that remain unknown. In this study, we established a global Zeb2 heterozygous knockout mouse model and observed reduced postnatal growth closely resembling the delayed physical development seen in patients with MWS. Both the daily and cumulative food intake of Zeb2+/- mice were significantly lower compared to their wild-type counterparts. This was accompanied by lower fat mass, reduced weights of epididymal,perigonadal, and mesenteric white adipose tissues, and reduced bone mass. H&E staining revealed a significant reduction in villi height. Downregulated genes in duodenum were enriched in fat and protein digestion and absorption pathways.Additionally, we observed a shift in the gut microbiome of Zeb2+/- mice, with multiple microbiota showing significant and positive correlations with postnatal growth-related indicators. Our findings underscore the critical role of the Zeb2 gene in physical development, its direct regulation of small intestine function, and its influence on the composition of the gut microbiome. The globally Zeb2 heterozygous knockout mouse model we established also provides a robust platform for gaining deeper insights into the physiological and pathophysiological impacts on various organs affected by MWS. we established a global Zeb2 heterozygous knockout mouse model to investigate the molecular underpinnings of the growth retardation observed in MWS.