Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS

Mowat‒Wilson syndrome (MWS), a rare genetic disorder caused by heterozygous loss-of-function mutations in ZEB2, is characterised by significant growth retardation with unclear mechanisms. In this study, we developed a Zeb2 haploinsufficient (Zeb2^+/-) mouse model that recapitulates key features of MWS, including reduced body weight, impaired intestinal development and skeletal hypoplasia. RNA sequencing revealed significant downregulation of nutrient digestion and absorption pathways in the duodenum of Zeb2^+/- mice, which was associated with reduced body fat and bone mass loss. Additionally, Zeb2^+/- mice presented severe gut microbiota dysbiosis, as indicated by the depletion of beneficial Actinobacteria and Bifidobacterium and increases in the abundances of the proinflammatory Proteobacteria and Rikenella. These microbial shifts correlated with impaired intestinal development and key growth indicators. Our findings delineate a pathological cascade wherein Zeb2 haploinsufficiency disrupts nutrient absorption and bone homeostasis, while concomitant dysbiosis likely exacerbates intestinal dysfunction, collectively driving growth retardation. The model we developed can provide a platform for exploring therapeutic interventions targeting nutritional support and microbiome modulation in MWS.