Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS
Abstract 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 fea...
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-16542-z |
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| author | Yangyang Ge Lingya Liu Lihua Wu Xiaofan Liu Yingao Hao Shixu Wang Yi Xiong Zi Yang Zhen Zhang Qi Li Bo Li Jianxin Wu Guangxu Ren Qian Jiang |
| author_facet | Yangyang Ge Lingya Liu Lihua Wu Xiaofan Liu Yingao Hao Shixu Wang Yi Xiong Zi Yang Zhen Zhang Qi Li Bo Li Jianxin Wu Guangxu Ren Qian Jiang |
| author_sort | Yangyang Ge |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-ccd714c9485846cdaf6664152002e183 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-ccd714c9485846cdaf6664152002e1832025-08-24T11:19:52ZengNature PortfolioScientific Reports2045-23222025-08-0115111410.1038/s41598-025-16542-zImpaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWSYangyang Ge0Lingya Liu1Lihua Wu2Xiaofan Liu3Yingao Hao4Shixu Wang5Yi Xiong6Zi Yang7Zhen Zhang8Qi Li9Bo Li10Jianxin Wu11Guangxu Ren12Qian Jiang13 Department of Medical Genetics, Capital Institute of PediatricsBeijing Tongren Hospital, Capital Medical University Department of Medical Genetics, Capital Institute of PediatricsInstitute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs of the Reople’s Republic of ChinaInstitute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs of the Reople’s Republic of ChinaInstitute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs of the Reople’s Republic of ChinaDepartment of General Surgery, Capital Center for Children’s Health, Capital Medical University Department of Medical Genetics, Capital Institute of PediatricsDepartment of General Surgery, Capital Center for Children’s Health, Capital Medical UniversityDepartment of General Surgery, Capital Center for Children’s Health, Capital Medical UniversityDepartment of Translational Medicine, Division of General and Thoracic Surgery, The Hospital for Sick ChildrenBeijing Tongren Hospital, Capital Medical UniversityInstitute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs of the Reople’s Republic of China Department of Medical Genetics, Capital Institute of PediatricsAbstract 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.https://doi.org/10.1038/s41598-025-16542-zZeb2Small intestineNutrient absorptionBone massMicrobiota |
| spellingShingle | Yangyang Ge Lingya Liu Lihua Wu Xiaofan Liu Yingao Hao Shixu Wang Yi Xiong Zi Yang Zhen Zhang Qi Li Bo Li Jianxin Wu Guangxu Ren Qian Jiang Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS Scientific Reports Zeb2 Small intestine Nutrient absorption Bone mass Microbiota |
| title | Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS |
| title_full | Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS |
| title_fullStr | Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS |
| title_full_unstemmed | Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS |
| title_short | Impaired nutrient absorption, reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of MWS |
| title_sort | impaired nutrient absorption reduced bone mass and alterations in the gut microbiome contribute to postnatal growth retardation in a mouse model of mws |
| topic | Zeb2 Small intestine Nutrient absorption Bone mass Microbiota |
| url | https://doi.org/10.1038/s41598-025-16542-z |
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