Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk
Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk
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DOI：
10.1073/pnas.1612158114
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发表时间：
2016-12-20
影响因子：
11.1
通讯作者：
Cummings, Richard D.
中科院分区：
文献类型：
--
作者：
Kudelka, Matthew R.;Hinrichs, Benjamin H.;Cummings, Richard D.
炎症性肠病（IBD）是由针对微生态失调的粘膜但相对保存的管腔微生物群的异常免疫刺激引起的，并且在早发性疾病中优先影响男性。然而，导致性别特异性风险和生态失调模式的因素在很大程度上尚未探索。核心蛋白1 β 3GalT特异性分子伴侣（Cosmc），编码一种对糖萼形成重要的X-连锁分子伴侣，最近被全基因组关联研究确定为IBD的危险因素。我们删除了小鼠肠上皮细胞（IEC）中的Cosmc，发现从近端到远端肠粘膜的微生物群多样性显著减少，但在IBD中观察到的覆盖管腔中没有减少。这种多样性的丧失与促炎性致病菌和远端肠道限制性病理的局部出现相一致。从机制上讲，我们发现Cosmc调节宿主基因，细菌配体和营养物质的可用性，以控制微生物群地理学。男性中一个Cosmc等位基因缺失（IEC-Cosmc-（γ））导致粘液层受损、自发性微生物依赖性炎症和增强的实验性结肠炎;然而，在50%的隐窝中缺失一个等位基因和Cosmc嵌合缺失的女性，（IEC-Cosmc（+/-））被保护免于自发性炎症并且部分地被保护免于实验性结肠炎，可能是由于正常粘蛋白糖萼从WT细胞侧向迁移到KO隐窝。这些研究在功能上验证了Cosmc作为IBD的危险因素，并暗示它在调节IBD的生态失调和性别偏见的空间模式。
Inflammatory bowel disease (IBD) results from aberrant immune stimulation against a dysbiotic mucosal but relatively preserved luminal microbiota and preferentially affects males in early onset disease. However, factors contributing to sex-specific risk and the pattern of dysbiosis are largely unexplored. Core 1 beta 3GalT-specific molecular chaperone (Cosmc), which encodes an X-linked chaperone important for glycocalyx formation, was recently identified as an IBD risk factor by genome-wide association study. We deleted Cosmc in mouse intestinal epithelial cells (IECs) and found marked reduction of microbiota diversity in progression from the proximal to the distal gut mucosa, but not in the overlying lumen, as seen in IBD. This loss of diversity coincided with local emergence of a proinflammatory pathobiont and distal gut restricted pathology. Mechanistically, we found that Cosmc regulates host genes, bacterial ligands, and nutrient availability to control microbiota biogeography. Loss of one Cosmc allele in males (IEC-Cosmc-(/y)) resulted in a compromised mucus layer, spontaneous microbe-dependent inflammation, and enhanced experimental colitis; however, females with loss of one allele and mosaic deletion of Cosmc in 50% of crypts (IEC-Cosmc(+/-)) were protected from spontaneous inflammation and partially protected from experimental colitis, likely due to lateral migration of normal mucin glycocalyx from WT cells over KO crypts. These studies functionally validate Cosmc as an IBD risk factor and implicate it in regulating the spatial pattern of dysbiosis and sex bias in IBD.