Sequencing assembly of Klebsiella variicola from defined culture collection. Klebsiella variicola

To gain insights into the interrelationships between childhood undernutrition, the gut microbiota, and gut mucosal immune/barrier function, we purified bacterial strains targeted by IgA from the fecal microbiota of two cohorts of Malawian infants/children. IgA responses to several bacterial taxa, including Enterobacteriaceae, correlated with anthropometric measurements of nutritional status in longitudinal studies. The relationship between IgA responses and growth was further explained by enteropathogen burden. Gnotobiotic mouse recipients of an IgA+-bacterial consortium purified from undernourished microbiota exhibited a diet-dependent enteropathy characterized by rapid disruption of the small intestinal and colonic epithelial barrier, weight loss and sepsis that could be prevented by administering two IgA-targeted bacterial species from a healthy microbiota. Dissection of a culture collection of 11 IgA-targeted strains from an undernourished donor, sufficient to transmit these phenotypes, disclosed that Enterobacteriaceae interacted with other consortium members to produce enteropathy. These findings indicate that bacterial targets of IgA responses have etiologic, diagnostic, and therapeutic implications for childhood undernutrition.

为深入解析儿童营养不良、肠道菌群与肠道黏膜免疫/屏障功能之间的内在关联，本研究从马拉维两队列婴幼儿的粪便菌群中分离纯化出免疫球蛋白A（IgA）靶向结合的细菌菌株。在纵向队列研究中，针对包括肠杆菌科（Enterobacteriaceae）在内的多种细菌类群的IgA免疫应答，与反映儿童营养状况的人体测量学指标呈显著相关。进一步分析显示，IgA免疫应答与儿童生长发育的关联可通过肠道病原体负荷得到合理解释。将从营养不良患儿菌群中纯化得到的IgA结合菌群落移植至悉生小鼠（gnotobiotic mouse）后，受试小鼠会出现饮食依赖性肠病，表现为小肠及结肠上皮屏障快速受损、体重下降与败血症；而通过移植来自健康菌群的两种IgA靶向细菌物种，即可有效预防该病症的发生。本研究对一名营养不良供体来源的11株IgA靶向菌株（该菌株集合足以传递上述表型）的培养集合进行拆解分析后发现，肠杆菌科与群落内其他成员相互作用即可诱发肠病。本研究结果表明，IgA免疫应答所靶向的细菌类群，对儿童营养不良的病因探究、临床诊断与治疗干预均具有重要的潜在价值与应用前景。