Mucosal Biology Research Center and Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2012;7(3):e33387. doi: 10.1371/journal.pone.0033387. Epub 2012 Mar 14.
Celiac disease (CD) is a unique autoimmune disorder in which the genetic factors (DQ2/DQ8) and the environmental trigger (gluten) are known and necessary but not sufficient for its development. Other environmental components contributing to CD are poorly understood. Studies suggest that aspects of gluten intake might influence the risk of CD occurrence and timing of its onset, i.e., the amount and quality of ingested gluten, together with the pattern of infant feeding and the age at which gluten is introduced in the diet. In this study, we hypothesize that the intestinal microbiota as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals. Using a sample of infants genetically at risk of CD, we characterized the longitudinal changes in the microbial communities that colonize infants from birth to 24 months and the impact of two patterns of gluten introduction (early vs. late) on the gut microbiota and metabolome, and the switch from gluten tolerance to immune response, including onset of CD autoimmunity. We show that infants genetically susceptible to CD who are exposed to gluten early mount an immune response against gluten and develop CD autoimmunity more frequently than at-risk infants in which gluten exposure is delayed until 12 months of age. The data, while derived from a relatively small number of subjects, suggest differences between the developing microbiota of infants with genetic predisposition for CD and the microbiota from infants with a non-selected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age. Furthermore, metabolomics analysis reveals potential biomarkers for the prediction of CD. This study constitutes a definite proof-of-principle that these combined genomic and metabolomic approaches will be key to deciphering the role of the gut microbiota on CD onset.
乳糜泻（CD）是一种独特的自身免疫性疾病，其遗传因素（DQ2/DQ8）和环境触发因素（麸质）是已知的，并且是其发展所必需的，但不是充分的。导致 CD 的其他环境因素知之甚少。研究表明，摄入麸质的某些方面可能会影响 CD 的发病风险及其发病时间，即摄入的麸质量和质量，以及婴儿喂养方式和引入饮食中的麸质年龄。在这项研究中，我们假设肠道微生物组作为一个整体，而不是特定的感染，决定了具有遗传易感性的个体从耐受向免疫反应的转变。使用一组在遗传上易患 CD 的婴儿样本，我们描述了从出生到 24 个月定植婴儿的微生物群落的纵向变化，以及两种引入麸质的模式（早期与晚期）对肠道微生物组和代谢组的影响，以及从麸质耐受向免疫反应的转变，包括 CD 自身免疫的发病。我们表明，暴露于早期麸质的易患 CD 的婴儿会对麸质产生免疫反应，并比易患 CD 的婴儿更频繁地发展 CD 自身免疫，后者将麸质暴露延迟到 12 个月大。尽管这些数据来自相对较少的受试者，但它们表明具有 CD 遗传易感性的婴儿的发育中微生物组与非选择性遗传背景的婴儿的微生物组之间存在差异，总体上缺乏厚壁菌门的细菌，同时Firmicutes 丰度较高，甚至在 2 岁时也与成人的微生物组不同。此外，代谢组学分析揭示了预测 CD 的潜在生物标志物。这项研究明确证明了这些组合的基因组和代谢组学方法将是揭示肠道微生物组在 CD 发病中的作用的关键。
