Objective IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives). Design Faecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls). Findings were validated in independent cohorts of 616 and 1173 subjects including patients with IBD, infants born to mothers with IBD and controls. 16S rRNA gene sequencing and global untargeted metabolomics profiling of faeces and serum were performed. Results Microbial and metabolomic parameters of dysbiosis progressively decreased from infancy until age 8. This microbial maturation process was slower in infants born to mothers with IBD. After age 15, dysbiosis steadily increased in unaffected relatives throughout adulthood. Dysbiosis was accompanied by marked shifts in the faecal metabolome and, to a lesser extent, the serum metabolome. Faecal and serum metabolomics dysbiosis indices were validated in an independent cohort. Dysbiosis was associated with elevated antimicrobial serologies but not with faecal calprotectin. Dysbiosis metrics differentiated IBD from non-IBD comparably to serologies, with a model combining calprotectin, faecal metabolomics dysbiosis index and serology score demonstrating highest accuracy. Conclusion These findings support that dysbiosis exists as a pre-disease state detectable by faecal and serum biomarkers for IBD risk prediction. Given the expansion of disease-modifying agents and non-invasive imaging, the indices developed here may facilitate earlier diagnoses and improved management in at-risk individuals. All data relevant to the study are included in the article or uploaded as supplementary information. Sequence data have been deposited in NCBI Bioproject under PRJNA1053656 ( ) and metabolomics data along with associated metadata are included in supplemental data files.

中文翻译：

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多重炎症性肠病家族中微生物菌群失调的年龄相关模式


客观 IBD 的特征是菌群失调，但目前尚不清楚菌群失调在未受影响的高危个体中的发展程度。为了解决这个问题，我们调查了高危多重 IBD 家族 （两个或多个受影响的一级亲属） 中与年龄相关的粪便和血清菌群失调标志物模式。设计 从多重 IBD 和对照家系 （95 例 IBD，292 例未受影响，51 例对照） 中收集粪便和血清样本。研究结果在 616 名和 1173 名受试者的独立队列中得到了验证，包括 IBD 患者、IBD 母亲所生婴儿和对照组。进行 16S rRNA 基因测序和粪便和血清的整体非靶向代谢组学分析。结果 从婴儿期到 8 岁，菌群失调的微生物和代谢组学参数逐渐降低。这种微生物成熟过程在 IBD 母亲所生的婴儿中较慢。15 岁以后，未受影响的亲属在整个成年期中菌群失调稳步增加。菌群失调伴有粪便代谢组的显着变化，在较小程度上还伴有血清代谢组的变化。粪便和血清代谢组学菌群失调指数在一个独立队列中得到验证。菌群失调与抗菌血清学升高有关，但与粪便钙卫蛋白无关。与血清学相比，菌群失调指标将 IBD 与非 IBD 区分开来，结合钙卫蛋白、粪便代谢组学菌群失调指数和血清学评分的模型显示出最高的准确性。结论 这些发现支持菌群失调作为一种病前状态存在，可通过粪便和血清生物标志物检测，用于 IBD 风险预测。 鉴于疾病调节剂和非侵入性影像学检查的扩展，此处开发的指数可能有助于高危个体的早期诊断和改善管理。与研究相关的所有数据都包含在文章中或作为补充信息上传。序列数据已存放在 NCBI Bioproject 的 PRJNA1053656 （ ） 下，代谢组学数据以及相关元数据包含在补充数据文件中。