Enhanced microbiota profiling in patients with quiescent Crohn's disease through comparison with paired healthy first-degree relatives using fecal metagenomics and metabolomics

Prior studies indicate no correlation between gut microbiota of healthy first-degree relatives (HFDRs) of Crohn's disease (CD) patients and development of CD. Here, we utilized HFDRs as controls to examine the microbiota and metabolome in individuals with active (CD-A) and quiescent (CD-R) CD, thereby minimizing the influence of genetic and environmental factors. Compared to non-relative controls, the use of HFDR controls identified fewer differential taxa. Faecalibacterium, Dorea, and Fusicatenibacter were decreased in CD-R, independent of inflammation, and correlated with fecal SCFAs. Validation with a large multi-center cohort confirmed decreased Faecalibacterium and other SCFA-producing genera in CD-R. Classification models based on these genera distinguished CD from healthy individuals, and demonstrated superior diagnostic power than models constructed with markers identified using unrelated controls. Thus, decreased Faecalibacterium, Dorea, and Fusicatenibacter in CD-R likely contributed to disease relapse through reduced SCFA production, highlighting their potential as diagnostic markers and therapeutic targets for CD. ### Competing Interest Statement The authors have declared no competing interest.