METAGENOMIC ANALYSIS OF INTRA-HOUSEHOLD TRANSMISSION PATTERNS OF THE GUT MICROBIOME IN CROHN'S DISEASE ACROSS POPULATIONS

Background The gut microbiome play an important role in Crohn’s disease (CD) pathogenesis. However, the extent to which interpersonal relations shape individual genetic makeup of the microbiome and its transmission in CD patients and their household members remains unknown. Here, we determined the transmission of gut microbiome between CD patients with their first-degree-relatives (FDR) and household members (HHM).

Methods Fecal samples from 511 subjects including CD patients (251), unrelated HHM cohabiting with CD (77), FDR cohabiting with CD (49), FDR not cohabiting with CD (38) and healthy controls not cohabiting with CD (Controls, 96) from three regions [Australia (AUS), Hong Kong (HK) and Kunming, China (KM)] were subjected to metagenomic sequencing. Strain-level profiles of gut microbiota was analyzed using StrainPhlAn3. MEGAHIT and Prodigal was used to analyze genome assembly and gene prediction. Phylogenetic tree based on genotypes was used to determine bacteria strain sharing.

Results Strains from 27 species including Bacteroides vulgatus, Eggerthella lenta and Escherichia coli were shared between CD patients and cohabitants in three regions. A substantial strain sharing among cohabitants of CD regardless of kinship across three regions, with 15.01% mean strain-sharing rates. Phylogenetic tree of shared strains was separated into distinct clusters based on individual region. By analyzing bacterial genes, we found the shared genes in urban area (HK and AUS) were totally different from that of rural area (KM), in particularly, over 300 genes shared between HK and AUS cohorts, while only two overlapped with KM cohort, implying that bacterial gene transmission may in part be influenced by diet and environmental exposures in different populations. Among shared bacterial genes in HK and AUS cohorts, 40 virulence genes were highly expressed in CD patients compared with Controls. CD and their cohabitants had a higher ratio of shared virulence genes compared with CD and non-cohabiting FDR, implying cohabitation is a predominant factor driving gene transmission (Fig 1A). Additionally, some shared pathogenic species, such as E. coli and Klebsiella pneumoniae were positively associated with shared virulence genes. Shared virulence genes belonging to the functions of adherence, exotoxin and immune modulation were seen in CD and cohabitants, while motility-related virulence genes were more likely to be shared between CD and non-cohabitating FDR. The variance of around 70% of virulence gene was explained by cohabitation (Fig 1B).

Conclusion Cohabitation has the largest impact on horizontal transmission of bacterial strains and genes which varies across populations. Understanding the person-to-person transmission of gut microbiome may underscore approaches to mitigate CD in at risk cohabitants.

The study is supported by Helmsley Charitable Trust and InnoHK