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Gardening Effect of Host Genetics on Human Intestinal Mucosal Microbiome and Its Link to Inflammatory Bowel Disease


Inflammatory bowel disease (IBD) is a set of chronic, relapsing inflammatory diseases of the intestine. The two major subtypes of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Although the pathogenesis of IBD remains largely unknown, Crohn's disease is considered to result from the interaction of environmental factors, including intestinal microbiota, with host immune mechanisms in genetically susceptible individuals. Recent advances in sequencing technologies have allowed us to characterize the IBD associated dysbiosis in unprecedented depth. However, phylogenetic profiling can only provide limited information on the functional implication of these alterations. To address this analytical challenge, we developed the novel mucosal lavage sampling approach, which enabled the profiling of multi'omic molecular features including microbiome, metaproteome and metabolome. Combined with host genomic information, these tools can provide us with unprecedented understanding of the dynamics of host-microbial interaction, and help us to investigate the pathogenesis of inflammatory bowel diseases.

Another analytical challenge to identify microbial taxa consistently representing IBD associated dysbiosis is the high complexity and low inter-individual overlap of intestinal microbial composition. This difficulty can be overcome by an ecologic analytic strategy to identify modules of interacting bacteria (rather than individual bacteria) as quantitative reproducible features of microbial composition in normal and IBD mucosa. We developed the strategy to analyze microbial composition using microbial co-occurrence network approach. This strategy uncovered 5 reproducible functional microbial communities (FMCs) detectable in the mucosa of all individuals. The quantitative levels of two FMCs were significantly associated with IBD states. Imputed metagenome analysis indicated the functional importance of the disease associated modules reflected by the enrichment of virulent and pathogenic pathways. Thus, these modules appear to define novel microbial communities within the intestinal microbial ecology, some of which are commonly and stably modified by the IBD disease state, and may be of particular relevance for microbial pathogenesis and intervention.

Using this experimental and bioinformatic framework, we investigated the microbial gardening effect of FUT2 gene and its link to Crohn's disease. Fucosyltransferase 2 (FUT2) is an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. Non-secretors, who are homozygous for the loss-of-function alleles of FUT2 gene (sese), have increased susceptibility to Crohn's disease. In healthy individuals, imputed metagenomic analysis revealed perturbations of energy metabolism in the microbiome of non-secretor and heterozygote individuals, notably the enrichment of carbohydrate and lipid metabolism, cofactor and vitamin metabolism, and glycan biosynthesis and metabolism related pathways; and, the depletion of amino acid biosynthesis and metabolism. Similar changes were observed in mice bearing the FUT2-/- genotype. Metabolomic analysis of human specimens revealed concordant as well as novel changes in the levels of several metabolites. Human metaproteomic analysis indicated that these functional changes were accompanied by sub-clinical levels of inflammation in the local intestinal mucosa. In an extended cohort containing both healthy and CD individuals, the phylogenetic composition of intestinal mucosal microbiota was affected by an interaction of Crohn's disease status and FUT2 genotype. Decreased abundances of Firmicutes were associated with both CD and FUT2 risk allele. At metagenomic level, a distinct signature of amino acid metabolism deficiency was identified in CD and non-secretor microbiome. Such changes were also reflected at metabolomic level in the proximal gut region. Taken together, FUT2 gene increased the risk of Crohn's disease by changing the microbial composition and function to a disease-like state. The CD associated perturbations of metagenome and metabolome were driven by the FUT2 risk allele.

The same experimental and bioinformatic approach can also be applied to study the composition and functional changes of mucosal associated microbiota in other chronic inflammatory disease, namely HIV-1 infection. In the rectal mucosa, microbial composition and imputed function in HIV-positive individuals not receiving cART was significantly different from HIV-negative individuals. Genera including Roseburia, Coprococcus, Ruminococcus, Eubacterium, Alistipes and Lachnospira were depleted in HIV-infected subjects not receiving cART, while Fusobacteria, Anaerococcus, Peptostreptococcus and Porphyromonas were significantly enriched. HIV-positive subjects receiving cART exhibited similar depletion and enrichment for these genera, but were of intermediate magnitude and did not achieve statistical significance. Imputed metagenomic functions, including amino acid metabolism, vitamin biosynthesis, and siderophore biosynthesis differed significantly between healthy controls and HIV-infected subjects not receiving cART. In the cervicovaginal mucosa, significant differences in alpha and beta diversity were observed between HIV-negative and HIV-positive women, with the latter enriched of organisms associated with bacterial vaginosis and depleted of Lactobacilli. These ecologic changes occurred concomitantly with significant metagenomic and immunologic differences. Such functional pathways may represent novel interventional targets for HIV therapy if normalizing the microbial composition or functional activity of the microbiota proves therapeutically useful.

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