Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

Abstract

BackgroundThe inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status.ResultsFirmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways.ConclusionsThis inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.

Automated and accurate estimation of gene family abundance from shotgun metagenomes

“…The increase in cobalamin biosynthetic genes we observe may translate into an increased ability to metabolize homocysteine, the levels of which have previously been shown to accumulate in patients with IBD [72][73][74]. Indeed, a prior study [46] noticed that genes from gut microbiota of IBD patients were enriched for sulfur transport (which we also find here, q = 0.21, and which could also relate to metabolism of sulfated GAGs as above) and sulfur amino acid metabolism, which would include methionine. Alternatively, given that pyridoxine [72,74] and cobalamin [74] serum levels have been shown to be significantly lower in patients with IBD, and that in one study Crohn's patients were observed to be more likely to be folate-or cobalamin-deficient than UC or control patients [75], bacteria that are capable of synthesizing their own B and K vitamins rather than scavenging from the environment could have an advantage within the IBD gut.…”

“…A permutational multivariate analysis of variance (adonis) quantified the reported p-values for the null hypothesis that the PCA axes are not different by group based on 1e4 permutations. These trends are also observed in an independent analysis of the MetaHIT cohort (S11 Fig). research on separate cohorts also found that the community structure of biopsy-associated microbiomes [46][47][48] differed substantially between UC and CD patients, with UC appearing more like controls in the latter two; one study also saw similar trends in functional annotation from shallow shotgun sequencing [46]. UC and CD can also be differentiated serologically, with UC tending to be characterized more by autoantibodies directed at host neutrophils [49] [50], though these may arise through cross-reactivity with microbial proteins like OmpC [51], and CD being characterized more by antibodies against cell-surface glycans [52], Saccharomyces cerevisiae [50], and proteins such as flagellin [53].…”

Inferred metagenomic comparison of mucosal and fecal microbiota from individuals undergoing routine screening colonoscopy reveals similar differences observed during active inflammation

“…[3][4][5] Most IBD studies have focused on luminal/fecal bacteria, instead of bacterial communities adherent to the intestinal mucosa, 6,7 although the mucosal microbiota are in closer proximity to immune cells. 8 Although the luminal microbiota may simply be a numerical transformation of the mucosal microbiome, 9 comparisons of mucosal and fecal samples have shown that these 2 intestinal compartments have significantly different microbial communities. [10][11][12] Next generation 16S rRNA sequencing reveals alterations to bacterial taxa, but not changes to the metabolic activity and function of microbial communities.…”

“…Recently, bacterial functional profiles can be investigated by inferring the metagenome of the closest available whole genome sequences using 16S gene sequence profiles. 9,13 This approach showed that in IBD, functional differences were more pronounced than taxonomic differences. 9 Using the same approach, we recently compared the microbial functional profiles of biopsies taken from regions of known inflammation states of IBD patients.…”

“…9,13 This approach showed that in IBD, functional differences were more pronounced than taxonomic differences. 9 Using the same approach, we recently compared the microbial functional profiles of biopsies taken from regions of known inflammation states of IBD patients. 14 We found that predicted microbial functions were significantly altered in inflamed tissue of ulcerative colitis (UC) patients (compared to normal tissue), with a reduction in carbohydrate and nucleotide metabolism in favor of increased lipid and amino acid metabolism.…”