Gut Microbiota and Metabolic Specificity in Ulcerative Colitis and Crohn's Disease

Abstract

Background: Inflammatory bowel disease (IBD) represents multifactorial chronic inflammatory conditions in the gastrointestinal tract and includes Crohn's disease (CD) and ulcerative colitis (UC). Despite similarities in pathobiology and disease symptoms, UC and CD represent distinct diseases and exhibit diverse therapeutic responses. While studies have now confirmed that IBD is associated with dramatic changes in the gut microbiota, specific changes in the gut microbiome and associated metabolic effects on the host due to CD and UC are less well-understood. Methods: To address this knowledge gap, we performed an extensive unbiased meta-analysis of the gut microbiome data from five different IBD patient cohorts from five different countries using QIIME2, DIAMOND, and STAMP bioinformatics platforms. In-silico profiling of the metabolic pathways and community metabolic modeling were carried out to identify disease-specific association of the metabolic fluxes and signaling pathways. Results: Our results demonstrated a highly conserved gut microbiota community between healthy individuals and IBD patients at higher phylogenetic levels. However, at or below the order level in the taxonomic rank, we found significant disease-specific alterations. Similarly, we identified differential enrichment of the metabolic pathways in CD and UC, which included enriched pathways related to amino acid and glycan biosynthesis and metabolism, in addition to other metabolic pathways. Conclusions: In conclusion, this study highlights the prospects of harnessing the gut microbiota to improve understanding of the etiology of CD and UC and to develop novel prognostic, and therapeutic approaches.

Keywords: Crohn's disease; gut microbiome; metabolism; prognosis; ulcerative colitis.

Figure 1

Alpha and beta diversity comparisons among HC, CD and UC cohorts. Analyses were performed on species-level taxa. (A) Boxplot showing Shannon diversity of each group. Each dot represents a sample and the lines in the boxes correspond to the median of samples; (B) Bray–Curtis distances between the comparison pair. Dots represent the distance between the samples in each comparison group and the lines in the boxes correspond to the median.

Figure 2

Comparison of microbial communities between IBD and HC cohorts across five different datasets. (A) An upset plot showing taxonomic intersections across the five datasets at the Order-level. Each bar represents the number of orders in that category and the orange dot below the bar indicates their conservation across the datasets. For instance, members of Bacteriodales and Clostridiales are conserved in all five datasets; (B) Stacked bar plots show the relative mean frequencies of significant species-level communities in IBD or HC that are present in at least in three out of five datasets. Corresponding values are provided in the 146 OTUs sheet in Supplementary Datasheet 3, where the columns contain data for five different datasets.

Figure 3

Comparison of microbial communities among CD, UC, and HC cohorts across five datasets. (A) An upset plot showing taxonomic intersections across the five datasets at the Order-level. Each bar represents the number of orders in that category and the orange dot below the bar indicates their conservation across the datasets. For instance, members of Clostridiales are conserved in all five datasets; (B) Stacked bar plots show the relative mean frequencies of significant species-level communities in CD, HC or UC that are present in at least in three out of five datasets. Corresponding values are provided in the 168 OTUs sheet in Supplementary Datasheet 4, where the columns contain data for five different datasets.

Figure 4

Comparison of microbial communities between CD and UC cohorts across five datasets. (A) An upset plot showing taxonomic intersections across the five datasets at the Order-level. Each bar represents the number of orders in that category and the orange dot below the bar indicates their conservation across the datasets. For instance, members of Bacteroidales and Clostridiales are conserved in all five datasets; (B) Stacked bar plots show the relative mean frequencies of significant species-level communities in CD or UC that are present in at least in three out of five datasets. Corresponding values are provided in the 195 OTUs sheet in Supplementary Datasheet 5, where the columns contain data for five different datasets.

Figure 5

Enriched pathways identified based on enriched metabolic reactions in disease-specific organisms for HC, CD, and UC cohorts.