Surgery for Crohn's Disease Is Associated With a Dysbiotic Microbiome and Metabolome: Results From Two Prospective Cohorts

Abstract

Background & aims: Crohn's disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn's disease surgery.

Methods: Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn's Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with ¹H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry.

Results: Intestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, Egerthella lenta, Adlercreutzia equalofaciens, and Gordonibacter pamelaeae were lower in abundance among patients with prior surgery in both cohorts.

Conclusions: In 2 different populations, prior surgery in Crohn's disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria and secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.

Keywords: Bile Acids; Butyrate; Crohn’s Disease; Dysbiosis; Microbiome.

Graphical abstract

Figure 1

Alpha and beta diversity association with surgical status. (A) Richness (P = .007) but not Shannon diversity index (P = .18) was significantly lower in those patients who had prior bowel resection in DINE-CD. Both indices were significantly lower in patients with prior surgery in the SPARC-IBD cohort. (B) Beta diversity differed among patients with prior surgery (DINE-CD unadjusted P = .001, adjusted P = .11; SPARC IBD unadjusted P = .01, adjusted P = .0001). (C) Relative abundance of phylum with and without surgery. There is greater relative abundance of Proteobacteria in patients who underwent surgery in the DINE-CD and SPARC IBD cohorts. Lower abundance phyla were reduced with surgery in both cohorts, whereas reduced abundance of Bacteroidetes in patients who underwent surgery was only significant in the SPARC-IBD cohort.

Figure 2

Correlation of the bacteria relative abundance and PC1 in the DINE-CD cohort. Taxa shown are those with greater than 1% mean abundance across samples in both cohorts. Correlations whose P values are less than .05 by Pearson product moment correlation are marked with an asterisk.

Figure 3

Correlation of the bacteria relative abundance and PC1 in the SPARC IBD cohort. Taxa shown are those with greater than 1% mean abundance across samples in both cohorts. Correlations whose P values are less than .05 by Pearson product moment correlation are marked with an asterisk.

Figure 4

Association of bowel resection surgery with abundance of microbial gene pathways in the DINE-CD (A) and SPARC IBD (B) cohorts. Positive values mean that there is an increase abundance in patients with prior surgery. Those in blue are statistically significant at FDR <0.05. Orange identifies those with FDR >0.05 and <0.10.

Figure 5

Association of bowel resection surgery with relative abundance of microbial genes for butyrate metabolism in the DINE-CD (A) and SPARC IBD (B) cohorts and fecal butyrate concentration (C). Positive values mean that there is an increase abundance in patients with prior surgery. Those in blue are statistically significant at FDR <0.05. Orange identifies those with FDR >0.05 and <0.10.

Figure 6

Association of bowel resection surgery with relative abundance of microbial genes for bile acid metabolism and bile acids in feces. (A) bai operon genes. (B) Bile salt hydrolase genes. Positive values mean that there is an increase abundance in patients with prior surgery. Those in orange identifies those with FDR >0.05 and <0.10. (C) Primary bile acids. (D) Secondary bile acids. BSH, bile salt hydrolase; PVA, penicillin V acylase.

Figure 7

Association of bowel resection surgery with isoLCA and bacteria that produce isoLCA. (A) Bacteria that produce isoLCA were significantly reduced in patients who had undergone prior surgery. (B) Fecal concentration of isoLCA was lower in patients who had undergone prior surgery.