Dysbiosis in Metabolic Genes of the Gut Microbiomes of Patients with an Ileo-anal Pouch Resembles That Observed in Crohn's Disease

Abstract

ABSTRACT Crohn's disease (CD), ulcerative colitis (UC), and pouchitis are multifactorial and chronic inflammatory bowel diseases (IBD). Pouchitis develops in former UC patients after proctocolectomy and ileal-pouch-anal anastomosis and is characterized by inflammation of the previously normal small intestine comprising the pouch. The extent to which microbial functional alteration (dysbiosis) in pouchitis resembles that of CD or UC has not been investigated, and the pathogenesis of pouchitis remains unknown. We collected 208 fecal metagenomes from 69 patients with a pouch (normal pouch and pouchitis) and compared them to publicly available metagenomes of patients with CD (n = 88), patients with UC (n = 76), and healthy controls (n = 56). Patients with pouchitis presented the highest alterations in species, metabolic pathways, and enzymes, which was correlated with intestinal inflammation. Ruminococcus gnavus strains encoding mucin-degrading glycoside hydrolases were highly enriched in pouchitis. Butyrate and secondary bile acid biosynthesis pathways were decreased in IBD phenotypes and were especially low in pouchitis. Pathways such as amino acid biosynthesis and degradation of aromatic compounds and sugars, encoded by members of the Enterobacteriaceae, were enriched in pouch and CD but not in UC. We developed microbial feature-based classifiers that can distinguish between patients with a normal pouch and pouchitis and identified species and genes that were predictive of pouchitis. We propose that the noninflamed pouch is already dysbiotic and microbially is similar to CD. Our study reveals microbial functions that outline the pathogenesis of pouchitis and suggests bacterial groups and functions that could be targeted for intervention to attenuate small intestinal inflammation present in pouchitis and CD. IMPORTANCE Crohn's disease (CD), ulcerative colitis (UC), and pouchitis are chronic inflammatory conditions of the bowel. Pouchitis develops in former UC patients after proctocolectomy and ileal-pouch-anal anastomosis and is characterized by inflammation of the previously normal small intestine comprising the pouch. The extent to which microbial dysbiosis in patients with pouchitis resembles that of CD or UC and the pathogenesis of pouchitis remains unclear. We investigated the functions in the gut microbiomes of these patients using metagenomics. We found that the noninflamed pouch is already dysbiotic and microbially is similar to CD. Our study reveals microbial functions with a potential role in pouchitis pathogenesis such as depletion in butyrate and secondary bile acid synthesis and enrichment of amino acid synthesis and degradation of aromatic compounds, encoded by members of the Enterobacteriaceae. We developed microbial feature-based classifiers that can distinguish between patients with a normal pouch and pouchitis and identified species and genes that were predictive of pouchitis. We suggest species and functions that could be targeted for intervention to attenuate small intestinal inflammation present in pouchitis and CD.

Keywords

• pouchitis
• UC
• CD
• mucin
• butyrate
• bile acids