P912 Increased Primary Bile Acids with Ileocolonic Resection Impact Ileal Inflammation and Gut Microbiota in Inflammatory Bowel Disease

Abstract

Background A majority of Crohn’s disease (CD) patients require surgery. Ileitis recurs after most ileocolectomies and is a critical determinant for outcomes. The impact of ileocolectomy-induced bile acid (BA) perturbations on intestinal microbiota and inflammation are unknown. We characterized relationships between ileocolectomy, stool BA, microbiota, and intestinal inflammation in inflammatory bowel disease (IBD). Methods Validated IBD clinical and endoscopic assessments were prospectively collected. Matched primary and secondary BA concentrations measured in stool using Agilent Quadrupole Time of Flight Liquid chromatography-mass spectrometry were compared based on ileocolectomy and ileitis status. Primary BA thresholds for ileitis were evaluated using area under the receiver operating characteristic curve analyses. In CD, endoscopic remission was defined as SES-CD <3 or Rutgeerts <i2b. Ileal ER was defined as ileal SES-CD ≤ 1 and colonic ER was defined as colonic SES-CD≤2 without any segment >1. In UC, ER was defined as UC-ESS ≤ 1. Metagenomic sequencing profiled microbial composition and function. Relationships between ileocolectomy, BA and microbiota were assessed. Results In 166 patients, elevated primary and secondary BA existed with ileocolectomy. With ileitis, only primary BA (795 nMol/g vs 398 nMol/g, p=0.009) were higher compared to without ileitis. The optimal primary BA threshold (≥228nMol/g) identified ileitis on multivariable analysis (OR=2.3, p=0.04). Similar primary (471 nMol/g vs. 606 nMol/g, p=0.8) and secondary (382 nMol/g vs. 242 nMol/g, p=0.2) BA concentrations existed with and without colonic inflammation. Microbial diversity (Shannon index, p=0.0006), Faecalibacterium prausnitzii and O-acetylhomoserine aminocarboxypropyltransferase (MetY, p=0.0002) were decreased with elevated primary BA. Amongst ileocolectomy patients, only those with elevated primary BA had diversity (p=0.01), F.prausnitzii and MetY (p=0.04) reductions. Those with both ileocolectomy and intermediate (p=0.002) or high (≥228nMol/g, p=9.1e-11) ) primary BA had reduced F.prausnitzii compared to without ileocolectomy (Figure 1). Those with ileocolectomy and low (<29.2nMol/g) primary BA had similar F.prausnitzii as those without ileocolectomy (P=0.13). MetY was reduced with ileitis (p=0.02). Conclusion Elevated primary bile acids were associated with ileitis, and reduced microbial diversity, F.prausnitzii abundance, and enzymatic expression of MetY (acetate and L-methionine producing enzyme expressed by F.prausnitzii) and were the only factor associated with these findings after ileocolectomy.

Crohn’s disease: Why the ileum?

“…Nevertheless, this finding should be interpreted with caution as malabsorption of bile acids was documented as a consequence of ileal CD especially in patients with a history of ileal resection[ 86 , 87 ]. Moreover, in a cohort of 166 patients, enhanced primary biliary level in the stool was independently associated with ileitis[ 88 ]. In a multi-omics approach based on a stool collection of 200 IBD patients, ileal CD profile was characterized by increased primary and secondary bile acid levels and shifts in taxa in favour of bacteria associated with bile acid-rich environments ( Gammaproteobacteria and Blautia sp .…”

“…Lastly, bile acids promoted the expression of long polar fimbriae favouring the interplay of these strains with Peyer’s patches and bacterial translocations[ 94 ]. For example, primary bile acid level was inversely correlated with the abundance of Faecalibacterium prausnitzii ( F. prausnitzii ) and its acetate and L-methionine producing enzyme[ 88 ]. In patients treated by surgery for ileal CD, bile acid metabolism specificities were associated with an ileal recurrence of CD[ 89 ].…”

“…Thus, elevated levels of primary bile acids were associated with a decreased abundance of F. prausnitzii . These two parameters were the only factors associated with ileitis in this cohort of 166 patients[ 88 ]. The administration of F. prausnitzii or of its supernatant in vitro and in vivo counterbalanced gut inflammation by blocking nuclear factor kB activation and IL-8 production[ 113 ].…”