Association of Baseline Luminal Narrowing with Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease

Allison D. Ta, Nicholas J. Ollberding, Rebekah Karns, Yael Haberman, Adina L. Alazraki, David Hercules, Robert Baldassano, James Markowitz, Melvin B. Heyman, Sandra Kim, Barbara Kirschner, Jason M. Shapiro, Joshua Noe, Maria Oliva-Hemker, Anthony Otley, Marian Pfefferkorn, Richard Kellermayer, Scott Snapper, Shervin Rabizadeh, Ramnik XavierMarla Dubinsky, Jeffrey Hyams, Subra Kugathasan, Anil G. Jegga, Jonathan R. Dillman, Lee A. Denson

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures. Materials and Methods: Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH. Results: After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression. Conclusions: Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.

Original languageEnglish (US)
Pages (from-to)1707-1718
Number of pages12
JournalInflammatory bowel diseases
Volume27
Issue number11
DOIs
StatePublished - Nov 1 2021

Keywords

  • gene expression
  • luminal narrowing
  • magnetic resonance enterography
  • microbiome
  • transmural healing

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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