Inflamm Bowel Dis. 2021 Oct 20;27(11):1707-1718. doi: 10.1093/ibd/izaa339.

Allison D Ta ¹, Nicholas J Ollberding ¹, Rebekah Karns ¹, Yael Haberman ^1 2, Adina L Alazraki ³, David Hercules ³, Robert Baldassano ⁴, James Markowitz ⁵, Melvin B Heyman ⁶, Sandra Kim ⁷, Barbara Kirschner ⁸, Jason M Shapiro ⁹, Joshua Noe ¹⁰, Maria Oliva-Hemker ¹¹, Anthony Otley ¹², Marian Pfefferkorn ¹³, Richard Kellermayer ¹⁴, Scott Snapper ¹⁵, Shervin Rabizadeh ¹⁶, Ramnik Xavier ^17 18, Marla Dubinsky ¹⁹, Jeffrey Hyams ²⁰, Subra Kugathasan ³, Anil G Jegga ¹, Jonathan R Dillman ¹, Lee A Denson ¹

Author information

¹Cincinnati Children's Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

²Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Tel Aviv, Israel.

³Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

⁴The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

⁵Cohen Children's Medical Center of New York, New Hyde Park, New York, USA.

⁶University of California San Francisco, San Francisco, California, USA.

⁷Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.

⁸The University of Chicago, Chicago, Illinois, USA.

⁹Hasbro Children's Hospital, Providence, Rhode Island, USA.

¹⁰Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

¹¹John Hopkins University, Baltimore, Maryland, USA.

¹²IWK Health Centre, Halifax, Nova Scotia, Canada.

¹³Indiana University School of Medicine, Indianapolis, Indiana, USA.

¹⁴Texas Children's Hospital, Baylor College School of Medicine, Houston, Texas, USA.

¹⁵Children's Hospital-Boston, Boston, Massachusetts, USA.

¹⁶Cedars-Sinai Medical Center, Los Angeles, California, USA.

¹⁷Broad Institute at Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

¹⁸Massachusetts General Hospital, Cambridge, Massachusetts, USA.

¹⁹Mount Sinai Hospital, New York, New York, USA.

²⁰Connecticut Children's Medical Center, Hartford, Connecticut, USA.

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.