Allison D Ta1, Nicholas J Ollberding1, Rebekah Karns1, Yael Haberman1,2, Adina L Alazraki3, David Hercules3, Robert Baldassano4, James Markowitz5, Melvin B Heyman6, Sandra Kim7, Barbara Kirschner8, Jason M Shapiro9, Joshua Noe10, Maria Oliva-Hemker11, Anthony Otley12, Marian Pfefferkorn13, Richard Kellermayer14, Scott Snapper15, Shervin Rabizadeh16, Ramnik Xavier17,18, Marla Dubinsky19, Jeffrey Hyams20, Subra Kugathasan3, Anil G Jegga1, Jonathan R Dillman1, Lee A Denson1. 1. Cincinnati Children's Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 2. Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Tel Aviv, Israel. 3. Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA. 4. The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 5. Cohen Children's Medical Center of New York, New Hyde Park, New York, USA. 6. University of California San Francisco, San Francisco, California, USA. 7. Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA. 8. The University of Chicago, Chicago, Illinois, USA. 9. Hasbro Children's Hospital, Providence, Rhode Island, USA. 10. Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 11. John Hopkins University, Baltimore, Maryland, USA. 12. IWK Health Centre, Halifax, Nova Scotia, Canada. 13. Indiana University School of Medicine, Indianapolis, Indiana, USA. 14. Texas Children's Hospital, Baylor College School of Medicine, Houston, Texas, USA. 15. Children's Hospital-Boston, Boston, Massachusetts, USA. 16. Cedars-Sinai Medical Center, Los Angeles, California, USA. 17. Broad Institute at Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 18. Massachusetts General Hospital, Cambridge, Massachusetts, USA. 19. Mount Sinai Hospital, New York, New York, USA. 20. Connecticut 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.
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.
Authors: Paul Shannon; Andrew Markiel; Owen Ozier; Nitin S Baliga; Jonathan T Wang; Daniel Ramage; Nada Amin; Benno Schwikowski; Trey Ideker Journal: Genome Res Date: 2003-11 Impact factor: 9.043
Authors: Daniel T Barkmeier; Jonathan R Dillman; Mahmoud Al-Hawary; Amer Heider; Matthew S Davenport; Ethan A Smith; Jeremy Adler Journal: Pediatr Radiol Date: 2015-12-05
Authors: Ryan W Stidham; Binu Enchakalody; Akbar K Waljee; Peter D R Higgins; Stewart C Wang; Grace L Su; Ashish P Wasnik; Mahmoud Al-Hawary Journal: Inflamm Bowel Dis Date: 2020-04-11 Impact factor: 5.325
Authors: Clara Moon; Megan T Baldridge; Meghan A Wallace; Carey-Ann D; Herbert W Virgin; Thaddeus S Stappenbeck Journal: Nature Date: 2015-02-16 Impact factor: 49.962
Authors: Shuai Zhao; Dina Dejanovic; Peng Yao; Shardul Bhilocha; Tammy Sadler; Anja Schirbel; Gail West; Genevieve Doyon; Rocio Lopez; Ren Mao; Satya Kurada; Sara El Ouali; Guntram Grassl; Paul L Fox; Michael Cruise; Daniel L Worthley; Carol de la Motte; Claudio Fiocchi; Florian Rieder Journal: Mucosal Immunol Date: 2020-02-04 Impact factor: 7.313
Authors: Ramnik J Xavier; Curtis Huttenhower; Jason Lloyd-Price; Cesar Arze; Ashwin N Ananthakrishnan; Melanie Schirmer; Julian Avila-Pacheco; Tiffany W Poon; Elizabeth Andrews; Nadim J Ajami; Kevin S Bonham; Colin J Brislawn; David Casero; Holly Courtney; Antonio Gonzalez; Thomas G Graeber; A Brantley Hall; Kathleen Lake; Carol J Landers; Himel Mallick; Damian R Plichta; Mahadev Prasad; Gholamali Rahnavard; Jenny Sauk; Dmitry Shungin; Yoshiki Vázquez-Baeza; Richard A White; Jonathan Braun; Lee A Denson; Janet K Jansson; Rob Knight; Subra Kugathasan; Dermot P B McGovern; Joseph F Petrosino; Thaddeus S Stappenbeck; Harland S Winter; Clary B Clish; Eric A Franzosa; Hera Vlamakis Journal: Nature Date: 2019-05-29 Impact factor: 49.962
Authors: Ilyssa O Gordon; Suha Abushamma; Jacob A Kurowski; Stefan D Holubar; Lei Kou; Ruishen Lyu; Florian Rieder Journal: J Crohns Colitis Date: 2022-06-24 Impact factor: 10.020