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Original research
Host transcriptome signatures in human faecal-washes predict histological remission in patients with IBD
  1. Bella Ungar1,2,
  2. Miri Yavzori1,
  3. Ella Fudim1,
  4. Orit Picard1,
  5. Uri Kopylov1,
  6. Rami Eliakim1,
  7. Dror Shouval3,
  8. Yishai Levin4,
  9. Alon Savidor4,
  10. Shani Ben-Moshe2,
  11. Rita Manco2,
  12. Stav Dan2,
  13. Adi Egozi2,
  14. Keren Bahar Halpern2,
  15. Chen Mayer5,
  16. Iris Barshack5,
  17. Shomron Ben-Horin1,
  18. Shalev Itzkovitz2
  1. 1Department of Gastroenterology, Sheba Medical Center Tel Hashomer & Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel
  2. 2Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  3. 3Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, & Sackler School of Medicine, Tel-Aviv University, Petah Tikva, Israel
  4. 4The De Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
  5. 5Department of Pathology, Sheba Medical Center Tel Hashomer & Sackler School of Medicine, Tel-Aviv University, Ramat Gan, Israel
  1. Correspondence to Shalev Itzkovitz, Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; shalev.itzkovitz{at}weizmann.ac.il

Abstract

Background Colonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBDs), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features.

Aims To assess the utility of host transcriptomics of faecal wash samples of patients with IBD compared with controls.

Methods In this prospective cohort study, we obtained biopsies and faecal-wash samples from patients with IBD and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching faecal-washes, and associated them with endoscopic and histological inflammation status. We also performed faecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes.

Results We analysed biopsies and faecal washes from 39 patients (20 IBD, 19 controls). Host faecal-transcriptome carried information that was distinct from biopsy RNAseq and faecal proteomics. Transcriptomics of faecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3×10−12). Faecal-transcriptome had significantly higher statistical power in identifying histological inflammation compared with transctiptome of intestinal biopsies (150 genes with area under the curve >0.9 in faecal samples vs 10 genes in biopsy RNAseq). These results were replicated in a validation cohort of 22 patients (10 IBD, 12 controls). Faecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells.

Conclusions Faecal wash host transcriptome is a statistically powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscured using biopsy transcriptomics.

  • IBD
  • gastrointestinal immune response
  • histopathology
  • RNA expression

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. All data relevant to the study is included as online supplemental tables.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. All data relevant to the study is included as online supplemental tables.

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Footnotes

  • Contributors SI and BU conceived the study and drafted the manuscript; SI performed the bioinformatics analysis and is the guarantor of the study; BU was involved in study conception, performed experiments, analyses and interpretation of data; MY, EF, OP, YL and AS took part in sample retrieval and analysis. SB-M, RM, AE and KBH took part in study design and data analysis. UK, RE and DS participated in study design and drafting of the manuscript. IB and SB-H participated in data interpretation and in critical revision of the manuscript. SD and CM were involved in final revision of the manuscript. All authors have approved the final draft submitted.

  • Funding SI is supported by the Helen and Martin Kimmel Institute for Stem Cell Research, the Wolfson Family Charitable Trust & Wolfson Foundation, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Dr. Beth Rom-Rymer Stem Cell Research Fund, the Minerva Stiftung grant, the Israel Science Foundation grant No. 1486/16, the Broad Institute‐Israel Science Foundation grant No. 2615/18, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program grant No. 768956, the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award. Bella Ungar is supported by the Talpiot Medical Leadership Program, The Chaim Sheba Medical Center and by the Kitner Scholarship, Sheba Medical Center. Shomron Ben-Horin is supported by the Leona and Harry Helmsley Charitable Trust. The use of faecal host transcriptomics for evaluation of IBD disease pathology and outcome is currently being patented. Figure 1 was created with Biorender.com.

  • Competing interests SB-H received consulting and advisoryboard fees and/or research support from AbbVie, MSD, Janssen, Takeda andCellTrion. UK received speaker and advisory fees from: Abbvie, Jannsen, Gilead, MSD, Medtronic, Takeda and research support from: Jannsen, Medtronic, Takeda. RE received consultant and speaker fees from Janssen, Abbvie, Takeda and Medtronic. BU received consultation fees from Neopharm, Takeda, Janssen and Abbvie. DS received research support from Takeda and consultation and lecturing fees from AbbVie.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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