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Looking beyond histological healing in ulcerative colitis: towards the establishment of a molecular signature for quiescent but progressive disease
  1. Mathias Chamaillard1,2,3,4,
  2. Jean-Baptiste Chevaux5,
  3. Laurent Peyrin-Biroulet5
  1. 1University Lille Nord de France, Lille, France
  2. 2Center for Infection and Immunity of Lille, Institut Pasteur de Lille, Lille, France
  3. 3Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, Lille, France
  4. 4U1019 Team 7, Institut National de la Santé et de la Recherche Médicale, Lille, France
  5. 5U954, Institut National de la Santé et de la Recherche Médicale, Vandœuvre-lès-Nancy, France
  1. Correspondence to Dr Mathias Chamaillard,U1019 Team 7, Institut National de la Santé et de la Recherche Médicale, BP 245, Lille cedex F-59019, France; mathias.chamaillard{at}inserm.fr

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Ulcerative colitis (UC) is a chronic, disabling, progressive inflammatory bowel disease (IBD).1 The condition is associated with an increased risk of colorectal cancer and other serious structural and functional consequences in the long term,1 which include the development of colonic strictures, dysmotility, anorectal dysfunction and impaired permeability.1 In this context, mucosal healing has emerged as a new therapeutic goal in the prevention of the long-term complications of IBD.2 ,3 Indeed, a growing body of evidence indicates that mucosal healing improves the natural course of the disease by lowering the need for colectomy and thus reducing hospitalisation rates in these patients.3 Histological healing is considered as the ultimate marker of quiescent disease activity in UC4 and thus an improvement in the patient's quality of life. However, it is not yet known whether persistent gene expression changes in intestinal tissues are related to incomplete histological healing in asymptomatic UC.

Planell et al5 have attempted to identify a transcriptional signature associated with the involved mucosa in active/remitting UC patients (when compared with uninvolved mucosa in patients or healthy mucosa from non-IBD subjects). By using a whole-genome approach, the researchers identified distinct sets of differentially expressed genes when comparing remitting UC patients with either active UC patients or non-IBD controls. A total of 3700 gene expression changes in active UC patients (relative to non-IBD controls) were also present in remitting UC patients, despite the complete endoscopic and histological healing observed in the latter group. Gene ontology analysis revealed that 945 of the above-mentioned 3700 differentially expressed genes were primarily involved in fatty acid and protein metabolism, movement, assembly and organisation of cells, actin filament formation and the proliferation of colon cancer. Planell et al5 suggested that the changes constituted a core transcriptional signature of quiescent UC by validating a set of 52 of the 945 genes through quantitative RT-PCRs in an independent cohort of patients.

The clinical observation of incomplete molecular mucosal healing in quiescent UC prompted the hypothesis whereby UC is a progressive disease rather than a relapsing-remitting intestinal illness. From a mechanistic viewpoint, several clinical lessons emerge from the study by Planell and collaborators.5 One may consider that the colonic mucosa of genetically predisposed patients may be intrinsically defective in terms of either repairing damaged epithelium or turning off a stress response that progressively damages the tissue. Several differentially expressed molecules involved in the regulation of cell-cycle progression and differentiation were identified (such as the S100 calcium binding protein P and the regenerating islet-derived family member 4, both of which are overexpressed in colorectal cancer). Likewise, immunohistochemical analysis revealed enhanced expression of the serpin peptidase inhibitor, clade B (ovalbumin), member 5, which is also involved in tumorigenesis. Alternatively, the colonic mucosa in remitting UC patients may fail to (i) restore the protective, mucosal-associated microbial architecture that is required for complete mucosal healing and/or (ii) sequester commensals at the epithelial surface, which may then promote fibrosis and neoplastic progression. It is noteworthy that in samples from remitting UC patients, Planell and collaborators observed low expression levels of several molecules involved in host defence (including β-defensin-1).5–7 More importantly, molecular analyses of the diversity of mucosal-associated bacterial commensals have revealed the presence of persistent dysbiosis within the colonic mucosa of both UC patients with flares and those in remission.8–10 In line with this hypothesis, Planell et al5 found that expression of the butyrate receptor (required for providing colonocytes with a source of energy in response to commensals) was impaired in UC patients. However, it now remains to be seen whether the above-mentioned dysbiosis is related to this unique transcriptional signature for remitting UC. Furthermore, several fundamental questions remain to be answered: does this UC-in-remission transcriptional signature have clinical value for either monitoring and/or predicting disease progression? And will it help to refine the interventional window for clinical recovery?

Planell et al5 have thus identified a new transcriptional signature associated with the involved mucosa of UC patients in remission. This signature may conceivably be of relevance in the discovery and development of more effective therapies for UC. The main limitation of the study of Planell et al5 is the lack of longitudinal follow-up required to assess the molecular signature's prognostic value in terms of disease outcomes (ie, the risk of developing colorectal cancer and other long-term complications, such as fibrosis and loss of intestinal function). A second limitation relates to the fact that the authors could not evaluate the impact of UC treatments, since biologics are known to induce dramatic changes in the expression profiles of mucosal genes.11 Other questions remain. Should this molecular signature be used as a new guideline in clinical practice and should we optimise therapy according to changes in these molecular pathways? In other words, should we develop early, interventional strategies aimed at modifying the course of UC on the basis of these findings?

References

Footnotes

  • Contributors All authors were involved in preparing and editing the final manuscript and writing the commentary.

  • Funding MC is supported, in part, by grants from FEDER, Région Nord/Pas-de-Calais, Agence Nationale de la Recherche (Biopanex), Institut Nationale du Cancer (INCa_6000) and Fondation pour la Recherche Médicale.

  • Competing interests None.

  • Provenance and peer review Commissioned; externally peer reviewed.

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