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February 21, 2020
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TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice

Publicated to:Gut. 65 (6): 935-943 - 2016-06-01 65(6), DOI: 10.1136/gutjnl-2014-308323

Authors: Vlantis, K; Polykratis, A; Welz, PS; van Loo, G; Pasparakis, M; Wullaert, A

Affiliations

Flanders Interuniversity Institute for Biotechnology - Author
IRB Barcelona - Institute for Research in Biomedicine - Author
IRB, Barcelona, Spain - Author
Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany - Author
Univ Cologne, Ctr Mol Med CMMC, D-50931 Cologne, Germany - Author
Univ Cologne, Inst Genet, D-50931 Cologne, Germany - Author
Univ Ghent, Dept Biochem, Technol Pk 927, B-9052 Ghent, Belgium - Author
Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium - Author
Universiteit Gent - Author
University of Cologne - Author
VIB, Dept Med Prot Res, Technol Pk 927, B-9052 Ghent, Belgium - Author
VIB, Inflammat Res Ctr, B-9052 Ghent, Belgium - Author
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Abstract

© 2016, BMJ Publishing Group. All rights reserved. Objective: The gut microbiota modulates host susceptibility to intestinal inflammation, but the cell types and the signalling pathways orchestrating this bacterial regulation of intestinal homeostasis remain poorly understood. Here, we investigated the function of intestinal epithelial toll-like receptor (TLR) responses in the dextran sodium sulfate (DSS)-induced mouse model of colitis. Design: We applied an in vivo genetic approach allowing intestinal epithelial cell (IEC)-specific deletion of the critical TLR signalling adaptors, MyD88 and/or TIR-domain-containing adapter-inducing interferon-β (TRIF), as well as the downstream ubiquitin ligase TRAF6 in order to reveal the IEC-intrinsic function of these TLR signalling molecules during DSS colitis. Results: Mice lacking TRAF6 in IECs showed exacerbated DSS-induced inflammatory responses that ensued in the development of chronic colon inflammation. Antibiotic pretreatment abolished the increased DSS susceptibility of these mice, showing that epithelial TRAF6 signalling pathways prevent the gut microbiota from driving excessive colitis. However, in contrast to epithelial TRAF6 deletion, blocking epithelial TLR signalling by simultaneous deletion of MyD88 and TRIF specifically in IECs did not affect DSS-induced colitis severity. This in vivo functional comparison between TRAF6 and MyD88/TRIF deletion in IECs shows that the colitis-protecting effects of epithelial TRAF6 signalling are not triggered by TLRs. Conclusions: Intestinal epithelial TRAF6-dependent but MyD88/TRIF-independent and, thus, TLR-independent signalling pathways are critical for preventing propagation of DSS-induced colon inflammation by the gut microbiota. Moreover, our experiments using mice with dual MyD88/TRIF deletion in IECs unequivocally show that the gut microbiota trigger non-epithelial TLRs rather than epithelial TLRs to restrict DSS colitis severity.

Keywords

experimental colitisAnimalsBarrier functionColitisColonDextran sulfateDisease models, animalExperimental colitisGenetic markersGut inflammationHomeostasisIkk-betaIn-vivoInflammationInjuryIntestinal mucosaMiceMicrobiotaMouse modelMyeloid cellsOpposing functionsSignal transductionTnf receptor-associated factor 6Toll-like receptor-4Toll-like receptors

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Gut due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2016, it was in position 2/79, thus managing to position itself as a Q1 (Primer Cuartil), in the category Gastroenterology & Hepatology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 2.48. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.47 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 19.33 (source consulted: Dimensions Sep 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-09-10, the following number of citations:

  • WoS: 84
  • Scopus: 43
  • Europe PMC: 55

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-09-10:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 113.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 113 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 5.75.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 4 (Altmetric).
  • The number of mentions on Wikipedia: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Belgium; Germany.