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Cited by 229Immune Response and InflammationInflammatory Bowel DiseaseGastrointestinal motility and disorders

Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation

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Rhee, Sang Hoon, Im, Eunok, Riegler, Martin, Kokkotou, Efi, O'Brien, Michael, Pothoulakis, Charalabos·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0502174102PMC PMC1224619
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Abstract

Commensal and enteroinvasive microbes in the human gut release bacterial flagellin, a specific microbial ligand of Toll-like receptor 5 (TLR5). However, the pathophysiological role of bacterial flagellin in gastrointestinal inflammation has not been determined. Here we evaluated the role of bacterial flagellin using native human colonic mucosa and the mouse colitis model of dextran sulfate sodium (DSS). We demonstrate that, in intact human colonic mucosa, the flagellin/TLR5 response occurs only after exposure to the basolateral, not the apical, surface, implying a basolaterally polarized TLR5 response in human colonic mucosa. In this context, flagellin exposure to injured colonic mucosa due to DSS administration in mice resulted in a TLR5-associated response evaluated by in vivo activation of mitogen-activated protein kinase/extracellular signal-related kinase 1/2 (MEK1/2) and elevated IL-6, TNF-α, and keratinocyte-derived chemokine production, whereas intact colonic mucosa did not respond to flagellin. Moreover, flagellin exposure to injured mouse colon in vivo , but not to intact colon, also significantly aggravated colonic inflammation, increased mouse mortality, and enhanced histopathological damage in the colonic mucosa. However, the TLR2-specific agonist, peptidoglycan or lipoteichoic acid, did not cause an inflammatory response in intact or DSS-injured mouse colon. Furthermore, intracolonic flagellin administration in mice causes severe apoptosis in colonic epithelium disrupted by DSS administration. These data suggest that intracolonic flagellin via TLR5 engagement is able to elicit inflammatory responses in disrupted colon, whereas the normal colon is not responsive to bacterial flagellin. These results demonstrate that bacterial flagellin plays an important role in the development and progress of colitis.

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  • The enteric microbiota can directly influence gut homeostasis by the regulation of bowel motility and modulation of intestinal pain, immune responses, and nutrient processing.

    “The enteric microbiota can directly influence gut homeostasis by the regulation of bowel motility and modulation of intestinal pain, immune responses, and nutrient processing.8-10”

    From Principles and clinical implications of the brain-gut-enteric microbiota axis (2009) · cites this paper as [9]

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References 32 · Cited by 229

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Authors
Rhee, S. H., Im, E., Riegler, M., Kokkotou, E., O'Brien, M., & Pothoulakis, C.
Affiliations
  • Boston University (US)
  • Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114; Vienna General Hospital, Waehrigner Guertel 18-20, A-1090 Vienna, Austria; and Department of Pathology, Boston University School of Medicine, Boston, MA 02218
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-09-12
Volume
102
Issue
38
Pages
13610-13615
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0502174102
PMC
PMC1224619
OpenAlex
W1965938761
Cited by
229
References
32
Citations by year
2026: 3 · 2025: 8 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 4 · 2019: 4 · 2018: 8 · 2017: 10 · 2016: 8 · 2015: 12 · 2014: 16 · 2013: 14 · 2012: 18
FWCI
5.79
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • Crohn's and Colitis Foundation of America
  • Crohn's and Colitis Foundation
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
TLR5, bacterial flagellin, colonic inflammation, colitis, DSS-induced colitis, colonic mucosa, MEK1/2 signaling, interleukin-6, TNF-α, keratinocyte-derived chemokine, epithelial apoptosis, TLR2, peptidoglycan, lipoteichoic acid, commensal bacteria
MeSH terms
Animals, Colitis, Colon, Flagellin, Humans, Inflammation, Intestinal Mucosa, Lipopolysaccharides, Male, Membrane Glycoproteins, Peptidoglycan, Receptors, Cell Surface, Teichoic Acids, Tumor Necrosis Factor-alpha, Signal Transduction, Keratinocytes, Interleukin-6, Apoptosis, Chemokines, Tissue Culture Techniques, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Toll-Like Receptors, Toll-Like Receptor 2, Toll-Like Receptor 5, Mice

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