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Cited by 4,251Immune Response and InflammationGut microbiota and healthGastrointestinal motility and disorders

Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis

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Rakoff-Nahoum, Seth, Paglino, Justin, Eslami-Varzaneh, Fatima, Edberg, Stephen, Medzhitov, Ruslan·2004·Cell
DOI 10.1016/j.cell.2004.07.002
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Abstract

Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.

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Crossref · 10.1016/j.cell.2004.07.002

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  • Mouse findings cannot be directly translated to patients because long-term use of the antibiotic cocktail would deplete almost all detectable commensal microbiota and includes nephrotoxic drugs such as neomycin.

    “However, findings from mice cannot be translated directly to patients as long-term administration of the employed antibiotic cocktail would be deleterious due to the depletion of almost all detectable commensal microbiota (>99.5%)73,104 and the inclusion of nephrotoxic drugs, such as neomycin.”

    From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [104]

  • TLRs are involved in host defense against pathogens, regulate the abundance of commensal microbes and maintain tissue integrity.

    “TLRs are involved in host defense against pathogens, regulate the abundance of commensal microbes and maintain tissue integrity.51”

    From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [51]

  • Antibiotic treatment worsens DSS-induced colitis in mice by depleting microbial ligands that signal through Toll-like receptors and maintain tissue homeostasis and repair mediators.

    “antibiotic-treatment worsens the severity of DSS-induced colitis in mice, by depleting microbial ligands that normally signal through Toll-like receptors (TLRs) and function to ensure expression of tissue homeostasis and repair mediators [16]”

    From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [16]

  • Previous studies have indicated that depletion of microbiota required a combination of at least 3 antibiotics for 3-4 weeks, and single antibiotics may not be sufficient to reduce total bacterial load.

    “This is not surprising, as previous studies have indicated that the depletion of microbiota required a combination of at least of 3 antibiotics for 3–4 weeks29, 30, and single antibiotics may not be sufficient to reduce the total bacterial load31.”

    From Gut Dysbiosis Is Linked to Hypertension (2015) · cites this paper as [29]

  • TLR signalling is important for tissue repair.

    “However, as TLR signalling is important for tissue repair113,114, caution must also be taken in devising a therapeutic strategy against TLR-mediated sterile inflammation.”

    From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [113]

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Authors
Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S., & Medzhitov, R.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Yale University (US)
Corresponding author
Medzhitov, Ruslan
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2004-07
Volume
118
Issue
2
Pages
229-241
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2004.07.002
OpenAlex
W2083089709
Cited by
4,251
References
63
Citations by year
2026: 110 · 2025: 105 · 2024: 115 · 2023: 156 · 2022: 201 · 2021: 204 · 2020: 206 · 2019: 178 · 2018: 200 · 2017: 179 · 2016: 211 · 2015: 199 · 2014: 234 · 2013: 243 · 2012: 234
FWCI
64.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (GM07205, T32GM007205)
  • National Institute of Allergy and Infectious Diseases (AI-46688)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
Toll-like receptors, commensal bacteria, intestinal epithelial homeostasis, host-microbe interactions, intestinal injury, microbial ligands, innate immunity, intestinal inflammation, host defense
MeSH terms
Animals, Antigens, Differentiation, Bacteria, Cells, Cultured, Chemotaxis, Leukocyte, Colon, Female, Heat-Shock Proteins, Homeostasis, Immunity, Immunity, Innate, Intestinal Mucosa, Ligands, Male, Membrane Glycoproteins, Receptors, Cell Surface, Receptors, Immunologic, Symbiosis, Cytokines, Mice, Knockout, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Mice, Myeloid Differentiation Factor 88

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