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Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis
Open accessAbstract
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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“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 118
- Issue
- 2
- Pages
- 229-241
- ISSN
- 0092-8674 (ISSN-L)
- 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
- bronze
- doi.org
- 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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