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Intestinal Epithelial Cell Toll-like Receptor 5 Regulates the Intestinal Microbiota to Prevent Low-Grade Inflammation and Metabolic Syndrome in Mice
Open accessAbstract
Background & aims Mice lacking the receptor Toll-like receptor 5 (TLR5-null mice), which recognizes flagellin, have an altered intestinal microbiota composition compared with wild-type mice; they develop low-grade inflammation and metabolic syndrome and are prone to colitis. The relative roles of intestinal epithelial cell (IEC) vs dendritic cell (DC) TLR5 in mediating these phenotypes are not clear; modification of intestinal microbiota composition has been reported to reflect animal husbandry practices rather than loss of TLR5. We generated mice with specific disruption of Tlr5 in IECs or DCs by using a breeding scheme that allows comparison with cohoused siblings as controls.Methods We generated C57BL/6 mice with LoxP sites flanking Tlr5. These mice were crossed with mice expressing Cre recombinase, regulated by the villin or CD11c promoters, to generate mice that lacked expression of TLR5 by IECs (TLR5(ΔIEC)) or DCs (TLR5(ΔDC)), respectively. Tlr5(fl/fl) siblings were used as controls. On weaning, mice were housed by sex and genotype or by sex only (genotypes cohoused). Mice were examined for basal phenotypes, including microbiota composition; we also analyzed responses to pathobiont challenge, administration of dextran sodium sulfate, and high-fat diets.Results Similar to previous findings from TLR5-null mice, TLR5(ΔIEC) mice had low-grade inflammation (mild splenomegaly, shortened colons, and increased fecal levels of lipocalin 2), metabolic syndrome, and an inability to clear pathobionts and were prone to developing colitis compared with their sibling controls under both housing conditions. Development of this inflammation in the TLR5(ΔIEC) mice was eliminated by administration of antibiotics and associated with alterations in localization of microbiota and levels of fecal lipopolysaccharide and flagellin. The composition of the microbiota clustered more closely according to genotype than housing. Loss of TLR5 from DCs did not associate with development of inflammation-associated phenotypes or alterations in the composition of the microbiota but resulted in complete loss of flagellin-induced production of interleukin-22.Conclusions In mice, flagellin activation of TLR5 on DCs leads to production of interleukin-22. Expression of TLR5 on IECs regulates the composition and localization of the intestinal microbiota, preventing diseases associated with intestinal inflammation.
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“It was demonstrated in numerous reports from Dr Gewirtz’s group that expression and activation of TLR5 on IECs regulates the composition and localization of microbiota and prevents disease associated intestinal inflammation.165, 166, 167, 168”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [165]
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Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome
Chassaing, B., Koren, O., Goodrich, J. K., Poole, A. C., Srinivasan, S., Ley, R. E., & Gewirtz, A. T. (2015) · Nature · doi:10.1038/nature14232 · Cited by 2,055
Self-citationHuman gut microbiome: Hopes, threats and promises
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Regulation of Intestinal Barrier Function by Microbial Metabolites
Ghosh, S., Whitley, C. S., Haribabu, B., & Jala, V. R. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.02.007 · Cited by 835
Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes
Scheithauer, T. P. M., Rampanelli, E., Nieuwdorp, M., Vallance, B. A., Verchere, C. B., van Raalte, D. H., & Herrema, H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.571731 · Cited by 715
Zou, J., Chassaing, B., Singh, V., Pellizzon, M., Ricci, M. R., Flythe, M. D. D., Kumar, M. V., & Gewirtz, A. T. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.11.003 · Cited by 570
Metadata
- Authors
- Chassaing, B., Ley, R. E., & Gewirtz, A. T.
- Affiliations
- Cornell University (US)
- Georgia State University (US)
- Corresponding author
- Gewirtz, Andrew T.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 147
- Issue
- 6
- Pages
- 1363-1377.e17
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4253564
- OpenAlex
- W2090488505
- Cited by
- 326
- References
- 48
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 38 · 2023: 31 · 2022: 29 · 2021: 39 · 2020: 33 · 2019: 28 · 2018: 23 · 2017: 23 · 2016: 17 · 2015: 18 · 2014: 2
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK083890, DK099071)
- Crohn's and Colitis Foundation of America (DK083890, DK099071)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- TLR5, intestinal epithelial cells, dendritic cells, gut microbiota, flagellin, low-grade inflammation, metabolic syndrome, colitis, IL-22, lipopolysaccharide, pathobionts, DSS-induced colitis, high-fat diet, antibiotic therapy, cohousing, host-microbe interactions
- MeSH terms
- Animals, Colitis, Enteritis, Female, Flagellin, Intestinal Mucosa, Male, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Metabolic Syndrome, Toll-Like Receptor 4, Toll-Like Receptor 5, Diet, High-Fat, Microbiota
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