Article | Published:

Barrier function and epithelial cell biology

Intestinal epithelial Toll-like receptor 4 prevents metabolic syndrome by regulating interactions between microbes and intestinal epithelial cells in mice

Mucosal Immunology volume 11, pages 727740 (2018) | Download Citation

Abstract

Little is known about the pathogenesis of metabolic syndrome, although Toll-like receptor 4 (TLR4) has been implicated. We investigated whether TLR4 in the intestinal epithelium regulates metabolic syndrome by coordinating interactions between the luminal microbiota and host genes that regulate metabolism. Mice lacking TLR4 in the intestinal epithelium (TLR4ΔIEC), but not mice lacking TLR4 in myeloid cells nor mice lacking TLR4 globally, developed metabolic syndrome; these features were not observed in TLR4ΔIEC mice given antibiotics. Metagenomic analysis of the fecal microbiota revealed differences between TLR4ΔIEC and wild-type mice, while meta-transcriptome analysis of the microbiota showed that intestinal TLR4 affected the expression of microbial genes involved in the metabolism of lipids, amino acids, and nucleotides. Genes regulated by peroxisome proliferator-activated receptors (PPARs) and the antimicrobial peptide lysozyme were significantly downregulated in TLR4ΔIEC mice, suggesting a mechanism by which intestinal TLR4 could exert its effects on the microbiota and metabolic syndrome. Supportingly, antibiotics prevented both downregulation of PPAR genes and the development of metabolic syndrome, while PPAR agonists prevented development of metabolic syndrome in TLR4ΔIEC mice. Thus, intestinal epithelial TLR4 regulates metabolic syndrome through altered host-bacterial signaling, suggesting that microbial or PPAR-based strategies might have therapeutic potential for this disease.

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Acknowledgements

DJH is supported by R01GM078238 and R01DK083752 from the National Institutes of Health.

Author information

Affiliations

  1. Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, Maryland, USA

    • P Lu
    • , C P Sodhi
    • , Y Yamaguchi
    • , H Jia
    • , T Prindle Jr.
    • , W B Fulton
    •  & D J Hackam
  2. Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    • A Vikram
    •  & K J Bibby
  3. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    • M J Morowitz

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The authors declared no conflict of interest.

Corresponding author

Correspondence to D J Hackam.

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DOI

https://doi.org/10.1038/mi.2017.114

Author contributions

Conceptualization, PL, CPS, and DJH; Methodology, PL, CPS, and DJH; Investigation, PL, CPS, YY, HJ, TPJ, WBF, AV, KJB, MJM; Writing—Original Draft, PL; Writing—Review and Editing, PL, CPS and DJH; Funding acquisition, DJH; Resources, DJH; Supervision, DJH.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/mi