Cited by 964Gut microbiota and healthInflammasome and immune disordersImmune Response and Inflammation

Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling

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Levy, Maayan, Thaiss, Christoph A., Zeevi, David, Dohnalová, Lenka, Zilberman-Schapira, Gili, Mahdi, Jemal Ali, David, Eyal, Savidor, Alon +12 more·2015·Cell

Abstract

Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.

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Crossref · 10.1016/j.cell.2015.10.048

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  • Free taurine generated by deconjugation can enhance NLRP6 inflammasome activation and increase IL-18 production by the intestinal epithelium, supporting barrier function and maintenance.

    “free taurine generated by deconjugation can enhance the activation of the NLRP6 inflammasome and thereby increase production of IL-18 by the intestinal epithelium, which supports epithelial barrier function and maintenance (Levy et al., 2015).”
  • Spermine and histamine inhibit activation of the NLRP6 inflammasome, which regulates IL-18 secretion.

    “Spermine and the monoamine histamine both inhibit activation of the NLRP6 inflammasome, a protein complex expressed by epithelial cells that regulates IL-18 secretion.”
  • Exogenous polyamines can reduce release of IL-18, a cytokine that promotes epithelial repair and barrier function.

    “Levy et al. recently reported that exogenous polyamines can reduce the release of IL-18, a cytokine that promotes epithelial repair and barrier function.”
  • Taurine counteracts the effects of spermine and histamine, indicating a finely tuned balance of opposing bacterial stimuli.

    “taurine, another microbial metabolite that derives from host-produced bile acids (see below), counteracts the effects of spermine and histamine, indicating a finely tuned balance of opposing bacterial stimuli (Levy et al., 2015).”
  • NLRP6 inflammasome signaling is co-modulated by microbiota-derived metabolites, which regulates epithelial IL-18 secretion and AMP expression profiles.

    “NLRP6 inflammasome signaling is co-modulated by microbiota-derived metabolites, which regulates epithelial IL-18 secretion and AMP expression profiles.71”

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Authors
Levy, M., Thaiss, C. A., Zeevi, D., Dohnalová, L., Zilberman-Schapira, G., Mahdi, J. A., David, E., Savidor, A., Korem, T., Herzig, Y., Pevsner-Fischer, M., Shapiro, H., Christ, A., Harmelin, A., Halpern, Z., Latz, E., Flavell, R. A., Amit, I., Segal, E., & Elinav, E.
Affiliations
  • Weizmann Institute of Science (IL)
  • Ben-Gurion University of the Negev (IL)
  • University of Bonn (DE)
  • Tel Aviv University (IL)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Segal, Eran
  • Elinav, Eran
Venue
Cell
Publisher
Elsevier BV
Published
2015-12
Volume
163
Issue
6
Pages
1428-1443
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2188593832
Cited by
960
References
51
Citations by year
2026: 63 · 2025: 67 · 2024: 95 · 2023: 106 · 2022: 109 · 2021: 112 · 2020: 96 · 2019: 108 · 2018: 69 · 2017: 78 · 2016: 51 · 2015: 3
FWCI
29.08
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Cancer Institute (P30CA016359)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034989)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
gut microbiota, NLRP6 inflammasome, host-microbiome interactions, taurine, histamine, spermine, IL-18, antimicrobial peptides, dysbiosis, colitis, fecal microbiota transplantation, postbiotics, innate immune modulation, intestinal epithelium
MeSH terms
Animals, Colitis, Colon, Germ-Free Life, Mice, Inbred C57BL, Receptors, Cell Surface, Taurine, Inflammatory Bowel Diseases, Signal Transduction, Interleukin-18, Antimicrobial Cationic Peptides, Mice, Inflammasomes, Microbiota, Dysbiosis

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