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Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling
Open accessAbstract
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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In the citing paper
“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).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Levy et al., 2015
In the citing paper
“Spermine and the monoamine histamine both inhibit activation of the NLRP6 inflammasome, a protein complex expressed by epithelial cells that regulates IL-18 secretion.”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Levy et al., 2015
In the citing paper
“Levy et al. recently reported that exogenous polyamines can reduce the release of IL-18, a cytokine that promotes epithelial repair and barrier function.”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Levy et al., 2015
In the citing paper
“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).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Levy et al., 2015
In the citing paper
“NLRP6 inflammasome signaling is co-modulated by microbiota-derived metabolites, which regulates epithelial IL-18 secretion and AMP expression profiles.71”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [71]
In the citing paper
“NLRP6 KO mice show dysbiosis and increased incidence of inflammation-associated CRC [135,136,137].”
From Gut Microbiota and Cancer: From Pathogenesis to Therapy (2019) · cites this paper as [136]
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Metadata
- 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
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 163
- Issue
- 6
- Pages
- 1428-1443
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5665753
- 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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 368 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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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