Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling
By M. Levy, Christoph A. Thaiss, D. Zeevi, L. Dohnalová, Gili Zilberman-Schapira, Jemal Ali Mahdi, Eyal David, A. Savidor, T. Korem, Yonatan Herzig and 10 more. Cell, 2015
859 citations recorded by the source corpus.
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.
Subfields: Biological Psychiatry, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/4e82cbb559e9c83c0f9c8aebb6b2d85a575b5993
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In Molecular Biology
Citations in the corpus
- Microbiota Diurnal Rhythmicity Programs Host Transcriptome Oscillations. (2016, neutral): “For antibiotic treatment, mice were given a combination of vancomycin (0.5 g/l), ampicillin (1 g/l), kanamycin (1 g/l), and metronidazole (1 g/l) in their drinking water for three weeks as previously described (Levy et al., 2015).”
- Interaction between microbiota and immunity in health and disease (2020, background): “NLRP6 inflammasome signaling is co-modulated by microbiota-derived metabolites, which regulates epithelial IL-18 secretion and AMP expression profiles.(71) Moreover, the NLRP6 inflammasome governs intestinal ‘sentinel’ goblet cell mucus secretion, which offers critical protection against pathogens.”
- The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “Of equal importance to the microbiome’s effects on host physiology is its role in the development and maintenance of local (Hooper et al., 2001; Levy et al., 2015) and systemic innate and adaptive immune function (Schirmer et al.”
- Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis (2019, background): “For example, NLRP6 deficiency leads to distorted colonization in intestinal microenvironment and possibly causes dysbiosis-driven diseases [23].”