Article

NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell (Impact Factor: 32.24). 05/2011; 145(5):745-57. DOI: 10.1016/j.cell.2011.04.022
Source: PubMed

ABSTRACT

Inflammasomes are multiprotein complexes that function as sensors of endogenous or exogenous damage-associated molecular patterns. Here, we show that deficiency of NLRP6 in mouse colonic epithelial cells results in reduced IL-18 levels and altered fecal microbiota characterized by expanded representation of the bacterial phyla Bacteroidetes (Prevotellaceae) and TM7. NLRP6 inflammasome-deficient mice were characterized by spontaneous intestinal hyperplasia, inflammatory cell recruitment, and exacerbation of chemical colitis induced by exposure to dextran sodium sulfate (DSS). Cross-fostering and cohousing experiments revealed that the colitogenic activity of this microbiota is transferable to neonatal or adult wild-type mice, leading to exacerbation of DSS colitis via induction of the cytokine, CCL5. Antibiotic treatment and electron microscopy studies further supported the role of Prevotellaceae as a key representative of this microbiota-associated phenotype. Altogether, perturbations in this inflammasome pathway, including NLRP6, ASC, caspase-1, and IL-18, may constitute a predisposing or initiating event in some cases of human IBD.

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Available from: Richard A Flavell, Aug 18, 2014
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    • "Similarly to Il18 D/EC mice, DSS-treated Il18r D/EC mice were protected against weight loss, as compared to Il18r fl/fl littermates (Figure 1C). To more rigorously assess these effects in the presence of a ''colitogenic'' microbiota, Il18r D/EC and Il18r fl/fl were cohoused for 8 weeks with dysbiotic Il18 À/À mice in order to introduce transmissible dominantly colitogenic bacteria (Elinav et al., 2011) (Figure S2B). Despite an overall higher degree of inflammation, Il18r D/EC mice had reduced weight loss and lower colonoscopy score than control Il18r fl/fl mice (Figures 1D and 1E). "
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    ABSTRACT: The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp-/-;Il18rΔ/EC mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis.
    Full-text · Article · Dec 2015 · Cell
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    • "A dysbiotic state can be established in multiple ways, including intestinal infection (Lupp et al., 2007; Stecher et al., 2007) auto-inflammation (Devkota et al., 2012), altered host genetics (Goodrich et al., 2014), and dietary modulation (David et al., 2014). Remarkably , disease-promoting dysbiotic microbiota in multiple mouse models harbors dominance, upon fecal transfer, over a previously stable wild-type (WT) microbiota, leading to transferable disease susceptibility (Couturier-Maillard et al., 2013; Elinav et al., 2011; Garrett et al., 2007; Henao-Mejia et al., 2012; Ivanov et al., 2009). The host immune system participates in the organization of the ''healthy'' host-microbial interface, with mechanisms ranging from IgA and mucus secretion to AMP production (Hooper et al., 2012). "
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    ABSTRACT: Summary 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.
    Full-text · Article · Dec 2015 · Cell
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    • "We and others previously demonstrated that the NLRP3 inflammasome regulates intestinal inflammation and tumorigenesis in mice (Allen et al., 2010; Hirota et al., 2011; Zaki et al., 2010a, 2010b). Recent studies showed that the inflammasome in the gut can be activated by other PRRs, such as NLRP1 and NLRP6, which also contribute to intestinal homeostasis (Elinav et al., 2011; Williams et al., 2015). However, until now, DNA-dependent activation of the AIM2 inflammasome and its physiological relevance to intestinal homeostasis in the gut has not been reported. "
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    ABSTRACT: Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2−/− mice are highly susceptible to dextran sodium sulfate-induced colitis that is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2−/− mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1β and IL-18 production are compromised in Aim2−/− mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E. coli burden as well as colitis susceptibility in Aim2−/− mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis.
    Full-text · Article · Nov 2015 · Cell Reports
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