8
NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis.
Cell. 2011 May 27; 145:745-57
All selected articles haveThis article has been added to your saved articles
You can follow/unfollow articles via MyF1000 or via the article or browse pages.
24 May 2011
New Finding
DOI: 10.3410/f.10712956.11649054
This study shows that the enhanced susceptibility of inflammasome-deficient mice to chemically induced colitis correlates with an altered gut microbiota. Fascinatingly, these bacteria and disease susceptibility were transferred to co-housed wild-type mice.
Elinav and colleagues investigated whether mice...Continue reading
Elinav and colleagues investigated whether mice...Continue reading
This study shows that the enhanced susceptibility of inflammasome-deficient mice to chemically induced colitis correlates with an altered gut microbiota. Fascinatingly, these bacteria and disease susceptibility were transferred to co-housed wild-type mice.
Elinav and colleagues investigated whether mice lacking caspase-1 or its adaptor ASC showed altered sensitivity to dextran sodium sulfate (DSS)-induced colitis. Careful attention to detail uncovered that increased sensitivity was observed only if the knock-out (KO) mice were housed separately. Thus, wild-type mice co-housed with KO animals acquired the microbiota of the KOs and exhibited similar sensitivity to DSS.
Further use of KO mice revealed that the intracellular protein NLRP6 likely engages ASC for caspase-1-dependent interleukin-18 (IL-18) production in non-hematopoietic cells in the colon to preserve a less colitogenic microbiota. The nature of the stimulus activating NLRP6 is unknown. Regardless, in the absence of the NLRP6 inflammasome, certain bacterial phyla dominated and induced inflammation that was driven in large part by host production of the chemokine Ccl5.
These findings might explain why previous studies examining inflammasome function in the intestine have provided conflicting results. Who lives with whom (and at what facility) before and during an experiment becomes extremely important.
Elinav and colleagues investigated whether mice lacking caspase-1 or its adaptor ASC showed altered sensitivity to dextran sodium sulfate (DSS)-induced colitis. Careful attention to detail uncovered that increased sensitivity was observed only if the knock-out (KO) mice were housed separately. Thus, wild-type mice co-housed with KO animals acquired the microbiota of the KOs and exhibited similar sensitivity to DSS.
Further use of KO mice revealed that the intracellular protein NLRP6 likely engages ASC for caspase-1-dependent interleukin-18 (IL-18) production in non-hematopoietic cells in the colon to preserve a less colitogenic microbiota. The nature of the stimulus activating NLRP6 is unknown. Regardless, in the absence of the NLRP6 inflammasome, certain bacterial phyla dominated and induced inflammation that was driven in large part by host production of the chemokine Ccl5.
These findings might explain why previous studies examining inflammasome function in the intestine have provided conflicting results. Who lives with whom (and at what facility) before and during an experiment becomes extremely important.
Disclosures
Vishva Dixit and Kim Newton are employees of Genentech, Inc.
Add Comment
Dixit V and Newton K: F1000Prime Recommendation of [Elinav E et al., Cell 2011, 145:745-57]. In F1000Prime, 24 May 2011; DOI: 10.3410/f.10712956.11649054. F1000Prime.com/10712956#eval11649054
26 May 2011
Controversial, New Finding, Refutation, Technical Advance
DOI: 10.3410/f.10712956.11718054
This paper demonstrates that the intestinal flora can be massively influenced by the genotype, leading to downstream changes in the phenotype (in this case, chemical-induced colitis) and, thus, researchers need to be very careful with their choice of controls and their animal husbandry techniques.
This...Continue reading
This...Continue reading
This paper demonstrates that the intestinal flora can be massively influenced by the genotype, leading to downstream changes in the phenotype (in this case, chemical-induced colitis) and, thus, researchers need to be very careful with their choice of controls and their animal husbandry techniques.
This remarkable paper contains several key findings. First, the authors find that dextran sodium sulfate (DSS) colitis is strongly influenced by the microbial flora. They show that colitic flora develops (and is perpetuated) in certain knockout strains involved with a specific type of inflammasome. However, severe colitis in susceptible knockout mice (in this case, ASC knockouts that lack many types of inflammasomes) was reversed by co-housing with 'normal' wild-type mice. To test this finding in greater detail, Elinav et al. mapped the microbial flora of the colon in key strains. Their results show that a massive and flexible alteration in flora is controlled by the host genotype. Second, the authors demonstrated that an inflammasome consisting of ASC and NLRP6 has a critical role in processing interleukin (IL)-18 and this pathway controls the microbial flora, and in the absence of NLRP6, ASC or IL-18, excessive production of the chemokine CCL5 has a key pro-colitic activity. Third, the authors question previous publications claiming important roles of the NLRP3 in DSS colitis because, in their hands, co-habitation with wild-type controls caused attenuated colitis in the knockouts. Collectively, the results reported in this study argue that much more attention should be placed on animal husbandry techniques to ensure that the gut flora in different strains is 'equalized' prior to experimental evaluation.
This remarkable paper contains several key findings. First, the authors find that dextran sodium sulfate (DSS) colitis is strongly influenced by the microbial flora. They show that colitic flora develops (and is perpetuated) in certain knockout strains involved with a specific type of inflammasome. However, severe colitis in susceptible knockout mice (in this case, ASC knockouts that lack many types of inflammasomes) was reversed by co-housing with 'normal' wild-type mice. To test this finding in greater detail, Elinav et al. mapped the microbial flora of the colon in key strains. Their results show that a massive and flexible alteration in flora is controlled by the host genotype. Second, the authors demonstrated that an inflammasome consisting of ASC and NLRP6 has a critical role in processing interleukin (IL)-18 and this pathway controls the microbial flora, and in the absence of NLRP6, ASC or IL-18, excessive production of the chemokine CCL5 has a key pro-colitic activity. Third, the authors question previous publications claiming important roles of the NLRP3 in DSS colitis because, in their hands, co-habitation with wild-type controls caused attenuated colitis in the knockouts. Collectively, the results reported in this study argue that much more attention should be placed on animal husbandry techniques to ensure that the gut flora in different strains is 'equalized' prior to experimental evaluation.
Disclosures
None declared
Murray P: F1000Prime Recommendation of [Elinav E et al., Cell 2011, 145:745-57]. In F1000Prime, 26 May 2011; DOI: 10.3410/f.10712956.11718054. F1000Prime.com/10712956#eval11718054
15 Jun 2011
Wolf-Dietrich Hardt
F1000 Microbiology
Swiss Federal Institute of Technology (ETH),
Zürich, Switzerland.
F1000 Microbiology
Swiss Federal Institute of Technology (ETH),
Zürich, Switzerland.
New Finding
DOI: 10.3410/f.10712956.12212054
This exciting study establishes that the microbiota composition has profound effects on the host’s susceptibility to colitogenic insults, i.e. colitis after the treatment with the detergent dextran sodium sulfate (DSS). Importantly, Elinav et al. demonstrate that a colitogenic microbiota can be transferred...Continue reading
This exciting study establishes that the microbiota composition has profound effects on the host’s susceptibility to colitogenic insults, i.e. colitis after the treatment with the detergent dextran sodium sulfate (DSS). Importantly, Elinav et al. demonstrate that a colitogenic microbiota can be transferred between different conventionally reared mouse lines.
In the DSS model, gut inflammation is thought to be triggered by products released by the microbiota. In line with earlier data, wild-type mice from different sources had low-grade DSS colitis. Strikingly, co-housing with mice with a defective innate immune response (NLRP6-/-, caspase-1-/-, IL-18-/- or ASC-/- colonies) increased the susceptibility of wild-type mice to DSS colitis. This was traced back to the transfer of the peculiar knockout (KO) mouse gut flora into the wild-type animals. In fact, the degree of DSS colitis in these co-housed wild-type mice was as severe as that observed in the KO mice themselves. Thus, the microbiota composition seems to define the susceptibility towards DSS colitis. Furthermore, Elinav et al. demonstrate that the host’s mucosal chemokine (C-C motif) ligand 5 (CCL5) response may control this microbiota-mediated exacerbation.
The findings raise several issues of great importance to the field. How does a colitogenic gut flora emerge? Are inflammasome components involved in this? Future experiments monitoring the time course of shifts in the microbiota community structure and its colitogenic potential after embryo transfer or after separation of +/+ and -/- littermates (procedures to establish a defined, non-colitogenic 'starting' microbiota) will be of great importance for establishing whether NLRP6, Casp-1 and/or ASC can affect the development of particular microbiota compositions in a predictable fashion.
Importantly, Elinav et al.'s data demonstrate that both the microbiota and the host’s genotype can affect mucosal disease. Therefore, this study underlines the importance of excluding mouse colony-specific differences in the microbiota composition to avoid misinterpretation of the results. In order to attribute a phenotype to a specific host gene defect, wild-type littermate controls with a gut microbiota composition identical to that of the KO animals are indispensible in mouse mucosal immunology.
In the DSS model, gut inflammation is thought to be triggered by products released by the microbiota. In line with earlier data, wild-type mice from different sources had low-grade DSS colitis. Strikingly, co-housing with mice with a defective innate immune response (NLRP6-/-, caspase-1-/-, IL-18-/- or ASC-/- colonies) increased the susceptibility of wild-type mice to DSS colitis. This was traced back to the transfer of the peculiar knockout (KO) mouse gut flora into the wild-type animals. In fact, the degree of DSS colitis in these co-housed wild-type mice was as severe as that observed in the KO mice themselves. Thus, the microbiota composition seems to define the susceptibility towards DSS colitis. Furthermore, Elinav et al. demonstrate that the host’s mucosal chemokine (C-C motif) ligand 5 (CCL5) response may control this microbiota-mediated exacerbation.
The findings raise several issues of great importance to the field. How does a colitogenic gut flora emerge? Are inflammasome components involved in this? Future experiments monitoring the time course of shifts in the microbiota community structure and its colitogenic potential after embryo transfer or after separation of +/+ and -/- littermates (procedures to establish a defined, non-colitogenic 'starting' microbiota) will be of great importance for establishing whether NLRP6, Casp-1 and/or ASC can affect the development of particular microbiota compositions in a predictable fashion.
Importantly, Elinav et al.'s data demonstrate that both the microbiota and the host’s genotype can affect mucosal disease. Therefore, this study underlines the importance of excluding mouse colony-specific differences in the microbiota composition to avoid misinterpretation of the results. In order to attribute a phenotype to a specific host gene defect, wild-type littermate controls with a gut microbiota composition identical to that of the KO animals are indispensible in mouse mucosal immunology.
Disclosures
None declared
Hardt W and Maier L: F1000Prime Recommendation of [Elinav E et al., Cell 2011, 145:745-57]. In F1000Prime, 15 Jun 2011; DOI: 10.3410/f.10712956.12212054. F1000Prime.com/10712956#eval12212054
15 Jul 2011
New Finding
DOI: 10.3410/f.10712956.13035061
This paper details an important and well-executed series of experiments exploring the interrelationships between specific components of the inflammasome, the gut microbiome, and colitis.
The authors found that mice deficient in the inflammasome components apoptosis-associated speck-like protein containing...Continue reading
The authors found that mice deficient in the inflammasome components apoptosis-associated speck-like protein containing...Continue reading
This paper details an important and well-executed series of experiments exploring the interrelationships between specific components of the inflammasome, the gut microbiome, and colitis.
The authors found that mice deficient in the inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain-containing 6 (NLRP6) experienced more severe colitis after dextran sodium sulfate (DSS) exposure. This increased severity was also seen in interleukin-18 (IL-18)-deficient mice and in wild-type mice co-housed with ASC-, NLRP6-, or IL-18-deficient mice. The transfer of susceptibility was linked to an altered gut microbial community. The colitis-enhancing microbial community exacerbated DSS-induced inflammation by promoting increased induction of chemokine (C-C motif) ligand 5 (CCL5). CCL5-deficient mice acquired these colitis-enhancing microbes from NLRP6-deficient mice, but developed less severe colitis compared to wild-type mice co-housed with NLRP6. The microbiota of NLRP6-/- and ASC-/- mice were distinct from wild-type mice based on 16SrRNA-based analysis. Transmissible microbiomes associated with increased colitis included a member of the Prevotellacea family, a member of the TM7 phylum, and the named Prevotella genus.
Consistent with some prior studies, the authors found that IL-18 produced by the non-hematopoetic compartment was protective in the colitis model. Thus, the inflammasomes and IL-18 production are increasingly implicated in regulation of gut inflammatory responses. As reported here, these effects appear to be due to both maintenance of epithelial integrity and effects on the microbial community.
The authors found that mice deficient in the inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain-containing 6 (NLRP6) experienced more severe colitis after dextran sodium sulfate (DSS) exposure. This increased severity was also seen in interleukin-18 (IL-18)-deficient mice and in wild-type mice co-housed with ASC-, NLRP6-, or IL-18-deficient mice. The transfer of susceptibility was linked to an altered gut microbial community. The colitis-enhancing microbial community exacerbated DSS-induced inflammation by promoting increased induction of chemokine (C-C motif) ligand 5 (CCL5). CCL5-deficient mice acquired these colitis-enhancing microbes from NLRP6-deficient mice, but developed less severe colitis compared to wild-type mice co-housed with NLRP6. The microbiota of NLRP6-/- and ASC-/- mice were distinct from wild-type mice based on 16SrRNA-based analysis. Transmissible microbiomes associated with increased colitis included a member of the Prevotellacea family, a member of the TM7 phylum, and the named Prevotella genus.
Consistent with some prior studies, the authors found that IL-18 produced by the non-hematopoetic compartment was protective in the colitis model. Thus, the inflammasomes and IL-18 production are increasingly implicated in regulation of gut inflammatory responses. As reported here, these effects appear to be due to both maintenance of epithelial integrity and effects on the microbial community.
Disclosures
None declared
Lenz L and Schmidt R: F1000Prime Recommendation of [Elinav E et al., Cell 2011, 145:745-57]. In F1000Prime, 15 Jul 2011; DOI: 10.3410/f.10712956.13035061. F1000Prime.com/10712956#eval13035061
F1000Prime Recommendations, Dissents and Comments for [Elinav E et al., Cell 2011, 145:745-57]. In F1000Prime, 26 May 2013; F1000Prime.com/10712956
Only registered/signed-in users can make comments.
Sign in or Subscribe to create your user account and join the discussion.
Sign in or Subscribe to create your user account and join the discussion.
No comments yet.
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.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2011.04.022
PMID: 21565393
