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Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Studies on NLRP6 predominate in the published literature. NLRP6 null mice develop more severe inflammation in DSS colitis, as do mice deficient in ASC. It was claimed that the altered microbiota seen in these null mice could transfer increased susceptibility to colitis to wild-type mice. NLRP null mice are also more susceptible to C. rodentium infection, attributable to changes in colonic goblet cells. Subsequent studies, however, cast doubt on some of these results. NRLP6 null mice and their control littermates (rather than co-housed mice) show no change in the microbiota or susceptibility to DSS colitis. This does not appear to be the case with NLRP12 null mice, since null littermates have a less diverse microbiota than their wild-type littermates.
The Microbiome – Role in Personalized Medicine
Published in David Perlmutter, The Microbiome and the Brain, 2019
It is now widely accepted that the status of the gut microbiome is linked to inflammatory cytokine production and alteration in metabolism. Disturbed gut microbiome composition is commonly referred to as dysbiosis and is linked to the increased production of inflammatory cytokines such as TNF-alpha, IFN-gamma, IL-1 beta, IL-6, and IL-17.37 These inflammatory cytokines are produced in response to the presence of metabolites from a dysbiotic microbiome, including palmitoleic acid metabolism and tryptophan degradation to tryptophol. The bacterial metabolites associated with dysbiosis shape the intestinal immune environment in part by regulating the NLRP6 inflammasome.38 One study of the immunomodulatory effect of 53 individual gut bacterial species found that most gut microbes exerted specialized, complementary, and redundant transcriptional effects. The research team behind this work concluded the following: “Microbial diversity in the gut ensures the robustness of the microbiota’s ability to generate a consistent immunomodulatory impact, serving as a highly important epigenetic system.”39 Imbalances in the composition of the microbiome can result in dysbiosis that can shift the immunomodulatory status into a Th1 dominant state that favors inflammation.
Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions
Published in Gut Microbes, 2018
Michail Mamantopoulos, Francesca Ronchi, Kathy D. McCoy, Andy Wullaert
Adding to the hypothesis that inflammasomes could be primary regulators of dysbiosis-associated diseases, Elinav et al. had shown that Nlrp6 deletion conferred increased susceptibility to DSS colitis secondary to intestinal microbial changes provoked by Nlrp6 deficiency.12 However, given our finding that Nlrp6 does not influence the gut microbiota composition, the host genetic effect of Nlrp6 on DSS colitis needed re-evaluation. Using the F2 Nlrp6−/− and F2 Nlrp6+/+ mice that showed no differences in gut microbiota composition, we could not observe any difference in DSS-induced colitis development between these genotypes.14 As such, our study showed that Nlrp6 neither affects intestinal microbiota composition nor predisposes mice to higher susceptibility to DSS-induced colitis. Therefore, whilst it is clear that microbial dysbiosis in some cases can provoke increased colitis, inflammasome deficiency does not drive a microbial dysbiosis capable of doing this. In addition, our DSS colitis results emphasize the importance of normalizing the gut microbiota between genotypes in order to reveal the physiological effect of a given host gene in DSS colitis.14,28
Transmissible inflammation-induced colorectal cancer in inflammasome-deficient mice
Published in OncoImmunology, 2019
Bo Hu, Gil Friedman, Eran Elinav, Richard A Flavell
NLRP6 is primarily expressed in the non-hematopoietic compartment, including intestinal epithelial cells, and has been implicated in host defense against certain bacteria.7 These and other results suggest that NLRP6 may play an important role in regulating the gut microbiota communities and maintaining intestinal tissue homeostasis. In support of this notion, we have recently shown that mice with perturbations in the NLRP6 inflammasome pathway featured a distorted microbiota composition, characterized by multiple microbial aberrations including overrepresentation of several bacterial taxa including Prevotellaceae and TM7 and under-representation of lactobacilli.11 This state of dysbiosis induced spontaneous intestinal auto-inflammation and enhanced susceptibility to chemically-induced colitis. Furthermore, dysbiosis in the NLRP6 inflammasome-deficiency setting was linked to an enhanced susceptibility to colorectal tumorigenesis in the AOM-DSS model, by promoting chronic inflammation characterized by IL-6 signaling dependent over-proliferation of intestinal epithelial cells.10 The dysbiotic microbiota was dominant over the wildtype (WT) microbiota, as it was fully transferable to WT mice horizontally upon prolonged co-habitation or by cross-fostering of newborn pups. This state of competitive dominance over the endogenous microbiota resulted in development of increased inflammation even in cohoused genetically-intact WT mice. Accordingly, enhanced CRC in this model was “infectious” in the sense that it could be fully transferrable to WT mice upon prolonged cohabitation. This interesting phenomenon suggests that at least in some settings, a dysbiotic microbiota may confer susceptibility to cancer in this model. Mechanistically, increased tumorigenesis was dependent on microbiota induced CCL5 (RANTES) driven inflammation, which in turn promoted epithelial IL-6 signaling pathway (Fig. 1). Of note, the bacteria of the family Prevotellaceae overrepresented in NLRP6 deficient mice were also found to expanded in the fecal microbiota in some patients with CRC compared to control subjects, suggesting this family may contain certain pathogenic bacterial species that promote inflammation associated intestinal tumorigenesis.12
A single cell survey of the microbial impacts on the mouse small intestinal epithelium
Published in Gut Microbes, 2022
Derek K.L. Tsang, Ryan J. Wang, Oliver De Sa, Arshad Ayyaz, Elisabeth G. Foerster, Giuliano Bayer, Shawn Goyal, Daniel Trcka, Bibaswan Ghoshal, Jeffrey L. Wrana, Stephen E. Girardin, Dana J. Philpott
To determine which cell clusters have a direct capacity to sense and respond to microbes, we annotated the expression profile of pattern recognition receptors (PRRs) and their adaptors within our integrated single-cell dataset. Across all epithelial cell lineages, PRRs were expressed at low levels and were not differentially expressed with the presence of microbiota in SPF mice (Figure. 2A). Tlr3, Nlrc4, Nlrp6 were the highest expressed PRRs along the crypt-villus axis, while Myd88 and Ticam1 were the highest expressed adaptors (Figure. 2A). Interestingly, Tlr4 and Tlr5 were not detected in any cells (Data not shown). Key crypt-villus axis distributions were observed with respect to the expression of Tlr3, Nlrc4, Nlrp6, Myd88, and Ticam1. Within the enterocyte lineages (TA2, V1-V2, V3-V4, and V5-V6), these clusters had the greatest expression and proportion of cells expressing PRRs and adaptors (Figure. 2A, B). In GCs, these genes are similarly expressed between GC1 and GC2, but expressed in a greater proportion of cells in GC1 relative to GC2 (Figure. 2A, B). This is a result of a smaller proportion of GC2 cells expressing these genes in greater abundance and suggests that there are two population of GCs differentially expressing PRRs. A similar observation was also made within the crypt compartment of ISC, PC, and TA1 cells, whereby a small proportion (<25%) of cells highly expressed these PRRs and adaptors (Figure. 2A, B). As expression of PRRs and their adaptors was elevated in a fraction of cells within the ISC, TA1 and PC clusters, we subclustered these populations to assess their expression profiles with greater resolution. Subclustering of the ISC, TA1, and PC clusters identified a population of high mitochondria-gene expressing enterocytes, EC (Supp Figure 3A, B). Mapping the expression of all PRRs, Tlr3 and its adaptor Ticam1 were more associated with TA cells than ISCs (Supp Figure 3C, D). Nlrp6 was expressed consistently across ISC, TA, and PCs (Supp Figure 3C, D) and Nlrc4 was strongly associated with PCs (Supp Figure 3C, D). To support these data, we validated the expression distribution of Tlr3, Ticam1, Nlrp6, and Nlrc4 in the jejunal/ileal crypt-villus axis. Nlrp6 was upregulated within the crypt and V1 region (Figure. 2C, D). Nlrc4 was expressed throughout the crypt and villus (Figure. 2C, D). Tlr3 and Ticam1 were upregulated within the crypt and V1 region (Figure. 2C, D). Taken together these findings suggest that progenitor cells exiting the crypt are transcriptionally primed for microbial sensing, that PRRs display regional specificity along the crypt-villus axis, and that expression of PRRs in the small intestinal epithelium is not significantly altered by microbial colonization.