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Asthma severity has been linked to exposure to gram-negative bacteria from the environment that are recognized by NOD1 receptor and are present in house dust mite (HDM) extracts. NOD1 polymorphism has been associated with asthma. We sought to evaluate whether either host or HDM-derived microbiota may contribute to NOD1-dependent disease severity. A model of HDM-induced experimental asthma was used and the effect of NOD1 deficiency was evaluated. Contribution of host microbiota was evaluated by fecal transplantation. Contribution of HDM-derived microbiota was assessed by 16S ribosomal RNA sequencing, mass spectrometry analysis, and peptidoglycan depletion of the extracts. In this model, loss of the bacterial sensor NOD1 and its adaptor RIPK2 improved asthma features. Such inhibitory effect was not related to dysbiosis caused by NOD1 deficiency, as shown by fecal transplantation of Nod1-deficient microbiota to wild-type germ-free mice. The 16S ribosomal RNA gene sequencing and mass spectrometry analysis of HDM allergen, revealed the presence of some muropeptides from gram-negative bacteria that belong to the Bartonellaceae family. While such HDM-associated muropeptides were found to activate NOD1 signaling in epithelial cells, peptidoglycan-depleted HDM had a decreased ability to instigate asthma in vivo. These data show that NOD1-dependent sensing of HDM-associated gram-negative bacteria aggravates the severity of experimental asthma, suggesting that inhibiting the NOD1 signaling pathway may be a therapeutic approach to treating asthma. [ABSTRACT FROM AUTHOR]

Background & Aims The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene−smoking interactions) that affect risk for Crohn’s disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD. Methods We used 55 Immunochip-wide datasets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10 −/− and Nod2 −/− mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction. Results We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P < 5.0 × 10 −5 ; heterogeneity Cochrane Q test P > .05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of Interleukin 10 (il10)-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke. Conclusions In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene−smoking interactions were confirmed in mice with disruption of Il10 and Nod2 —variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants. [ABSTRACT FROM AUTHOR]

Background Postoperative complications are relatively frequent in Crohn's disease (CD) and several risk factors have been identified. The influence of genetic factors, however is unknown. Methods CD patients who underwent CD-related bowel resection were identified from the “Nancy IBD cohort.” Postoperative complications were defined as intraabdominal infectious complications and non–intraabdominal infectious complications occurring within 90 days after operation. The influence of 203 single nucleotide polymorphisms on postoperative complication rates was analyzed. Results Of the 137 patients who had undergone a CD-related bowel resection in our cohort, postoperative complications occurred in 34 cases (24.8%). Postoperative intraabdominal infections occurred in 18 cases (13.1%): 12 had anastomotic leakage and 6 had intraabdominal abscesses. In multivariate analysis, current smoker status (odds ratio [OR], 2.71; 95% CI, 1.18–6.21; P = .02) and homozygosity for the risk allele (T) Nucleotide-binding Oligomerization Domain-containing protein 2 (rs5743289; NOD2; OR, 2.07 [95% CI 1.15–3.72]; P = .01) were independent risk factors of postoperative intraabdominal infectious complications. Current smoker status NOD2 homozygosity for the risk allele (T) were not associated with non–intraabdominal infectious complications. Conclusion Current smoker status was associated with increased risk of postoperative intraabdominal infectious complications. A novel association between the NOD2 allele and an increased risk of postoperative intraabdominal infectious complications was observed in this study. [ABSTRACT FROM AUTHOR]

Background and aims Post-operative recurrence is frequent in Crohn's disease. Genetic factors associated with post-operative recurrence remain poorly understood. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. Methods Crohn's disease patients who had at least one bowel resection were retrospectively identified from the “Nancy IBD cohort”. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan–Meier curves for time to surgical recurrence were developed for 200 genetic variants and analyzed with the log-rank test. Results 137 patients had at least 1 resection in our cohort: 38 had a surgical recurrence (28%). In multivariate analysis, current smoker status (OR 6.97, 95% CI 1.85–26.22, p = 0.004), post-operative complications after prior surgery (OR 2.72, 95% CI 1.02–7.22, p = 0.044), and Caspase recruitment domain-containing protein 8 (CARD8) homozygosity for the risk allele (OR 7.56, 95% CI 1.13–50.37, p = 0.036) remained significantly and independently associated with surgical recurrence. Conclusion Current smoker status was associated with increased risk of surgical recurrence. A novel association between CARD8 and increased risk of surgical recurrence in Crohn's disease was observed. CARD8 could be a new marker for risk stratification and prevention of recurrent surgery. [ABSTRACT FROM AUTHOR]

Background & Aims: The low calcium response V (LcrV) protein synthesized by gram-negative, pathogenic yersiniae participates in bacterial evasion of the host’s innate immune response by stimulating synthesis of the anti-inflammatory interleukin (IL)-10 and preventing the activation of proinflammatory cytokines. Methods: We genetically engineered the food-grade bacterium Lactococcus lactis to secrete the LcrV protein from the enteropathogenic species Yersinia pseudotuberculosis. The protective and therapeutic potential of orally administered LcrV-secreting L lactis was evaluated in 2 models of acute experimental colitis (induced by trinitrobenzene sulfonic acid [TNBS] and dextran sodium sulfate [DSS], respectively) in wild-type and knockout mice. Results: Oral administration of LcrV-secreting L lactis led to active delivery of LcrV and induction of IL-10 (via a Toll-like receptor 2–dependent pathway) in the colon and prevented TNBS-induced colitis, in contrast to the L lactis control not producing LcrV. Down-regulation of tissue inflammatory markers correlated well with the reduction in damage to the colonic mucosa. In contrast, TNBS-induced colitis was not prevented in IL-10−/− mice pretreated with LcrV-secreting L lactis, thus showing that IL-10 is required for LcrV protection. Administration of LcrV-secreting L lactis also proved to be very effective in preventing and treating acute DSS-induced colitis. Conclusions: LcrV-secreting L lactis decreased experimentally induced intestinal inflammation in 2 murine models of colitis. This novel approach highlights the potential of using pathogen-derived immunomodulating molecules in vivo as novel therapeutics for inflammatory bowel diseases. [Copyright &y& Elsevier]

Several clinical and biological phenotypes define complex diseases such as inflammatory bowel disease (IBD). There is a critical role of the caspase recruitment domain protein 15/nucleotide-binding oligomerization protein 2–dependent (CARD15-NOD2) sensing of bacterial cell wall components in health and disease. The current etiologic model for IBD emphasizes an interaction between susceptibility and modifier genes along with environmental factors. Together, these lead to disease progression. However, further work should clarify the pathophysiological mechanisms leading to IBD and how innate immune signaling confers susceptibility to intestinal inflammation. This is a prerequisite for rational clinical management of IBD. Genetic, functional, serologic testing and development of therapeutics in IBD are discussed. [Copyright &y& Elsevier]

Recognition of pathogenic bacteria by mammalian hosts is largely mediated by membrane-bound Toll-like receptors (TLRs). Recently, a family of cytosolic proteins, termed NODs, with homology to plant disease-resistance gene products has been implicated in sensing microbes within the cytosol. The role of NOD family members in host defense is largely unknown. However, a recent report revealed that Nod1 is a crucial sensor for certain enteroinvasive bacteria that avoid TLR signaling. This finding suggests that Nod1 plays an important role in the initial recognition of pathogenic bacteria at epithelial surfaces, such as the gut, where innate immune responses to commensal bacteria must be avoided. [Copyright &y& Elsevier]

Candida albicans is a diploid fungus that colonizes the gastrointestinal tract asymptomatically in a large proportion of the human population, but can cause life-threatening conditions in immunocompromised patients. Recent immunological investigations have revealed the Nod-like receptor pyrin domain-containing protein 3 (NLRP3) to be a cytosolic surveillance mechanism against germinating Candida. These observations point to the idea of a molecular link between Candida and a spectrum of auto-inflammatory diseases. When excessive activation of NLRP3 occurs, it can confer resistance against disseminating Candida infection but might also cause NLRP3-associated periodic syndromes. Alternatively, we propose a pathophysiological model whereby a defective NLRP3-coupled inflammasome can result in enhanced mucosal colonization of granuloma-provoking microorganisms, including C. albicans, precipitating the formation of Crohn''s disease-associated inflammatory lesions. [Copyright &y& Elsevier]

• Composition of the gut microbiome modulates cancer immune set-points. • Microbiome may trigger immune system to observe more systemic abscopal effect. • Current evidence suggests that the gut microbiome influences radiotherapy efficacy. • Gut microbiome is a key modulator in radiation-induced gastro-intestinal mucositis. Radiation therapy (RT) is an essential component of therapy either curative or palliative armamentarium in oncology, but its efficacy varies considerably among patients through many extrinsic and intrinsic mechanisms of the tumour, which are beginning to be better understood. Recent studies have shown that the gut microbiome represents a key factor in the modulation of the systemic immune response and consequently on patients' outcome. Moreover, the emergence of biomarkers that are derived from the gut microbiota has fuelled the development of adjuvant strategies for patients treated with immunotherapy in combination or not with RT. Despite progress in development of more precise radiotherapy techniques, almost all patients undergoing RT to the abdomen, pelvis, or rectum develop acute adverse events as a consequence of several dose-limiting parameters such as the location of irradiation that may subsequently damage normal tissue including the intestinal epithelium. Several lines of evidence in preclinical models identified that vancomycin improves RT-induced gastrointestinal toxicities such as diarrhea and oral mucositis. In order to gain further insight into this rapidly evolving field, we have systematically reviewed the studies that have described how the gut microbiome may directly or indirectly modulate RT efficacy and its gastro-intestinal toxicities. Lastly, we outline current knowledge gaps and discuss potentially more satisfactory therapeutic options to restore the functionality of the gut microbiome of patients treated with RT. [ABSTRACT FROM AUTHOR]

Abstract: NOD2 mutations are associated with the development of granulomatous inflammatory diseases, such as early-onset sarcoidosis (EOS), Blau syndrome (BS) and Crohn''s disease (CD). As a pathogen-recognition molecule for muramyl dipeptide (MDP), NOD2 controls both innate and adaptive immune responses, through the regulation of cytokines, chemokines and antimicrobial peptides production. Notably, Nod2-deficient mice experienced increased susceptibility to enteric infection and to antigen-specific colitis. Furthermore, mutant mice bearing the orthologue of the major CD-associated NOD23020ins allele showed increased susceptibility to DSS-induced colitis. However, many questions remain open. (i) Is antimicrobial function deficiency sufficient to initiate the development of CD? (ii) How impaired and mutant NOD2 might lead to increased adaptive immune response? (iii) How do the other disease-associated NOD2 mutations contribute to the development of chronic intestinal inflammation? Whatever the relevant mechanism(s), it provides a casual link between abnormal bacterial sensing and development of inflammatory disorders. Further work should now focus on restoring abnormal NOD2 function by modulating antimicrobial function and regulatory mechanisms of the adaptive immune system. [Copyright &y& Elsevier]

Defensins and cathelicidins are prevalent and essential gastrointestinal cationic antimicrobial peptides (CAPs). However, these defensive peptides are not infallible because certain enteropathogens can overcome their protective function. Furthermore, impaired defensin synthesis has been linked to the occurrence of Crohn''s disease (CD), a chronic inflammatory bowel disease. Recently, defective bacterial sensing through NOD1 and NOD2 has been related to reduced defensin production, CD predisposition and susceptibility to enteric infection. Hence, we propose that microbial sensors at the gut interface monitor the levels of these effector peptides, which might function as ’danger’ signals to confer tolerance and alert immunocytes. Further work is required to clarify how gastrointestinal CAPs are regulated and to assess their role in maintaining epithelial homeostasis and triggering adaptive immunity. [Copyright &y& Elsevier]

Shigella-induced macrophage cell death is an important step in the induction of acute inflammatory responses that ultimately lead to bacillary dysentery. Cell death was previously reported to be dependent upon the activation of caspase-1 via interaction with IpaB secreted by intracellular Shigella, but in this study, we show that Shigella infection of macrophages can also induce cell death independent of caspase-1 or IpaB activity. Time-lapse imaging and electron microscopic analyses indicated that caspase-1-dependent and -independent cell death is morphologically indistinguishable and that both resemble necrosis. Analyses of Shigella mutants or Escherichia coli using co-infection with Listeria suggested that a component common to Gram-negative bacteria is involved in inducing caspase-1-independent cell death. Further studies revealed that translocation of bacterial lipid A into the cytosol of macrophages potentially mediates cell death. Notably, cell death induced by cytosolic bacteria was TLR4-independent. These results identify a novel cell death pathway induced by intracellular Gram-negative bacteria that may play a role in microbial-host interactions and inflammatory responses. [ABSTRACT FROM AUTHOR]

Discusses the activation of the nuclear factor-kappa b pathway through the peptidoglycan general sensor Nod2. Association of Nod2 mutations to Crohn's disease; Detection of the bioactive peptidoglycan motif in bacteria; Characterization of Nod2 as a pathogen-recognition molecule which detects muramyl dipeptide.