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Summary Colonization resistance by gut microbiota is a fundamental phenomenon in infection prevention and control. Hospitalized patients may be exposed to multi-drug-resistant bacteria when hand hygiene compliance among healthcare workers is not adequate. An additional layer of defence is provided by the healthy gut microbiota, which helps clear the exogenous bacteria and acts as a safety net when hand hygiene procedures are not followed. This narrative review focuses on the role of the gut microbiota in colonization resistance against multi-drug-resistant bacteria, and its implications for infection control. The review discusses the underlying mechanisms of colonization resistance (direct or indirect), the concept of resilience of the gut microbiota, the link between the antimicrobial spectrum and gut dysbiosis, and possible therapeutic strategies. Antimicrobial stewardship is crucial to maximize the effects of colonization resistance. Avoiding unnecessary antimicrobial therapy, shortening the antimicrobial duration as much as possible, and favouring antibiotics with low anti-anaerobe activity may decrease the acquisition and expansion of multi-drug-resistant bacteria. Even after antimicrobial therapy, the resilience of the gut microbiota often occurs spontaneously. Spontaneous resilience explains the existence of a window of opportunity for colonization of multi-drug-resistant bacteria during or just after antimicrobial therapy. Strategies favouring resilience of the gut microbiota, such as high-fibre diets or precision probiotics, should be evaluated.

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International audience; Mitochondrial dysfunctions are implicated in several pathologies, such as metabolic, cardiovascular, respiratory, and neurological diseases, as well as in cancer and aging. These metabolic alterations are usually assessed in human or murine samples by mitochondrial respiratory chain enzymatic assays, by measuring the oxygen consumption of intact mitochondria isolated from tissues, or from cells obtained after physical or enzymatic disruption of the tissues. However, these methodologies do not maintain tissue multicellular organization and cell-cell interactions, known to influence mitochondrial metabolism. Here, we develop an optimal model to measure mitochondrial oxygen consumption in heart and lung tissue samples using the XF24 Extracellular Flux Analyzer (Seahorse) and discuss the advantages and limitations of this technological approach. Our results demonstrate that tissue organization, as well as mitochondrial ultrastructure and respiratory function, are preserved in heart and lung tissues freshly processed or after overnight conservation at 4 °C. Using this method, we confirmed the repeatedly reported obesity-associated mitochondrial dysfunction in the heart and extended it to the lungs. We set up and validated a new strategy to optimally assess mitochondrial function in murine tissues. As such, this method is of great potential interest for monitoring mitochondrial function in cohort samples.

The development of nanotechnologies is leading to greater abundance of engineered nanoparticles (EN) in the environment, including in the atmospheric air. To date, it has been shown that the most prevalent EN found in the air are silver (Ag), titanium dioxide (TiO

Graphical abstract Characteristics of host-microbiota interactions in asthmatic children favor asthma attacks and may allow to define asthma endotypes. This knowledge offers promising perspectives to treat asthmatic children using precision medicine, Exacerbations are a main characteristic of asthma. In childhood, the risk is increasing with severity. Exacerbations are a strong phenotypic marker, particularly of severe and therapy-resistant asthma. These early-life events may influence the evolution and be involved in lung function decline. In children, asthma attacks are facilitated by exposure to allergens and pollutants, but are mainly triggered by microbial agents. Multiple studies have assessed immune responses to viruses, and to a lesser extend bacteria, during asthma exacerbation. Research has identified impairment of innate immune responses in children, related to altered pathogen recognition, interferon release, or anti-viral response. Influence of this host-microbiota dialog on the adaptive immune response may be crucial, leading to the development of biased T helper (Th)2 inflammation. These dynamic interactions may impact the presentations of asthma attacks, and have long-term consequences. The aim of this review is to synthesize studies exploring immune mechanisms impairment against viruses and bacteria promoting asthma attacks in children. The potential influence of the nature of infectious agents and/or preexisting microbiota on the development of exacerbation is also addressed. We then discuss our understanding of how these diverse host-microbiota interactions in children may account for the heterogeneity of endotypes and clinical presentations. Finally, improving the knowledge of the pathophysiological processes induced by infections has led to offer new opportunities for the development of preventive or curative therapeutics for acute asthma. A better definition of asthma endotypes associated with precision medicine might lead to substantial progress in the management of severe childhood asthma.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. The major bacterial cause of COPD exacerbations is non-typeable Haemophilus influenzae (NTHi). This susceptibility to infection involves a defective production of interleukin (IL)-22 which plays an important role in mucosal defense. Prophylactic administration of flagellin, a Toll-like receptor 5 (TLR5) agonist, protects healthy mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might prevent COPD exacerbations due to NTHi. Mice were chronically exposed to cigarette smoke and then infected with NTHi. According our preventive or therapeutic protocol, flagellin was administered intraperitoneally. Cigarette smoke-exposed mice treated with flagellin showed a lower bacterial load in the airways, the lungs and the blood. This protection was associated with an early neutrophilia, a lower production of pro-inflammatory cytokines and an increased IL-22 production. Flagellin treatment decreased the recruitment of inflammatory cells and the lung damages related to exacerbation. Protective effect of flagellin against NTHi was altered by treatment with anti-IL-22 blocking antibodies in cigarette smoke-exposed mice and in Il22−/− mice. Flagellin treatment also amplified the production of the β-defensin2 anti-bacterial peptides. This study shows that stimulation of innate immunity by a TLR5 ligand is a potent antibacterial treatment in cigarette smoke exposed mice, suggesting innovative therapeutic strategies against acute exacerbation in COPD.

Mitochondrial metabolic dysfunctions are implicated in several pathologies such as heart, lung, neurological or cancer diseases. These metabolic alterations are usually assessed by enzymatic assays of the mitochondrial respiratory chain or by measuring oxygen consumption in mitochondria isolated from tissues or in cells obtained by physical or enzymatic disruption of tissues. These methodologies do not maintain the multi-cellular organization of tissue and the cell-cell interactions known to influence the mitochondrial metabolism. In this study, we proposed a new method to evaluate mitochondrial oxygen consumption from heart or lung tissue using XF24 Seahorse. Our results demonstrate that tissue organisation, mitochondrial ultrastructure, mitochondrial network and oxidative phosphorylation level, are preserved either from freshly collected tissue or after overnight conservation at 4°C. We validated in heart or lung tissue from mice under physiological (low fat diet) or pathological conditions (high fat diet).

Introduction: Smoking and unhealthy diet (SCUD) are risk factors involved in chronic obstructive pulmonary disease or obesity. Our aim is to better describe the impact of cigarette smoke (CS), associated with High Fat Diet (HFD), on pulmonary, intestinal and metabolic homeostasis and to identify physiopathologic mechanisms. Methods: C57Bl6 mice were subjected for 18 weeks to a HFD at 45% Kcal vs Low Fat Diet (LFD) at 10% Kcal. After 4 weeks, mice were exposed to CS or to filtered air. Lung function, anatomic, inflammatory and immune alterations as well as multi-omics studies were performed in these compartments. Results: SCUD revealed cumulative effect on the lung, with emphysema, tissues damage and immune cell recruitment. HFD induced weight gain, insulin resistance and glucose intolerance whereas CS limited these negative effects. However, SCUD induced visceral fat accumulation and inflammation vs HFD alone, associated with a specific metabolomics signature in the serum. Transcriptome analysis essentially revealed a HFD-related signature. Colon damage was moderate. However, metagenomics and metabolomics analyses in the caecum showed a specific signature due to SCUD, associated with some modifications in the colon transcriptoma. Conclusion: These results identify SCUD impacts on lung, metabolic and intestinal functions and reveal specific signatures related to combined exposure to unhealthy diet and CS. Bioinformatic analysis is ongoing to decipher the interactions between these compartments. These data will also allow to identify targets for preventive/therapeutic tools controling lung, intestinal and metabolic disorders due to SCUD.

Background Preschool asthma/recurrent wheeze is a heterogeneous condition. Different clinical phenotypes have been described, including episodic viral wheeze (EVW), severe intermittent wheeze (SIW), and multiple-trigger wheeze (MTW). Objective To compare clinical, viral, and inflammatory/immune profiling at exacerbation between MTW, SIW, and EVW phenotypes. Methods Multicenter, prospective, observational cohort (VIRASTHMA-2). Children (1-5 years) with preschool asthma were enrolled during hospitalization for a severe exacerbation. History and anamnestic data, plasma, and nasal samples were collected at exacerbation (T1) and at steady state, 8 weeks later (T2), and sputum samples were collected at T1. Results A total of 147 children were enrolled, 37 (25%) had SIW, 18 (12.2%) EVW, and 92 (63%) MTW. They were atopic (47%), exposed to mold (22%) and cigarette smoke (50%), and prone to exacerbations (≥2 in the previous year in 70%). At exacerbation, at least one virus was isolated in 94% and rhinovirus in 75%, with no difference between phenotypes. Children with MTW and SIW phenotypes displayed lower plasma concentrations of IFN-γ (P = .002), IL-5 (P = .020), TNF-α (P = .038), IL-10 (P = .002), IFN-β (P = .036), and CXCL10 (P = .006) and lower levels of IFN-γ (P = .047) in sputum at exacerbation than children with EVW. At T2, they also displayed lower plasma levels of IFN-γ (P = .045) and CXCL10 (P = .013). Conclusion Among preschool asthmatic children, MTW and SIW, prone to exacerbations, display lower systemic levels of Th1, Th2 cytokines, pro- and anti-inflammatory cytokines, and antiviral responses during severe virus-induced exacerbation.

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Objective: Describe the microbiological status during a severe asthma exacerbation and at steady state in preschool children ( Methods: Multicenter prospective study (Hauts-de-France, France). 147 asthmatic children were included during an hospitalization for a severe exacerbation (2015-2018). Phenotype, atopic status, viral status (PCR, nasal swab sample), bacteriological status (culture, induced sputum) were assessed during the exacerbation and at steady state, 8 weeks later. Results: We observed a seasonal distribution of the inclusions (figure). During the exacerbation, a virus was identified in 94% (V+); rhinovirus (RV) in 74% (R+), more frequently in June (95%) and September (82%) (p Conclusion: We confirm a high prevalence of RV infection during asthma exacerbations, frequently associated with bacteria. We now aim at exploring the host immune innate responses to these microorganisms.

Unhealthy lifestyle choices, such as bad eating behaviors and cigarette smoking, have major detrimental impacts on health. However, the inter-relations between obesity and smoking are still not fully understood. We thus developed an experimental model of high-fat diet-fed obese C57BL/6 male mice chronically exposed to cigarette smoke. Our study evaluated for the first time the resulting effects of the combined exposure to unhealthy diet and cigarette smoke on several metabolic, pulmonary, intestinal, and cardiac parameters. We showed that the chronic exposure to cigarette smoke modified the pattern of body fat distribution in favor of the visceral depots in obese mice, impaired the respiratory function, triggered pulmonary inflammation and emphysema, and was associated with gut microbiota dysbiosis, cardiac hypertrophy and myocardial fibrosis.

Introduction La BPCO est une pathologie inflammatoire chronique pulmonaire qui peut etre exacerbee par des virus, comme le virus respiratoire syncitial (VRS) ou le virus de la grippe. Les cytokines IL-20 dont la secretion est induite dans l’epithelium respiratoire apres infection virale, interviennent dans les mecanismes de defense anti-infectieuse. Dans la BPCO, ces cytokines participent a la susceptibilite aux infections bacteriennes. Notre objectif est de definir leur role lors des exacerbations virales de la BPCO et des surinfections bacteriennes qui en decoulent. Methodes Des souris C57/Bl6 WT et IL20Rb-/− sont exposees a la fumee de cigarette puis infectees par le PVM (Pneumonia virus of mice), homologue du VRS ou IAV. L’inflammation et l’expression des cytokines IL-20 ont ete evalues par histologie, PCR, ELISA et cytometrie en flux. Le role des cytokines IL-20 dans la surinfection bacterienne a ete evaluee par l’administration d’anticorps anti-IL20Rb au cours de l’infection par le PVM ou IAV chez des souris Air et BPCO puis infectee par Streptococcus pneumoniae. Resultats L’exposition a la fumee de cigarettes et l’infection par PVM induisent chez la souris WT l’augmentation de l’inflammation et de l’expression d’IL-24 pulmonaire associee a un defaut des mecanismes de defense antivirale. Les parametres inflammatoire et antiviraux ne sont pas affectes par la deletion de l’IL-20RB. La surinfection-post-PVM etant difficilement maitrisable, le role des cytokines IL-20 a ete evalue dans un modele de surinfection post-grippale. Chez les souris air, l’administration de l’anti-IL20Rb entraine une augmentation de la charge bacterienne pulmonaire et systemique associee a de l’inflammation. En effet, on observe une augmentation de l’expression et de production pulmonaire de CXCL1, d’IL-1B et de S100A9 et un recrutement de cDC2. Conclusion Ces Resultats montrent que le PVM peut exacerber la BPCO chez la souris. Cependant, les cytokines IL-20 ne semblent pas impliquees dans la reponse au virus chez les souris fumeuses. L’administration de l’anti-IL20RB semble n’avoir que tres peu d’impact sur les infections virales. Dans un contexte de surinfection, le blocage du recepteur aux cytokines IL-20 semble faciliter les infections bacteriennes pulmonaires.

Introduction L’apparition precoce de sensibilisations allergeniques et leur caractere multiple parait favoriser un asthme persistant et plus severe au cours de l’enfance, d’ou l’importance de leur mise en evidence en terme de pronostic. Notre objectif est de decrire les sensibilisations identifiees par la puce ImmunoCAP® ISAC (Thermofischer) dans une cohorte d’enfants asthmatiques d’âge prescolaire et d’evaluer son apport en regard des explorations allergologiques d’usage courant. Methodes Les donnees cliniques et les resultats des explorations allergologiques : puce ISAC® (n = 98), tests cutanes (TC) (n = 89) et tests multi-allergeniques (TMA) Phadiatop®/trophatop® (n = 96) ont ete recueillies chez 98 enfants asthmatiques de 1 a 5 ans, inclus durant une exacerbation severe au sein de la cohorte prospective lilloise VIRASTHMA2. Resultats A l’inclusion, 70 % etaient exacerbateurs frequents (≥ 2 en 6 mois). Une maladie allergique autre que l’asthme etait retrouvee dans 56 % des cas (dermatite atopique : 37 %, allergie alimentaire : 8 %). 28 % presentait une polysensibilisation (≥ 2 allergenes). Sur les donnees ISAC® : acariens (30 %), chat (18 %), chien (8 %), graminees (9 %), arachide (7 %) et œuf (7 %) etaient les allergenes les plus frequemment retrouves. Les donnees comparatives des tests allergologiques sont decrites en Fig. 1 . Dans notre population, par rapport aux TC et aux TMA, la puce ISAC® a permis de rattraper respectivement 6,7 % et 3,1 % de sensibilisations. Ces sensibilisations etaient principalement dirigees vers les chats et les acariens. Conclusion Des discordances entre TC/TMA et puce ISAC® ont ete identifiees. La puce ISAC® complete l’evaluation des sensibilisations. La valeur predictive de l’histoire naturelle clinique et fonctionnelle de l’asthme sera evaluee prospectivement en precisant l’apport de cette puce.

Chronic obstructive pulmonary disease is a major health problem becoming a leading cause of morbidity and mortality worldwide. A large part of these disorders is associated with acute exacerbations resulting from infection by bacteria, such as non-typeable Haemophilus influenzae (NTHi). Our understanding of the pathogenesis of these exacerbations is still elusive. We demonstrate herein that NTHi infection of mice chronically exposed to cigarette smoke (CS), an experimental model of chronic obstructive pulmonary disease (COPD), not only causes acute pulmonary inflammation but also impairs the production of interleukin (IL)-22, a cytokine with potential anti-bacterial activities. We also report that mice lacking IL-22, as well as mice exposed to CS, have a delayed clearance of NTHi bacteria and display enhanced alveolar wall thickening and airway remodeling compared with controls. Supplementation with IL-22 not only boosted bacterial clearance and the production of anti-microbial peptides but also limited lung damages induced by infection both in IL-22-/- and CS-exposed mice. In vitro exposure to CS extract altered the NTHi-induced IL-22 production by spleen cells. This study shows for the first time that a defect in IL-22 is involved in the acute exacerbation induced by NTHi infection during experimental COPD and opens the way to innovative therapeutic strategies.

Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease. This pathology can be exacerbated by bacteria or viruses, such as respiratory syncytial virus (RSV). The expression of IL-20 cytokines (IL-19, IL-20, IL24) is induced by different types of infections, but also by cigarette smoke exposure. They are involved in the control of inflammation and anti-infective mechanisms. They act in many physio-pathological processes affecting different organs. Thus, an imbalance of these cytokines could be involved in the susceptibility to infections responsible for COPD exacerbations. Aim: Our goal is to define the role of IL-20 cytokines during viral exacerbations of COPD. Methods: C57/Bl6 mice are chronically exposed to cigarette smoke for 12 weeks and then infected with PVM (Pneumonia virus of mice), a murine homologue of RSV. Inflammation and IL-20 cytokines expression were assessed by histology, PCR, ELISA and flow cytometry at the pulmonary level. Results: Chronic exposure to cigarette smoke and PVM infection induce pulmonary inflammation characterized by increased expression and production of pro-inflammatory cytokines such as: CXCL-1, IFNg, massive recruitment of dendritic cells, NKT cells and CD8+ T cells. This response is associated with an early increase of IL-24 expression in cigarette smoke exposed mice. Interestingly, a defect of anti-viral defense mechanisms is observed, with lower expression of the Rsad2 gene and lower production of IL-28AB and IFNb. Conclusions: The results obtained in our experimental model show that PVM can exacerbate COPD, and that IL-20 cytokines are increased in the lung tissues.

COPD is a public health burden mainly due to cigarette smoking (CS). It is now well recognized that respiratory infections are important triggers for the progression and exacerbation of the disease, consecutive to a defective immune responses. Since IL-20 cytokines (IL-19, IL-20 and IL-24) inhibits cutaneous antibacterial responses, we evaluated their implication during COPD exacerbation in order to restore an efficient immune response. C57BL/6 mice were daily exposed to CS during 12 weeks before infection by Streptococcus pneumoniae (Sp). Moreover, human monocyte-derived dendritic cells (MDDC) were treated with IL-20 cytokines during Sp-induced maturation. Expression of IL-20 cytokines and their receptors was evaluated. The role of IL-20 cytokines was assessed in vivo and in vitro using IL-20RB receptor blocking mAbs. CS exposure and Sp challenge increased IL-20 cytokines in vivo and in vitro in MDDC. Treatment with anti-IL-20RB mAb strongly reduced bacterial burden and inflammatory responses in Sp infected CS-exposed mice. It also modulated DC number and activation. MDDC expressed IL-20 receptor IL-20Ra, IL-20Rb and IL22Ra. Incubation with IL-20 cytokines inhibited Sp-induced MDDC maturation as shown by polarizing cytokines (IL-1β, IL-6, IL-23) as well as their capacity to activate naive T lymphocytes. Addition of IL-20RB blocking mAbs before cytokine treatment restores MDDC maturation and function. We show that IL-20 cytokines inhibit antibacterial responses in CS-mice potentially through the modulation of DC function. Therefore, targeting IL-20 pathway could represent a novel therapeutic strategy in COPD exacerbation.

Background: COPD is an inflammatory and chronic lung disease due to chronic exposure to cigarette smoke (CS). Patients are more susceptible to infection with Streptoccocus pneumoniae (Sp) leading to exacerbation of COPD. Airway epithelial cells (AEC) play a role in the disease and in the anti-bacterial defense. CS induces the expression of the IL-20 cytokines family known to modulate epithelial function. Objectives: Our goal is to decipher the role of IL-20 cytokines in human and murine AEC during COPD and the exposure to Sp. Methods: Expression of IL-20 cytokines and receptors was analyzed by immunohistochemistry in the lung samples from not smoker vs smoker controls and COPD patients and in mice exposed to CS. Implication of IL-20 cytokines in response to Sp and wound healing (WH) was analyzed by treatment with an anti-IL-20Rb blocking antibody on the human cell line Beas2B and on AEC from CS-exposed mice. Results: IL-19 and the receptors IL-20RA and IL-20RB were expressed in AEC from controls. The expression of IL-24 and IL-20RB is increased in smokers and COPD patients and for IL-20 only in COPD patients. Chronic exposure to CS also increased the expression of IL-20RB. The production of chemokines and antibacterial peptides was not modulated by IL-20 cytokines whereas the response to Sp was not affected by anti-IL-20RB. Addition of IL-20 cytokines accelerated the WH whereas anti-20Rb antibody dropped it. In addition, exposure to CS considerably reduces the WH. Conclusions: Smoking amplified the expression of IL-20 and IL-20RB whereas COPD disease is also associated with an upregulation with IL-24. IL-20 cytokines are involved in WH in AEC.

Background: Ambient particulate matter (PM) exposure has been shown to increase the risks of respiratory diseases and to contribute to the substantial worldwide burden of respiratory infections. However, the immune response to inhaled PM remains largely unexplored. Aim: We studied the effects of urban coarse PM on the pulmonary immunologic homeostasis. Methods: Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 3 and 15 days at a concentration relevant to episodic elevation peak of air pollution. Then the characteristics of PM-induced inflammation were assessed by flow cytometry and real-time PCR. Results: Acute and chronic exposures to urban coarse PM led to different immune patterns in the lung compartment. The acute phase was associated to the recruitment of neutrophils and activated alveolar macrophages. The chronic phase was characterized by the influx of activated conventional T cells whereas invariant natural killer T (iNKT) cells were recruited during both phases. Moreover, genes involved in anti-microbial responses, such as Reg3g, Lcn-2, Lyz and Slpi were downregulated in the lungs after acute PM exposure, whereas they were going back to baseline or slightly increased after chronic exposure. Independently of the time course, exposure to PM, leads to a decrease in IL-1b expression. Conclusion: This study provided a characterization of immunologic profiles in lungs following acute and chronic exposure to a realistic dose of PM. It suggested new mechanistic insights which should be further explored, especially the involvement of iNKT cells in pulmonary response to PM inhalation and the effects of PM exposure on the susceptibility to pulmonary infections.

Background: Cigarette smoking (CS) and obesity are leading causes of morbidity and mortality worldwide and are frequently associated. Both behaviors provoke inflammation and induce lung, metabolic, intestine and cardiovascular dysfunctions leading to e.g. chronic obstructive pulmonary disease and metabolic syndrome. However, the effect of combined exposure is not well unraveled. Objectives: We aimed to define the effect of combined exposure to CS and high fat diet (HFD) on the cardiovascular, metabolic, respiratory and intestinal functions. Moreover, we evaluate if smoking cessation may limit the dysfunctions due to this exposure. Methods: C57BL6 mice were exposed to 4 weeks of HFD followed by 12 weeks of combined exposure to CS and HFD. Then, some mice were submitted to CS cessation during 8 weeks. Metabolic, immunological and inflammatory parameters were evaluated. Results: Conjugated exposure increases lung inflammatory cell recruitment and activation as well as tissue lesions compared with exposure to CS and HFD alone. CS limits the body weight, affects adipose tissue repartition and reduces HFD-induced glucose intolerance. CS/HFD combination leads to cardiomyocyte hypertrophy. CS decreases colonic inflammation and the number of commensal bacteria in the caecum. Smoking cessation was not able to reverse these effects. Conclusion: Our murine model reproduced the human situation. While combined exposure leads to strong cardiovascular and lung dysfunctions, it had a mild impact on metabolic and intestinal compartment. In this context, CS cessation is not able to reverse the lesions related to combined exposure. We will now focus on the role of oxidative stress on these effects.

International audience; The mycotoxin deoxynivalenol (DON) is a frequent contaminant of cereals and their by-products in areas with a moderate climate. Produced by Fusarium species, it is one of the most prevalent mycotoxins in cereal crops worldwide, and the most frequently occurring type B trichothecene in Europe. Due to its toxic properties, high stability and prevalence, the presence of DON in the food chain could represent a major public health risk. However, despite its well-known acute toxicological effects, information on the adverse effects of realistic exposure remains limited. We orally exposed mice during 9 months to DON at doses relevant for currently estimated human intake and explored the impact on various gut health parameters. DON exposure induced recruitment of regulatory B cells, and activation of regulatory T cells and dendritic cells in mesenteric lymph nodes. Several inflammatory parameters were increased in colon of DON-exposed mice, whereas inversely inflammatory markers were decreased in ileum. Histomorphological impairments were observed from the duodenum to the colon. Both colon and jejunum presented a hyperproliferation of epithelial cells and an increased expression of mature absorptive cells markers. Finally, DON exposure reshaped gut microbial structure and drastically disturbed the abundance of several bacterial phyla, families, and genera, leading to dysbiosis. Chronic oral exposure to human relevant doses of DON induces several disturbances of gut homeostasis with likely pathological implications for susceptible individuals.

International audience; Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways caused mainly by cigarette smoke exposure. COPD progression is marked by exacerbations of the disease, often associated with infections. Recent data show the involvement in COPD pathophysiology of interleukin (IL)-17 and IL-22, two cytokines that are important in the control of lung inflammation and infection. During the initiation and progression of the disease, increased IL-17 secretion causes neutrophil recruitment, leading to chronic inflammation, airways obstruction and emphysema. In the established phase of COPD, a defective IL-22 response facilitates pathogen-associated infections and disease exacerbations. Altered production of these cytokines involves a complex network of immune cells and dysfunction of antigen-presenting cells. In this review, we describe current knowledge on the involvement of IL-17 and IL-22 in COPD pathophysiology at steady state and during exacerbations, and discuss implications for COPD management and future therapeutic approaches.

Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. It is mainly associated to acute exacerbations due to bacterial infection, by non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (SP). Prophylactic administration of flagellin, the Toll-like receptor 5 (TLR5) agonist, protects mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might prevent COPD exacerbation. Flagellin was intraperitoneally administrated to treat NTHi or SP-infected COPD animals. Compared with control, COPD mice treated with flagellin showed a lower bacterial load in the BAL and the lungs and less bacterial dissemination in the blood. This was associated with an early neutrophilia, a lower production of proinflammatory cytokines but also an increased production of anti-bacterial peptides and of IL-22. Interestingly, the treatment with flagellin decreased the inflammatory cell recruitment and limited lung damage related to exacerbation. Lastly, administration of neutralizing anti-IL-22 antibody attenuated the beneficial effect of Flagellin against NTHI infection. This study shows for the first time that innate immunity stimulation with flagellin is a potent antibacterial treatment against exacerbation during experimental COPD through an IL-22 dependent mechanism. This opens the way to innovative therapeutic strategies. This work is sponsored by INSERM-Transfert, Paris, France.

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.

Chronic obstructive pulmonary disease (COPD) is a major clinical challenge mostly due to cigarette smoke (CS) exposure. Invariant natural killer T (iNKT) cells are potent immunoregulatory cells that have a crucial role in inflammation. In the current study, we investigate the role of iNKT cells in COPD pathogenesis. The frequency of activated NKT cells was found to be increased in peripheral blood of COPD patients relative to controls. In mice chronically exposed to CS, activated iNKT cells accumulated in the lungs and strongly contributed to the pathogenesis. The detrimental role of iNKT cells was confirmed in an acute model of oxidative stress, an effect that depended on interleukin (IL)-17. CS extracts directly activated mouse and human dendritic cells (DC) and airway epithelial cells (AECs) to trigger interferonγ and/or IL-17 production by iNKT cells, an effect ablated by the anti-oxidant N-acetylcystein. In mice, this treatment abrogates iNKT-cell accumulation in the lung and abolished the development of COPD. Together, activation of iNKT cells by oxidative stress in DC and AECs participates in the development of experimental COPD, a finding that might be exploited at a therapeutic level.

Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1(-/-) mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a(-/-) or Nlrp3(-/-) mice. AHR was also associated with the expansion of CCR6(+) type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2(-/-); Il2rg(-/-) mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.

Background Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation. Results The collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15 days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM. Conclusions Coarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases. Electronic supplementary material The online version of this article (10.1186/s12989-017-0227-z) contains supplementary material, which is available to authorized users.