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Journal articleMolyneaux PL, Willis Owen SA, Cox MJ, et al., 2017,
Host-microbial interactions in idiopathic pulmonary fibrosis
, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1640-1650, ISSN: 1535-4970RATIONALE: Changes in the respiratory microbiome are associated with disease progression in Idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome however remains unknown. OBJECTIVES: To explore the host-microbial interaction in IPF. METHODS: Sixty patients diagnosed with IPF were prospectively enrolled, together with 20 matched controls. Subjects underwent bronchoalveolar lavage (BAL) and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For IPF subjects additional samples were taken at 1, 3, and 6 months and (if alive) a year. Gene expression profiles were generated using Affymetrix Human Gene1.1ST Arrays. MEASUREMENTS AND MAIN RESULTS: Network analysis of gene expression data identified two gene modules that strongly associate with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative PCR) and specific microbial OTUs, as well as lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defence response include NLRC4, PGLYRP1, MMP9, DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal over expression in subjects experiencing disease progression, further strengthening their relationship with disease. CONCLUSIONS: Integrated analysis of the host transcriptome and microbial signatures demonstrates an apparent host response to the presence of an altered or more abundant microbiome. These responses remain elevated on longitudinal follow up, suggesting that the bacterial communities of the lower airways may be acting as persistent stimuli for repetitive alveolar injury in IPF.
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Journal articleFarrer RA, Martel A, Verbrugghe E, et al., 2017,
Genomic innovations linked to infection strategies across emerging pathogenic chytrid fungi
, NATURE COMMUNICATIONS, Vol: 8, Pages: 1-11, ISSN: 2041-1723To understand the evolutionary pathways that lead to emerging infections of vertebrates, here we explore the genomic innovations that allow free-living chytrid fungi to adapt to and colonize amphibian hosts. Sequencing and comparing the genomes of two pathogenic species of Batrachochytrium to those of close saprophytic relatives reveals that pathogenicity is associated with remarkable expansions of protease and cell wall gene families, while divergent infection strategies are linked to radiations of lineage-specific gene families. By comparing the host–pathogen response to infection for both pathogens, we illuminate the traits that underpin a strikingly different immune response within a shared host species. Our results show that, despite commonalities that promote infection, specific gene-family radiations contribute to distinct infection strategies. The breadth and evolutionary novelty of candidate virulence factors that we discover underscores the urgent need to halt the advance of pathogenic chytrids and prevent incipient loss of biodiversity.
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Journal articleDominguez-Huettinger E, Boon NJ, Clarke TB, et al., 2017,
Mathematical Modeling of Streptococcus pneumoniae Colonization, Invasive Infection and Treatment
, FRONTIERS IN PHYSIOLOGY, Vol: 8, ISSN: 1664-042XStreptococcus pneumoniae (Sp) is a commensal bacterium that normally resides on the upper airway epithelium without causing infection. However, factors such as co-infection with influenza virus can impair the complex Sp-host interactions and the subsequent development of many life-threatening infectious and inflammatory diseases, including pneumonia, meningitis or even sepsis. With the increased threat of Sp infection due to the emergence of new antibiotic resistant Sp strains, there is an urgent need for better treatment strategies that effectively prevent progression of disease triggered by Sp infection, minimizing the use of antibiotics. The complexity of the host-pathogen interactions has left the full understanding of underlying mechanisms of Sp-triggered pathogenesis as a challenge, despite its critical importance in the identification of effective treatments. To achieve a systems-level and quantitative understanding of the complex and dynamically-changing host-Sp interactions, here we developed a mechanistic mathematical model describing dynamic interplays between Sp, immune cells, and epithelial tissues, where the host-pathogen interactions initiate. The model serves as a mathematical framework that coherently explains various in vitro and in vitro studies, to which the model parameters were fitted. Our model simulations reproduced the robust homeostatic Sp-host interaction, as well as three qualitatively different pathogenic behaviors: immunological scarring, invasive infection and their combination. Parameter sensitivity and bifurcation analyses of the model identified the processes that are responsible for qualitative transitions from healthy to such pathological behaviors. Our model also predicted that the onset of invasive infection occurs within less than 2 days from transient Sp challenges. This prediction provides arguments in favor of the use of vaccinations, since adaptive immune responses cannot be developed de novo in such a short time. We furthe
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Journal articleMolyneaux PL, Cox MJ, Wells AU, et al., 2017,
Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis
, Respiratory Research, Vol: 18, ISSN: 1465-9921Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) have been defined as events of clinically significant respiratory deterioration with an unidentifiable cause. They carry a significant mortality and morbidity and while their exact pathogenesis remains unclear, the possibility remains that hidden infection may play a role. The aim of this pilot study was to determine whether changes in the respiratory microbiota occur during an AE-IPF. Bacterial DNA was extracted from bronchoalveolar lavage from patients with stable IPF and those experiencing an AE-IPF. A hyper-variable region of the 16S ribosomal RNA gene (16S rRNA) was amplified, quantified and pyrosequenced. Culture independent techniques demonstrate AE-IPF is associated with an increased BAL bacterial burden compared to stable disease and highlight shifts in the composition of the respiratory microbiota during an AE-IPF.
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Journal articleChilloux J, Dumas ME, 2017,
Are gut microbes responsible for post-dieting weight rebound?
, Cell Metabolism, Vol: 25, Pages: 6-7, ISSN: 1932-7420One of the dieting conundrums in the age of the obesity epidemic is the cycle of weight loss and regain known as the "yo-yo effect." Thaiss et al. (2016) demonstrate that the microbiome plays a key role in this phenomenon and that simple dietary supplementations can reset the weight-rebound clock.
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Journal articleDepner M, Ege MJ, Cox MJ, et al., 2016,
Bacterial microbiota of the upper respiratory tract and childhood asthma
, Journal of Allergy and Clinical Immunology, ISSN: 1097-6825BACKGROUND: Patients with asthma and healthy controls differ in bacterial colonization of the respiratory tract. The upper airways have been shown to reflect colonization of the lower airways, the actual site of inflammation in asthma, which is hardly accessible in population studies. OBJECTIVE: We sought to characterize the bacterial communities at 2 sites of the upper respiratory tract obtained from children from a rural area and to relate these to asthma. METHODS: The microbiota of 327 throat and 68 nasal samples from school-age farm and nonfarm children were analyzed by 454-pyrosequencing of the bacterial 16S ribosomal RNA gene. RESULTS: Alterations in nasal microbiota but not of throat microbiota were associated with asthma. Children with asthma had lower α- and β-diversity of the nasal microbiota as compared with healthy control children. Furthermore, asthma presence was positively associated with a specific operational taxonomic unit from the genus Moraxella in children not exposed to farming, whereas in farm children Moraxella colonization was unrelated to asthma. In nonfarm children, Moraxella colonization explained the association between bacterial diversity and asthma to a large extent. CONCLUSIONS: Asthma was mainly associated with an altered nasal microbiota characterized by lower diversity and Moraxella abundance. Children living on farms might not be susceptible to the disadvantageous effect of Moraxella. Prospective studies may clarify whether Moraxella outgrowth is a cause or a consequence of loss in diversity.
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Journal articleChilloux J, Neves AL, Boulangé CL, et al., 2016,
The microbial-mammalian metabolic axis: a critical symbiotic relationship
, Current Opinion in Clinical Nutrition and Metabolic Care, Vol: 19, Pages: 250-256, ISSN: 1473-6519Purpose of review: The microbial-mammalian symbiosis plays a critical role in metabolic health. Microbial metabolites emerge as key messengers in the complex communication between the gut microbiota and their host. These chemical signals are mainly derived from nutritional precursors, which in turn are also able to modify gut microbiota population. Recent advances in the characterization of the gut microbiome and the mechanisms involved in this symbiosis allow the development of nutritional interventions. This review covers the latest findings on the microbial-mammalian metabolic axis as a critical symbiotic relationship particularly relevant to clinical nutrition.Recent findings: The modulation of host metabolism by metabolites derived from the gut microbiota highlights the importance of gut microbiota in disease prevention and causation. The composition of microbial populations in our gut ecosystem is a critical pathophysiological factor, mainly regulated by diet, but also by the host's characteristics (e.g. genetics, circadian clock, immune system, age). Tailored interventions, including dietary changes, the use of antibiotics, prebiotic and probiotic supplementation and faecal transplantation are promising strategies to manipulate microbial ecology.Summary: The microbiome is now considered as an easily reachable target to prevent and treat related diseases. Recent findings in both mechanisms of its interactions with host metabolism and in strategies to modify gut microbiota will allow us to develop more effective treatments especially in metabolic diseases.
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Journal articleBoulangé CL, Neves AL, Chilloux J, et al., 2016,
Impact of the gut microbiota on inflammation, obesity, and metabolic disease
, Genome Medicine, Vol: 8, ISSN: 1756-994XThe human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.
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Journal articleZhang Q, Cox M, Liang Z, et al., 2016,
Airway microbiota in severe asthma and relationship to asthma severity and phenotypes
, PLOS One, Vol: 11, ISSN: 1932-6203Background: The lower airways harbor a community of bacterial species which is altered in asthma. Objectives: We examined whether the lower airway microbiota were related to measures of asthma severityMethods: We prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed. Results: We obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P=2.8x10-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR=2.26; 95% CI=1.94-2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR=2.15; 95%CI=1.89-2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia.Conclusions: Sputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.
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Journal articleDumas M-E, 2016,
Is the way we're dieting wrong?
, Genome Medicine, Vol: 8, ISSN: 1756-994XProgress in personalized medicine is now beingtranslated to personalized nutrition. A recent proofof-conceptstudy shows that the increase in bloodglucose levels after a meal is highly variable betweenindividuals, but can be predicted by using acomputational model that combines information fromgut microbiome profiles and dietary questionnaires.This study raises questions about the usefulness ofuniversal diet recommendations, and suggests wemight need to move on to personalized diets.
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