Fungal microbiota dysbiosis in IBD.

International audienceThe bacterial intestinal microbiota plays major roles in human physiology and IBDs. Although some data suggest a role of the fungal microbiota in IBD pathogenesis, the available data are scarce. The aim of our study was to characterise the faecal fungal microbiota in patients with IBD. Bacterial and fungal composition of the faecal microbiota of 235 patients with IBD and 38 healthy subjects (HS) was determined using 16S and ITS2 sequencing, respectively. The obtained sequences were analysed using the Qiime pipeline to assess composition and diversity. Bacterial and fungal taxa associated with clinical parameters were identified using multivariate association with linear models. Correlation between bacterial and fungal microbiota was investigated using Spearman's test and distance correlation. We observed that fungal microbiota is skewed in IBD, with an increased Basidiomycota/Ascomycota ratio, a decreased proportion of Saccharomyces cerevisiae and an increased proportion of Candida albicans compared with HS. We also identified disease-specific alterations in diversity, indicating that a Crohn's disease-specific gut environment may favour fungi at the expense of bacteria. The concomitant analysis of bacterial and fungal microbiota showed a dense and homogenous correlation network in HS but a dramatically unbalanced network in IBD, suggesting the existence of disease-specific inter-kingdom alterations. Besides bacterial dysbiosis, our study identifies a distinct fungal microbiota dysbiosis in IBD characterised by alterations in biodiversity and composition. Moreover, we unravel here disease-specific inter-kingdom network alterations in IBD, suggesting that, beyond bacteria, fungi might also play a role in IBD pathogenesis

Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5-9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10-13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target

Spent nuclear fuel/water interface behavior: Alpha dose rate profile determination for model surfaces and microcracks by using Monte-Carlo methods

International audienceThis work aims to better understand the nature and evolution of energy deposits at the UO2/water reactional interface subjected to alpha irradiation, through an original approach based on Monte-Carlo-type simulations, using the MCNPX code. Such an approach has the advantage of describing the energy deposit profiles on both sides of the interface (UO2 and water). The calculations have been performed on simple geometries, with data from an irradiated UOX fuel (burnup of 47 GWd.tHM−1 and 15 years of alpha decay). The influence of geometric parameters such as the diameter and the calculation steps at the reactional interface are discussed, and the exponential laws to be used in practice are suggested. The case of cracks with various different apertures (from 5 to 35 μm) has also been examined and these calculations have also enabled new information on the mean range of radiolytic species in cracks, and thus on the local chemistry

ADF/Cofilin Accelerates Actin Dynamics by Severing Filaments and Promoting Their Depolymerization at Both Ends

Actin-depolymerizing factor (ADF)/cofilins contribute to cytoskeletal dynamics by promoting rapid actin filament disassembly. In the classical view, ADF/cofilin sever filaments, and capping proteins block filament barbed ends whereas pointed ends depolymerize, at a rate that is still debated. Here, by monitoring the activity of the three mammalian ADF/cofilin isoforms on individual skeletal muscle and cytoplasmic actin filaments, we directly quantify the reactions underpinning filament severing and depolymerization from both ends. We find that, in the absence of monomeric actin, soluble ADF/cofilin can associate with bare filament barbed ends to accelerate their depolymerization. Compared to bare filaments, ADF/cofilin-saturated filaments depolymerize faster from their pointed ends and slower from their barbed ends, resulting in similar depolymerization rates at both ends. This effect is isoform specific because depolymerization is faster for ADF-than for cofilin-saturated filaments. We also show that, unexpectedly, ADF/cofilin-saturated filaments qualitatively differ from bare filaments: their barbed ends are very difficult to cap or elongate, and consequently undergo depolymerization even in the presence of capping protein and actin monomers. Such depolymerizing ADF/cofilin-decorated barbed ends are produced during 17% of severing events. They are also the dominant fate of filament barbed ends in the presence of capping protein, because capping allows growing ADF/cofilin domains to reach the barbed ends, thereby promoting their uncapping and subsequent depolymerization. Our experiments thus reveal how ADF/cofilin, together with capping protein, control the dynamics of actin filament barbed and pointed ends. Strikingly, our results propose that significant barbed-end depolymerization may take place in cells.Peer reviewe

Alpha dose rate and alpha decay dose impacts on the residual alteration rate regime of HLW nuclear glasses

International audienceThe long-term behavior of high-level nuclear glass subjected to alpha radiation by long-life minor actinides must be investigated with respect to geological disposal. This study focuses on the effects of alpha radiation on the chemical reactivity of R7T7-type glasses with pure water, mainly on the residual alteration rate regime, by considering separately the alpha dose rate and the alpha decay dose. Old SON68 glasses doped with $^(238/239)$PuO2 or $^(244)$CmO2 were studied in order to simulate high alpha dose rates corresponding to an early water ingress and also high level of alpha decay doses corresponding to long-term disposal conditions. A part of the $^(238/239)$Pu-doped glass block was annealed to fully recover the irradiation induced damage accumulated since the glass fabrication and to dissociate the effect of the alpha dose rate from the one of alpha decay dose. The glasses were then leached under static conditions in argon atmosphere at 90°C for several years. The results showed that the residual alteration rate is not impacted by the alpha dose rate parameter on a wide range of the dose rate values expected under disposal conditions, even in the eventuality of an early water ingress. It means that a SON68-type glass remained poorly sensitive to the alpha particle energy deposition at the glass-water interface. However, the residual alteration rate of the damaged $^(238/239)$Pu-doped glass was enhanced compared to the one of the annealed glass. This result is in agreement with the one obtained on the $^(244)$Cm-doped glass, and also with the literature about simplified glasses externally irradiated, indicating that the ballistic effects of the recoil nuclei are thus responsible for this increase of the residual alteration rate. A link between the glass structure and its leaching behavior is evidenced on these radioactive glasses and the role of the reactive interface is highly suspected

Effect of low dose electron beam irradiation on the alteration layer formed during nuclear glass leaching

International audienceThis investigation concerns borosilicate glass leaching mechanisms and the evolution of alteration layer under electron beam irradiation. A simple glass doped with rare earth elements was selected in order to access mechanistic and structural information and better evaluate the effects of irradiation. It was fully leached in initially pure water at 90 °C and at high glass surface area to solution volume ratio (S/V = 20 000 m−1) in static conditions. Under these conditions, the system quickly reaches the residual alteration rate regime. A small particle size fraction (2–5 μm) was sampled in order to obtain a fairly homogeneous altered material enabling the use of bulk characterization methods. External irradiations with 10 MeV electrons up to a dose of 10 MGy were performed either before or after leaching, to investigate respectively the effect of initial glass irradiation on its alteration behavior and the irradiation stability of the alteration layer. Glass dissolution rate was analyzed by regular leachate samplings and the alteration layer structure was characterized by Raman, luminescence (continuous or time-resolved), and 29Si MAS NMR and EPR spectroscopy. It was shown that the small initial glass evolutions under irradiation did not induce any modification of the leaching kinetic nor of the structure of the alteration layer. The alteration process seemed to “smooth over” the created defects. Otherwise, the alteration layer and initial glass appeared to have different behaviors under irradiation. No Eu3+ reduction was detected in the alteration layer after irradiation and the defect creation efficiency was much lower than for initial glass. This can possibly be explained by the protective role of pore water contained in the altered material (∼20%). Moreover, a slight depolymerization of the silicon network of the altered glass under irradiation with electrons was evidenced, whereas in the initial glass it typically repolymerizes

Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis

International audiencePatients with primary sclerosing cholangitis (PSC) were previously shown to display a bacterial gut dysbiosis but fungal microbiota has never been examined in these patients. The aim of this study was to assess the fungal gut microbiota in patients with PSC

New insights about the importance of the alteration layer/glass interface

International audienceThis work addresses the impact of radiation damage on the leaching of international simple glass (ISG). Pristine and specimens irradiated with multi-energy Au ions were leached for 82 days at 90°C in pure water and pH 9 and regularly sampled. Samples leached for 13 and 58 days were characterized using transmission electron microscopy (TEM) to study the microstructure(s) of the alteration layers formed from the radiation-damaged and pristine glasses. Furthermore, a sample altered for 82 days was immersed in water enriched in isotopically tagged water molecules (H$_2$$^{18}$O) to study and compare the mobility and reactivity in the alteration layers formed on these glasses. The studies revealed that radiation damage diminished the chemical durability of the ISG glass since the beginning of the leaching experiment. Concomitantly, the formation of a non-porous alteration layer of about 237 nm after 13 days of leaching evolving into the formation of a nanoporous alteration layer of about 570 nm after 58 days of leaching was observed in the irradiated glasses. In contrast, a non-porous altered layer of about 138 nm only developed in the non-irradiated specimen altered for 58 days. Using energy-filtered transmission electron microscopy, the altered layers in all the cases were found to be depleted in boron, in agreement with the time of flight secondary ion mass spectroscopy studies. Despite pore formation, similar behaviour in the $^{18}$O — $^{16}$O exchanges (with respect to the uncertainties) was observed in the major part of the alteration layers whether formed from the irradiated or pristine ISG, leading to the conclusion that the greater alterability of the radiation-damaged ISG may not be due to the porosity. However, isotopic exchanges also revealed a significantly higher reactivity of the alteration-layer/glass interface for the irradiated glass. While these studies provide important insights about the role of porosity and radiation damages, they also highlight the complex nature of glass dissolution and, suggest that studies directed at alteration-layer/glass interface are needed to better understand and explain the mechanisms controlling the glass dissolution in the residual alteration rate regime

Specificities of the intestinal microbiota in patients with inflammatory bowel disease and Clostridium difficile infection

International audienceBackground and Aims: Clostridium difficile infection (CDI) is a common complication in inflammatory bowel disease (IBD) and has been associated with poor IBD outcome. Intestinal microbiota composition in IBD patients with CDI has not been specifically evaluated to date.Methods: The fecal microbiota of 56 IBD patients, including 8 in flare with concomitant CDI, 24 in flare without CDI, and 24 in remission, as well as 24 healthy subjects, was studied using 16S sequencing. Analysis was performed using the Qiime pipeline.Results: Compared to IBD patients without CDI, IBD patients with CDI had more pronounced dysbiosis with higher levels of Ruminococcus gnavus and Enterococcus operational taxonomic units (OTUs) and lower levels of Blautia and Dorea OTUs. Correlation network analysis suggested a disrupted ecosystem in IBD patients in flare, particularly in those with CDI.Conclusions: In patients with IBD, CDI is associated with a more pronounced intestinal dysbiosis with specific alterations in intestinal microorganisms

Enterobacteriaceae are essential for the modulation of colitis severity by fungi

Abstract Background Host-microbe balance maintains intestinal homeostasis and strongly influences inflammatory conditions such as inflammatory bowel diseases (IBD). Here we focused on bacteria-fungi interactions and their implications on intestinal inflammation, a poorly understood area. Methods Dextran sodium sulfate (DSS)-induced colitis was assessed in mice treated with vancomycin (targeting gram-positive bacteria) or colistin (targeting Enterobacteriaceae) and supplemented with either Saccharomyces boulardii CNCM I-745 or Candida albicans. Inflammation severity as well as bacterial and fungal microbiota compositions was monitored. Results While S. boulardii improved DSS-induced colitis and C. albicans worsened it in untreated settings, antibiotic treatment strongly modified DSS susceptibility and effects of fungi on colitis. Vancomycin-treated mice were fully protected from colitis, while colistin-treated mice retained colitis phenotype but were not affected anymore by administration of fungi. Antibacterial treatments not only influenced bacterial populations but also had indirect effects on fungal microbiota. Correlations between bacterial and fungal relative abundance were dramatically decreased in colistin-treated mice compared to vancomycin-treated and control mice, suggesting that colistin-sensitive bacteria are involved in interactions with fungi. Restoration of the Enterobacteriaceae population by administrating colistin-resistant Escherichia coli reestablished both beneficial effects of S. boulardii and pathogenic effects of C. albicans on colitis severity. This effect was at least partly mediated by an improved gut colonization by fungi. Conclusions Fungal colonization of the gut is affected by the Enterobacteriaceae population, indirectly modifying effects of mycobiome on the host. This finding provides new insights into the role of inter-kingdom functional interactions in intestinal physiopathology and potentially in IBD