Der Einfluss der Darmmikrobiota auf mikrobielle Infektionen

A diverse community of microorganisms colonizes the gastrointestinal tract and has been termed the intestinal microbiota. In particular, resident bacteria promote the development and maturation of the immune system, but also protect the host against invading enteric pathogens by a process called colonization resistance. Until now, little is known about the contributions of individual members of the intestinal microbiota to confer colonization resistance. To understand how different intestinal microbial communities influence the susceptibility to enteric pathogens, isogenic mouse lines from different breeding facilities were analyzed. Subsequently, mouse lines were challenged with Salmonella Typhimurium (non-typhoidal model) and Citrobacter rodentium to identify microbial signatures associated with decreased disease severity. Analyzing the fecal microbiota by 16S rRNA gene amplicon sequencing revealed that isogenic mouse lines from different breeding facilities featured a distinct microbiota composition. Moreover, isogenic mouse lines displayed different susceptibilities to S. Typhimurium infection. Statistical analysis of 16S rRNA sequencing data identified bacteria of the families S24-7, Prevotellaceae and Verrucomicrobiaceae to be associated with increased resistance. Transfer of 11 bacterial species, cultured from protected mice, in susceptible mice diminished disease severity. Interferon-gamma was identified as novel microbiota modulated factor that it is required for conferring resistance through immune-mediated colonization resistance. In addition, isogenic mouse lines with different microbiota composition varied in their susceptibility to Citrobacter rodentium infection. By using cohousing experiments of susceptible and resistance mice coupled with statistical analysis of 16S rRNA sequencing data, two bacteria of the family Lachnospiraceae were identified important to diminish luminal colonization. The results of the study could identify novel microbial signatures and mechanisms, which confer resistance to S. Typhimurium and C. rodentium infections. Characterization of microbial interactions and metabolites as well as the corresponding immune factors that influence host physiology are important contributions that may enable developing improved therapies for mucosal infections.Eine vielfältige Gemeinschaft von Mikroorganismen kolonisiert den Gastrointestinaltrakt, die als Darmmikrobiota bezeichnet wird. Insbesondere fördern kommensale Bakterien die Entwicklung und Reifung des Immunsystems. Darüber hinaus schützen sie den Wirt vor Krankheitserregern, was auch als Kolonisationsresistenz bezeichnet wird. Bisher ist nur wenig darüber bekannt, ob und wie die einzelnen Mitglieder der Darmmikrobiota zu der Kolonisationsresistenz beitragen. Um zu verstehen, wie verschiedene mikrobielle Gemeinschaften die Anfälligkeit des Wirts gegenüber Enteropathogenen beeinflussen, wurden isogene Mauslinien verschiedener Züchtungseinrichtungen untersucht. Anschließend wurden diese Mauslinien mit Salmonella Typhimurium (nicht-typhoides Modell) und Citrobacter rodentium infiziert, um Bakterien zu identifizieren, die den Schweregrad der Erkrankung positiv beeinflussen. 16S-rRNA-Sequenzierungen ergaben, dass isogene Mauslinien aus verschiedenen Züchtungseinrichtungen eine unterschiedliche Zusammensetzung der Mikrobiota aufweisen. Zudem zeigten isogene Mauslinien unterschiedliche Anfälligkeiten gegenüber Infektionen mit S. Typhimurium. Insbesondere Bakterien der Familien S24-7, Prevotellaceae und Verrucomicrobiaceae waren mit einer erhöhten Resistenz assoziiert. Die Übertragung von 11 bakteriellen Spezies, die aus geschützten Mäusen kultiviert wurden, verminderte bei anfälligen Mäusen die Schwere der Erkrankung. Zudem wurde Interferon-gamma als neuartiger Mikrobiota-modulierender Faktor identifiziert, der für den Transfer der immun-vermittelten Kolonisationsresistenz erforderlich ist. Isogene Mauslinien, die eine unterschiedliche Zusammensetzung der Mikrobiota aufweisen, zeigten außerdem eine unterschiedliche Anfälligkeit gegenüber C. rodentium. Unter Verwendung von Cohousing-Experimenten von anfälligen und resistenten Mäusen, die gekoppelt wurden mit einer statistischen Analyse von 16S-rRNA-Seqeuenzierungsdaten, wurden zwei Bakterien der Familie Lachnospiraceae identifiziert, die mit verringerter luminalen Kolonisation assoziiert sind. In dieser Arbeit konnten neue mikrobielle Signaturen und Mechanismen identifiziert werden, die mit Resistenzen gegenüber Infektionen mit S. Typhimurium und C. rodentium assoziiert sind. Die Charakterisierung der mikrobiellen Wechselwirkungen und Metabolite, sowie die entsprechenden Immunfaktoren, welche die Wirtsphysiologie beeinflussen, sind wesentlich, um verbesserte Therapien für mukosale Infektionen zu ermöglichen

No detection of methane on Mars from early ExoMars Trace Gas Orbiter observations

The detection of methane on Mars has been interpreted as indicating that geochemical or biotic activities could persist on Mars today. A number of different measurements of methane show evidence of transient, locally elevated methane concentrations and seasonal variations in background methane concentrations. These measurements, however, are difficult to reconcile with our current understanding of the chemistry and physics of the Martian atmosphere, which-given methane's lifetime of several centuries-predicts an even, well mixed distribution of methane. Here we report highly sensitive measurements of the atmosphere of Mars in an attempt to detect methane, using the ACS and NOMAD instruments onboard the ESA-Roscosmos ExoMars Trace Gas Orbiter from April to August 2018. We did not detect any methane over a range of latitudes in both hemispheres, obtaining an upper limit for methane of about 0.05 parts per billion by volume, which is 10 to 100 times lower than previously reported positive detections. We suggest that reconciliation between the present findings and the background methane concentrations found in the Gale crater would require an unknown process that can rapidly remove or sequester methane from the lower atmosphere before it spreads globally

Martian dust storm impact on atmospheric H₂O and D/H observed by ExoMars Trace Gas Orbiter

Global dust storms on Mars are rare but can affect the Martian atmosphere for several months. They can cause changes in atmospheric dynamics and inflation of the atmosphere, primarily owing to solar heating of the dust. In turn, changes in atmospheric dynamics can affect the distribution of atmospheric water vapour, with potential implications for the atmospheric photochemistry and climate on Mars. Recent observations of the water vapour abundance in the Martian atmosphere during dust storm conditions revealed a high-altitude increase in atmospheric water vapour that was more pronounced at high northern latitudes, as well as a decrease in the water column at low latitudes. Here we present concurrent, high-resolution measurements of dust, water and semiheavy water (HDO) at the onset of a global dust storm, obtained by the NOMAD and ACS instruments onboard the ExoMars Trace Gas Orbiter. We report the vertical distribution of the HDO/H O ratio (D/H) from the planetary boundary layer up to an altitude of 80 kilometres. Our findings suggest that before the onset of the dust storm, HDO abundances were reduced to levels below detectability at altitudes above 40 kilometres. This decrease in HDO coincided with the presence of water-ice clouds. During the storm, an increase in the abundance of H2O and HDO was observed at altitudes between 40 and 80 kilometres. We propose that these increased abundances may be the result of warmer temperatures during the dust storm causing stronger atmospheric circulation and preventing ice cloud formation, which may confine water vapour to lower altitudes through gravitational fall and subsequent sublimation of ice crystals. The observed changes in H2O and HDO abundance occurred within a few days during the development of the dust storm, suggesting a fast impact of dust storms on the Martian atmosphere

Geographical area and life history traits influence diet in an Arctic marine predator

Global changes are thought to affect most Arctic species, yet some populations are more at risk. Today, the Barents Sea ecoregion is suffering the strongest sea ice retreat ever measured; and these changes are suspected to modify food access and thus diet of several species. Biochemical diet tracers enable investigation of diet in species such as polar bears (Ursus maritimus). We examined individual diet variation of female polar bears in Svalbard, Norway, and related it to year, season (spring and autumn), sampling area and breeding status (solitary, with cubs of the year or yearlings). Sampling areas were split according to their ice cover: North-West (less sea ice cover), South-East (larger amplitude in sea ice extent) and North-East/South-West (NESW) as bears from that zone are more mobile among all regions of Svalbard. We measured fatty acid (FA) composition in adipose tissue and carbon (δ13C) and nitrogen (δ15N) stable isotopes in plasma and red blood cells. Females feeding in the North-West area had lower δ15N values than those from the NESW. In South-East females, δ13C values were lower in autumn compared to spring and females seemed less selective in their diet as depicted by large variances in stable isotope values. Considering the differences in FA composition and stable isotope values, we suggest that females from the North-West and South-East could ingest a higher proportion of avian prey. With regard to breeding status, solitary females had higher δ15N values and smaller variance in their stable isotopic values than females with cubs, suggesting that solitary females were more selective and prey on higher trophic level species (i.e. seals). Overall, our results indicate that prey availability for Svalbard polar bears varies according to geographical area and prey selectivity differs according to breeding status. Our findings suggest that complex changes in sea ice and prey availability will interact to affect Svalbard polar bear feeding patterns and associated nutrition

Loss of CNFY toxin-induced inflammation drives Yersinia pseudotuberculosis into persistency.

Gastrointestinal infections caused by enteric yersiniae can become persistent and complicated by relapsing enteritis and severe autoimmune disorders. To establish a persistent infection, the bacteria have to cope with hostile surroundings when they transmigrate through the intestinal epithelium and colonize underlying gut-associated lymphatic tissues. How the bacteria gain a foothold in the face of host immune responses is poorly understood. Here, we show that the CNFY toxin, which enhances translocation of the antiphagocytic Yop effectors, induces inflammatory responses. This results in extensive tissue destruction, alteration of the intestinal microbiota and bacterial clearance. Suppression of CNFY function, however, increases interferon-γ-mediated responses, comprising non-inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life style

Distinct Polysaccharide Utilization Determines Interspecies Competition between Intestinal Prevotella spp.

CD81 plays a role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus. Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81-cholesterol association, but had disparate effects on HCV, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified an allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol unbound) or closed (cholesterol bound) conformation. The open mutant of CD81 exhibited reduced receptor activity whereas the closed mutant was enhanced. These data are consistent with cholesterol switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81-partner networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in health and disease

An German Short-Version of the Sensory Perception Quotient for Adults With Autism Spectrum Disorder

Sensory features in autism spectrum disorder (ASD) have received increasing interest in clinical work and research during the recent years. With the Sensory Perception Quotient (SPQ), Tavasolli and colleagues have produced a self-rating scale for adults with ASD that measures sensory hyper-sensitivity in different sensory modalities, without also tapping cognitive or motivational aspects that precede or follow autistic sensory experiences. Here, we present the results of a translation of the SPQ to German and its short version as well as their validation in samples of autistic or neuro-typical participants. We, furthermore, present the psychometric properties and validities of Tavasolli's original SPQ-short version as well as an alternative short version based on different psychometric item-selection criteria. We can show here that our alternative SPQ-short version, overlapping with the original short-version in 61% of its items, exhibits superior reliabilities, reasonable concurrent validities with other related measures. It, furthermore, exhibits excellent differentiation between autistic and non-autistic samples, underscoring its utility as a screening instrument in research and a clinical instrument to supplement the ASD diagnostic process

Diet and metabolic state are the main factors determining concentrations of perfluoroalkyl substances in female polar bears from Svalbard

Perfluoroalkyl substances (PFASs) have been detected in organisms worldwide, including Polar Regions. The polar bear (Ursus maritimus), the top predator of Arctic marine ecosystems, accumulates high concentrations of PFASs, which may be harmful to their health. The aim of this study was to investigate which factors (habitat quality, season, year, diet, metabolic state [i.e. feeding/fasting], breeding status and age) predict PFAS concentrations in female polar bears captured on Svalbard (Norway). We analysed two perfluoroalkyl sulfonates (PFSAs: PFHxS and PFOS) and C8-C13 perfluoroalkyl carboxylates (PFCAs) in 112 plasma samples obtained in April and September 2012–2013. Nitrogen and carbon stable isotope ratios (δ15N, δ13C) in red blood cells and plasma, and fatty acid profiles in adipose tissue were used as proxies for diet. We determined habitat quality based on movement patterns, capture position and resource selection functions, which are models that predict the probability of use of a resource unit. Plasma urea to creatinine ratios were used as proxies for metabolic state (i.e. feeding or fasting state). Results were obtained from a conditional model averaging of 42 general linear mixed models. Diet was the most important predictor of PFAS concentrations. PFAS concentrations were positively related to trophic level and marine diet input. High PFAS concentrations in females feeding on the eastern part of Svalbard, where the habitat quality was higher than on the western coast, were likely related to diet and possibly to abiotic factors. Concentrations of PFSAs and C8-C10 PFCAs were higher in fasting than in feeding polar bears and PFOS was higher in females with cubs of the year than in solitary females. Our findings suggest that female polar bears that are exposed to the highest levels of PFAS are those 1) feeding on high trophic level sea ice-associated prey, 2) fasting and 3) with small cubs

Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation

Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1-/- and Casp11-/- mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1-/- mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis

Multiple-stressor effects in an apex predator: combined influence of pollutants and sea ice decline on lipid metabolism in polar bears

There is growing evidence from experimental and human epidemiological studies that many pollutants can disrupt lipid metabolism. In Arctic wildlife, the occurrence of such compounds could have serious consequences for seasonal feeders. We set out to study whether organohalogenated compounds (OHCs) could cause disruption of energy metabolism in female polar bears ( Ursus maritimus ) from Svalbard, Norway (n = 112). We analyzed biomarkers of energy metabolism including the abundance profiles of nine lipid-related genes, fatty acid (FA) synthesis and elongation indices in adipose tissue, and concentrations of lipid-related variables in plasma (cholesterol, high-density lipoprotein, triglycerides). Furthermore, the plasma metabolome and lipidome were characterized by low molecular weight metabolites and lipid fingerprinting, respectively. Polychlorinated biphenyls, chlordanes, brominated diphenyl ethers and perfluoroalkyl substances were significantly related to biomarkers involved in lipid accumulation, FA metabolism, insulin utilization, and cholesterol homeostasis. Moreover, the effects of pollutants were measurable at the metabolome and lipidome levels. Our results indicate that several OHCs affect lipid biosynthesis and catabolism in female polar bears. Furthermore, these effects were more pronounced when combined with reduced sea ice extent and thickness, suggesting that climate- driven sea ice decline and OHCs have synergistic negative effects on polar bears