8 research outputs found
Members of a highly widespread bacteriophage family are hallmarks of metabolic syndrome gut microbiomes
No full textThere is significant interest in altering the course of cardiometabolic disease development via the gut microbiome. Nevertheless, the highly abundant phage members -which impact gut bacteria- of the complex gut ecosystem remain understudied. Here, we characterized gut phageome changes associated with metabolic syndrome (MetS), a highly prevalent clinical condition preceding cardiometabolic disease. MetS gut phageome populations exhibited decreased richness and diversity, but larger inter-individual variation. These populations were enriched in phages infecting Bacteroidaceae and depleted in those infecting Ruminococcaeae. Differential abundance analysis identified eighteen viral clusters (VCs) as significantly associated with either MetS or healthy phageomes. Among these are a MetS-associated Roseburia VC that is related to healthy control-associated Faecalibacterium and Oscillibacter VCs. Further analysis of these VCs revealed the Candidatus Heliusviridae, a highly widespread gut phage lineage found in 90+% of the participants. The identification of the temperate Ca. Heliusviridae provides a novel starting point to a better understanding of the effect that phages have on their bacterial hosts and the role that this plays in MetS
Causality of small and large intestinal microbiota in weight regulation and insulin resistance
No full textObjective<br/><br/>The twin pandemics of obesity and Type 2 diabetes (T2D) are a global challenge for health care systems. Changes in the environment, behavior, diet, and lifestyle during the last decades are considered the major causes. A Western diet, which is rich in saturated fat and simple sugars, may lead to changes in gut microbial composition and physiology, which have recently been linked to the development of metabolic diseases.<br/><br/>Methods<br/><br/>We will discuss evidence that demonstrates the influence of the small and large intestinal microbiota on weight regulation and the development of insulin resistance, based on literature search.<br/><br/>Results<br/><br/>Altered large intestinal microbial composition may promote obesity by increasing energy harvest through specialized gut microbes. In both large and small intestine, microbial alterations may increase gut permeability that facilitates the translocation of whole bacteria or endotoxic bacterial components into metabolic active tissues. Moreover, changed microbial communities may affect the production of satiety-inducing signals. Finally, bacterial metabolic products, such as short chain fatty acids (SCFAs) and their relative ratios, may be causal in disturbed immune and metabolic signaling, notably in the small intestine where the surface is large. The function of these organs (adipose tissue, brain, liver, muscle, pancreas) may be disturbed by the induction of low-grade inflammation, contributing to insulin resistance.<br/><br/>Conclusions<br/><br/>Interventions aimed to restoring gut microbial homeostasis, such as ingestion of specific fibers or therapeutic microbes, are promising strategies to reduce insulin resistance and the related metabolic abnormalities in obesity, metabolic syndrome, and type 2 diabetes. This article is part of a special issue on microbiota.<br/><p>Objective The twin pandemics of obesity and Type 2 diabetes (T2D) are a global challenge for health care systems. Changes in the environment, behavior, diet, and lifestyle during the last decades are considered the major causes. A Western diet, which is rich in saturated fat and simple sugars, may lead to changes in gut microbial composition and physiology, which have recently been linked to the development of metabolic diseases. Methods We will discuss evidence that demonstrates the influence of the small and large intestinal microbiota on weight regulation and the development of insulin resistance, based on literature search. Results Altered large intestinal microbial composition may promote obesity by increasing energy harvest through specialized gut microbes. In both large and small intestine, microbial alterations may increase gut permeability that facilitates the translocation of whole bacteria or endotoxic bacterial components into metabolic active tissues. Moreover, changed microbial communities may affect the production of satiety-inducing signals. Finally, bacterial metabolic products, such as short chain fatty acids (SCFAs) and their relative ratios, may be causal in disturbed immune and metabolic signaling, notably in the small intestine where the surface is large. The function of these organs (adipose tissue, brain, liver, muscle, pancreas) may be disturbed by the induction of low-grade inflammation, contributing to insulin resistance. Conclusions Interventions aimed to restoring gut microbial homeostasis, such as ingestion of specific fibers or therapeutic microbes, are promising strategies to reduce insulin resistance and the related metabolic abnormalities in obesity, metabolic syndrome, and type 2 diabetes. This article is part of a special issue on microbiota.</p
Yeast cell wall derivatives as a potential strategy for modulating oral microbiota and dental plaque biofilm
No full textIntroduction: Derivatives from Saccharomyces cerevisiae yeast including yeast extracts and yeast cell walls are sustainable sources of valuable nutrients, including dietary fibers and proteins. Previous studies have shown that certain components from these yeast derivatives can inhibit the growth of harmful intestinal bacteria and promote the growth of beneficial bacteria. However, the effects of yeast derivatives on oral health have not yet been investigated. Methods: An in vitro oral biofilm model was employed to examine the impacts of yeast derivatives on the oral microbiota and their potential benefits for maintaining oral homeostasis. The model incorporated dental plaque donor material from both healthy and periodontitis diagnosed individuals. Biofilm formation, density, and microbial composition were quantified. Additionally, the production of short-chain fatty acids in the biofilm supernatants was measured. Results: Yeast extracts had only minor effects on oral biofilm formation. In contrast, yeast cell wall derivatives, which are rich in polysaccharides such as beta-glucans and mannans, significantly reduced the density of the oral biofilms in vitro. This reduction in biofilm density was associated with an overall shift in the bacterial community composition, including an increase in beneficial bacteria and a decrease in the abundance of Tannerella forsythia, an important species involved in bacterial coaggregation and the development and maturation of the oral biofilm. Furthermore, the yeast cell wall derivatives decreased the production of short-chain fatty acids, including acetic and butyric acid. These findings were consistent across both healthy and periodontitis microbiomes. Conclusion: This study has demonstrated the potential of yeast cell wall derivatives to positively impact oral health by significantly reducing biofilm density, modulating the oral microbial composition, and decreasing the production of short-chain fatty acids. The observed effects highlight the promising applications of these yeast-based compounds as an approach to managing oral diseases. Further research is needed to fully elucidate the mechanisms of action and explore the clinical potential of yeast cell wall derivatives in promoting and maintaining oral health.</p
Faecal Microbiota transplantation affects liver DNA methylation in Non-alcoholic fatty liver disease: a multi-omics approach
No full textABSTRACTIndividuals with nonalcoholic fatty liver disease (NAFLD) have an altered gut microbiota composition. Moreover, hepatic DNA methylation may be altered in the state of NAFLD. Using a fecal microbiota transplantation (FMT) intervention, we aimed to investigate whether a change in gut microbiota composition relates to altered liver DNA methylation in NAFLD. Moreover, we assessed whether plasma metabolite profiles altered by FMT relate to changes in liver DNA methylation. Twenty-one individuals with NAFLD underwent three 8-weekly vegan allogenic donor (n = 10) or autologous (n = 11) FMTs. We obtained hepatic DNA methylation profiles from paired liver biopsies of study participants before and after FMTs. We applied a multi-omics machine learning approach to identify changes in the gut microbiome, peripheral blood metabolome and liver DNA methylome, and analyzed cross-omics correlations. Vegan allogenic donor FMT compared to autologous FMT induced distinct differential changes in I) gut microbiota profiles, including increased abundance of Eubacterium siraeum and potential probiotic Blautia wexlerae; II) plasma metabolites, including altered levels of phenylacetylcarnitine (PAC) and phenylacetylglutamine (PAG) both from gut-derived phenylacetic acid, and of several choline-derived long-chain acylcholines; and III) hepatic DNA methylation profiles, most importantly in Threonyl-TRNA Synthetase 1 (TARS) and Zinc finger protein 57 (ZFP57). Multi-omics analysis showed that Gemmiger formicillis and Firmicutes bacterium_CAG_170 positively correlated with both PAC and PAG. E siraeum negatively correlated with DNA methylation of cg16885113 in ZFP57. Alterations in gut microbiota composition by FMT caused widespread changes in plasma metabolites (e.g. PAC, PAG, and choline-derived metabolites) and liver DNA methylation profiles in individuals with NAFLD. These results indicate that FMTs might induce metaorganismal pathway changes, from the gut bacteria to the liver
Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction
No full textHyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied, but causal links remain enigmatic. Obese individuals with or without T2D were included from two independent Dutch cohorts. Human data were translated in vitro and in vivo by using pancreatic islets from C57BL6/J mice and by injecting flagellin into obese mice. Flagellin is part of the bacterial locomotor appendage flagellum, present in gut bacteria including Enterobacteriaceae, which we show to be more abundant in the gut of individuals with T2D. Subsequently, flagellin induces a pro-inflammatory response in pancreatic islets mediated by the Toll-like receptor (TLR)-5 expressed on resident islet macrophages. This inflammatory response is associated with beta-cell dysfunction, characterized by reduced insulin gene expression, impaired proinsulin processing and stress-induced insulin hypersecretion in vitro and in vivo in mice. We postulate that increased systemically disseminated flagellin in T2D is a contributing factor to beta-cell failure in time and represents a novel therapeutic target
Detection of the gravitational redshift in the orbit of the star S2 near the Galactic centre massive black hole
No full textInternational audienceThe highly elliptical, 16-year-period orbit of the star S2 around the massive black hole candidate Sgr A✻ is a sensitive probe of the gravitational field in the Galactic centre. Near pericentre at 120 AU ≈ 1400 Schwarzschild radii, the star has an orbital speed of ≈7650 km s−1, such that the first-order effects of Special and General Relativity have now become detectable with current capabilities. Over the past 26 years, we have monitored the radial velocity and motion on the sky of S2, mainly with the SINFONI and NACO adaptive optics instruments on the ESO Very Large Telescope, and since 2016 and leading up to the pericentre approach in May 2018, with the four-telescope interferometric beam-combiner instrument GRAVITY. From data up to and including pericentre, we robustly detect the combined gravitational redshift and relativistic transverse Doppler effect for S2 of z = Δλ / λ ≈ 200 km s−1/c with different statistical analysis methods. When parameterising the post-Newtonian contribution from these effects by a factor f , with f = 0 and f = 1 corresponding to the Newtonian and general relativistic limits, respectively, we find from posterior fitting with different weighting schemes f = 0.90 ± 0.09|stat ± 0.15|sys. The S2 data are inconsistent with pure Newtonian dynamics.Key words: Galaxy: center / gravitation / black hole physics⋆ This paper is dedicated to Tal Alexander, who passed away about a week before the pericentre approach of S2.⋆⋆ GRAVITY is developed in a collaboration by the Max Planck Institute for extraterrestrial Physics, LESIA of Paris Observatory/CNRS/Sorbonne Université/Univ. Paris Diderot and IPAG of Université Grenoble Alpes/CNRS, the Max Planck Institute for Astronomy, the University of Cologne, the CENTRA – Centro de Astrofisica e Gravitação, and the European Southern Observatory.⋆⋆⋆ Corresponding author: F. Eisenhauer e-mail: [email protected]
Imaging of mice and men; adventures in multispectral imaging
No full textCancer of the brain and CNS account for only 2% of new cancer cases in the UK however it is responsible for 7% of cancer deaths of those aged under 70 years of age. Although surgery falls short of a cure it is the primary method of treatment. Two of the key problems in tumour surgery in the brain are a) that many tumours are visually indistinguishable from normal tissue even for experienced surgeons and b) that the risk of post-surgical neurological deficit is related to the proximity of functional (or 'eloquent') neurological tissue. In collaboration with surgeons at the Southampton University NHS Hospitals Trust we seek to address both of these problems. Firstly there is literature evidence that normal and neoplastic tissue have different spectral characteristics in the visible and near-infrared region. We investigate whether these can be practically imaged intraoperatively to establish disease state. Secondly the redox state of haemoglobin is known to affect it's visible and near-infrared spectral characteristics. This project investigates whether it is possible to identify the haemodynamic response associated with functional activity intraoperatively in the human brain. Prion diseases are fatal chronic neurodegenerative diseases of animals and man. They have gained notoriety due to recent outbreaks of Bovine Spongiform Encephalopathy (BSE) and the evidence that they can be transmitted between species, including to man. Exposure to BSE infected material has been shown to cause variant Creutzfeldt-Jacob disease in man. Prion disease is also used as a model of other neurodegenerative diseases, such as Alzheimers disease. Remarkably little is known about this class of disease including the specific cause of the neurodegeneration. Prions are a mis-folded protein which have a different conformation than the normal protein. Certain spectral features in the mid infrared region are associated with protein conformation. In collaboration with neuro-biologists within the university and using a synchrotron light source we investigate the application of multispectral imaging in early stage prion disease. By analysis of the protein conformation sensitivity of the mid infrared spectra (with particular interest in the Amide I band) we seek to identify structurally relevant markers in a mouse model before clinical symptoms of the disease are evident. This may lead to better understanding of the disease progression and the neurotoxic element
Towards the optimization of tumor targeting radiolabeled peptides for molecular imaging and therapy
No full textRadiopharmaceuticals based on regulatory peptides have become an indispensable tool in nuclear medicine for the diagnosis (molecular imaging) and radionuclide therapy of cancer. The specificity of these radiopeptides towards G-protein-coupled receptors (GPCR), which are overexpressed by various cancer cells and their favorable pharmacological properties make them ideal vectors for the targeted delivery of radioactivity to tumors and metastases. However, there are still challenges to be met in order to develop peptide-based radiopharmaceuticals with ideal properties in terms of imaging quality and therapeutic efficacy where therapeutic radionuclides are employed.
A potential drawback of several radiolabeled peptides under investigation is represented by a rapid washout of radioactivity after receptor-mediated internalization into tumor cells. In certain cases, the washout of radioactivity from cells occurs at a rate comparable to that required for accumulation in cancerous tissues. This not only renders the initial efforts of targeted delivery in part futile but also results in an imaging quality and therapeutic efficiency lower than achievable. To address this issue, novel strategies are needed to improve the cellular retention of the radioactivity. A possible approach may include the employment of multi-targeting radioconjugates made of different moieties specific for extra- and intracellular targets. Towards this goal, we investigated the combination of tumor targeting peptides with an additional moiety specific for an intracellular target and radiolabeled the conjugate with the 99mTc-tricarbonyl core as a reporter probe for single-photon emission computed tomography (SPECT). We envisioned that enabling interactions of radioconjugates with intracellular targets after receptor-mediated uptake by endocytosis would result in the trapping of radioactivity in tumors.
Specifically, we combined a modified binding sequence of the peptide bombesin, [Nle14]BBS(7-14), for extracellular targeting of the tumor-associated gastrin releasing peptide receptor (GRP-r) with a triphenylphosphonium group for intracellular targeting of the organelle mitochondria or with the peptide shepherdin, an inhibitor of the cytosolic chaperon heat-shock protein 90 (Hsp90). The conjugates were assembled by the "Click-to-Chelate" approach, an efficient synthetic strategy for the preparation of bifunctional 99mTc-labeled radiopharmaceuticals. The radioconjugates were evaluated in vitro using GRP-r-overexpressing PC-3 cells. Our investigations revealed that the additional moiety for intracellular targeting did not impact the tumor-targeting capability of the bombesin-derived conjugates but neither did it result in an improved cellular retention of the radioactivity. Drawing from our experience and considering recent literature data, we conclude that endosomal entrapment or lysosomal degradation of the bifunctional radiopeptide conjugates is likely to impede with intracellular interactions and thus, responsible for the observed unaltered cellular efflux of radioactivity. Future studies will be directed towards the combination of bifunctional radiopeptide conjugates with drug delivery systems designed to facilitate endosomal escape.
A different approach for the optimization of peptidic radiotracers includes the improvement of their metabolic stability since most of them exhibit a very short biological half-life due to rapid degradation by endogenous peptidases. Enhancement of the stability of radiopeptides results in a prolonged circulation time in the blood and, as a consequence, an improved tumor uptake in vivo. A number of different strategies have been reported for the stabilization of regulatory peptides, however, with varying degree of success in providing peptidomimetics with retained affinity to the corresponding GPCR. In an effort to probe a novel peptide backbone modification methodology, the use of 1,4-disubstituted 1,2,3-triazoles as metabolically stable trans amide bond isosters was investigated. The systematic replacement of amide bonds within the binding sequence of the tumor-affine peptide bombesin, [Nle14]BBS(7-14), by triazoles provided a series of 177Lu-labeled peptidomimetics with both retained affinity towards GRP-r and an increased stability in blood serum. In vivo evaluation of a lead compound in xenografted mice showed that the enhanced stability of the radiopeptidomimetic resulted in a doubling of the uptake of radioactivity in tumors. The described amide-to-triazole substitution methodology is currently being applied to other tumor targeting peptides of medicinal interest.
The specificity and affinity of radiopeptides towards different receptor subtypes is another aspect to consider for optimizations. Inhomogeneous expression of receptor subtypes by tumors may influence the efficiency of a radiotracer. For example, intratumoral administration of radiolabeled substance P (SP) led to significant differences in the clinical response of patients suffering from gliomas despite proven expression of its target, the neurokinin-1 receptor (NK1R). In an effort to identify factors that may be responsible for the varying therapeutic outcome observed, several SP conjugates were evaluated in vitro using four established glioma cell lines differing in their level of RNA expression of the full length and truncated receptor isoforms. Cell binding and internalization of SP-conjugates were only observed with cell lines exhibiting high expression of RNA of the full-length NK1R. Pre-therapeutic screening for NK1R isoforms may therefore be advisable for the selection of glioma patients for NK1R-targeted radionuclide therapy
