Specific Wheat Fractions Influence Hepatic Fat Metabolism in Diet-Induced Obese Mice

Low whole grain consumption is a risk factor for the development of non-communicable diseases such as type 2 diabetes. Dietary fiber and phytochemicals are bioactive grain compounds, which could be involved in mediating these beneficial effects. These compounds are not equally distributed in the wheat grain, but are enriched in the bran and aleurone fractions. As little is known on physiological effects of different wheat fractions, the aim of this study was to investigate this aspect in an obesity model. For twelve weeks, C57BL/6J mice were fed high-fat diets (HFD), supplemented with one of four wheat fractions: whole grain flour, refined white flour, bran, or aleurone. The different diets did not affect body weight, however bran and aleurone decreased liver triglyceride content, and increased hepatic n-3 polyunsaturated fatty acid (PUFA) concentrations. Furthermore, lipidomics analysis revealed increased PUFA concentration in the lipid classes of phosphatidylcholine (PC), PC-ether, and phosphatidylinositol in the plasma of mice fed whole grain, bran, and aleurone supplemented diets, compared to refined white flour. Furthermore, bran, aleurone, and whole grain supplemented diets increased microbial α-diversity, but only bran and aleurone increased the cecal concentrations of short-chain fatty acids. The effects on hepatic lipid metabolism might thus at least partially be mediated by microbiota-dependent mechanism

Gut microbiome composition in obese and non-obese persons: a systematic review and meta-analysis

Whether the gut microbiome in obesity is characterized by lower diversity and altered composition at the phylum or genus level may be more accurately investigated using high-throughput sequencing technologies. We conducted a systematic review in PubMed and Embase including 32 cross-sectional studies assessing the gut microbiome composition by high-throughput sequencing in obese and non-obese adults. A significantly lower alpha diversity (Shannon index) in obese versus non-obese adults was observed in nine out of 22 studies, and meta-analysis of seven studies revealed a non-significant mean difference (−0.06, 95% CI −0.24, 0.12, I(2) = 81%). At the phylum level, significantly more Firmicutes and fewer Bacteroidetes in obese versus non-obese adults were observed in six out of seventeen, and in four out of eighteen studies, respectively. Meta-analyses of six studies revealed significantly higher Firmicutes (5.50, 95% 0.27, 10.73, I(2) = 81%) and non-significantly lower Bacteroidetes (−4.79, 95% CI −10.77, 1.20, I(2) = 86%). At the genus level, lower relative proportions of Bifidobacterium and Eggerthella and higher Acidaminococcus, Anaerococcus, Catenibacterium, Dialister, Dorea, Escherichia-Shigella, Eubacterium, Fusobacterium, Megasphera, Prevotella, Roseburia, Streptococcus, and Sutterella were found in obese versus non-obese adults. Although a proportion of studies found lower diversity and differences in gut microbiome composition in obese versus non-obese adults, the observed heterogeneity across studies precludes clear answers

Global Genotype-Phenotype Correlations in Pseudomonas aeruginosa

Once the genome sequence of an organism is obtained, attention turns from identifying genes to understanding their function, their organization and control of metabolic pathways and networks that determine its physiology. Recent technical advances in acquiring genome-wide data have led to substantial progress in identifying gene functions. However, we still do not know the function of a large number of genes and, even when a gene product has been assigned to a functional class, we cannot normally predict its contribution to the phenotypic behaviour of the cell or organism - the phenome. In this study, we assessed bacterial growth parameters of 4030 non-redundant PA14 transposon mutants in the pathogenic bacterium Pseudomonas aeruginosa. The genome-wide simultaneous analysis of 119 distinct growth-related phenotypes uncovered a comprehensive phenome and provided evidence that most genotypes are not phenotypically isolated but rather define specific complex phenotypic clusters of genotypes. Since phenotypic overlap was demonstrated to reflect the relatedness of genotypes on a global scale, knowledge of an organism's phenome might significantly contribute to the advancement of functional genomics

The molecular pharmacology and in vivo activity of 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase.

The microsomal prostaglandin E2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of α-(n-hexyl)- substituted pirinixic acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino) pyrimidin-2-ylthio)octanoic acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC 50 = 3.4 μM), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 (KD = 10-14 μM). In lipopolysaccharide-stimulated human whole blood, PGE2 formation was concentration dependently inhibited (IC50 =2 μM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B2 and 6-keto PGF1α and the COX-1-derived 12(S)-hydroxy-5-cis-8,10- transheptadecatrienoic acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE2 and leukotriene B4 but also of 6-keto PGF 1α. Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo

Potential contribution of HIV during first-line tuberculosis treatment to subsequent rifampicin-monoresistant tuberculosis and acquired tuberculosis drug resistance in South Africa: a retrospective molecular epidemiology study

Background: South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis. Methods: In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness. Findings: The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22.7%) with RMR tuberculosis and 1354 (66.3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2.07, 95% CI 1.35-3.18), and three or more previous tuberculosis treatment episodes versus one (1.96, 1.21-3.17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30.8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4.96, 3.40-7.23), HIV positivity during previous tuberculosis treatment (1.71, 1.03-2.84), and diagnosis in 2013-17 (1.42, 1.02-1.99) versus 2008-12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5.13, 1.61-16.32) was associated with uniqueness as was female sex (2.50 [1.18-5.26]). Interpretation: These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk. Funding: Swiss National Science Foundation, South African National Research Foundation, and Wellcome Trust

Capsule depolymerase activity of phages infecting the Acinetobacter baumannii-calcoaceticus complex

To be able to enter and replicate in exopolysaccharide (EPS) slime or capsule surrounded bacteria, bacteriophages (phages) have evolved the ability to overcome the EPS structure by producing virion-associated proteins with polysaccharide depolymerization activities. We have studied phages infecting the Acinetobacter baumannii-Acinetobacter calcoaceticus (ACB) complex, which groups A. baumannii, A. calcoaceticus, A. pittii, A. nosocomialis and A. seifertii species. It is known that about 100 different capsule polysaccharide (CPS) synthetic loci are found in A. baumannii genomes alone. This situation is even more complex, with some strains of A. baumannii having nearly identical CPS synthetic loci to strains of A. nosocomialis or A. pittii, and supposedly producing identical CPS. We have isolated and characterized 21 phages infecting the ACB complex and demonstrate that they have specialized depolymerases that degrade polymers (e.g. capsular and structural polysaccharides) to facilitate their access to the hosts. To further characterize the phage-host interactions, we have sequenced bacterial genomes and mutated the CPS synthetic loci to create CPS-deficient mutants, to prove that the ACB phages recognize the CPS as the primary receptor. We further demonstrate that recombinantly expressed depolymerases are active and key components in the tail specificity apparatus of Podoviridae viruses. We could conclude that phages infecting the ACB complex represent a source of enzymes that degrade a complex variety of polymeric substances that can be further exploited as a serotyping scheme currently inexistent for Acinetobacter species

The Pseudomonas aeruginosa Transcriptional Landscape Is Shaped by Environmental Heterogeneity and Genetic Variation

Phenotypic variability among bacteria depends on gene expression in response to different environments, and it also reflects differences in genomic structure. In this study, we analyzed transcriptome sequencing (RNA-seq) profiles of 151 Pseudomonas aeruginosa clinical isolates under standard laboratory conditions and of one P. aeruginosa type strain under 14 different environmental conditions. Our approach allowed dissection of the impact of the genetic background versus environmental cues on P. aeruginosa gene expression profiles and revealed that phenotypic variation was larger in response to changing environments than between genomically different isolates. We demonstrate that mutations within the global regulator LasR affect more than one trait (pleiotropy) and that the interaction between mutations (epistasis) shapes the P. aeruginosa phenotypic plasticity landscape. Because of pleiotropic and epistatic effects, average genotype and phenotype measures appeared to be uncorrelated in P. aeruginosa