Genome-scale analyses of health-promoting bacteria: probiogenomics

The human body is colonized by an enormous population of bacteria (microbiota) that provides the host with coding capacity and metabolic activities. Among the human gut microbiota are health-promoting indigenous species (probiotic bacteria) that are commonly consumed as live dietary supplements. Recent genomics-based studies (probiogenomics) are starting to provide insights into how probiotic bacteria sense and adapt to the gastrointestinal tract environment. In this Review, we discuss the application of probiogenomics in the elucidation of the molecular basis of probiosis using the well-recognized model probiotic bacteria genera Bifidobacterium and Lactobacillus as examples

Effect of interventions to reduce potentially inappropriate use of drugs in nursing homes: a systematic review of randomised controlled trials

Background Studies have shown that residents in nursing homes often are exposed to inappropriate medication. Particular concern has been raised about the consumption of psychoactive drugs, which are commonly prescribed for nursing home residents suffering from dementia. This review is an update of a Norwegian systematic review commissioned by the Norwegian Directorate of Health. The purpose of the review was to identify and summarise the effect of interventions aimed at reducing potentially inappropriate use or prescribing of drugs in nursing homes. Methods We searched for systematic reviews and randomised controlled trials in the Cochrane Library, MEDLINE, EMBASE, ISI Web of Knowledge, DARE and HTA, with the last update in April 2010. Two of the authors independently screened titles and abstracts for inclusion or exclusion. Data on interventions, participants, comparison intervention, and outcomes were extracted from the included studies. Risk of bias and quality of evidence were assessed using the Cochrane Risk of Bias Table and GRADE, respectively. Outcomes assessed were use of or prescribing of drugs (primary) and the health-related outcomes falls, physical limitation, hospitalisation and mortality (secondary). Results Due to heterogeneity in interventions and outcomes, we employed a narrative approach. Twenty randomised controlled trials were included from 1631 evaluated references. Ten studies tested different kinds of educational interventions while seven studies tested medication reviews by pharmacists. Only one study was found for each of the interventions geriatric care teams, early psychiatric intervening or activities for the residents combined with education of health care personnel. Several reviews were identified, but these either concerned elderly in general or did not satisfy all the requirements for systematic reviews. Conclusions Interventions using educational outreach, on-site education given alone or as part of an intervention package and pharmacist medication review may under certain circumstances reduce inappropriate drug use, but the evidence is of low quality. Due to poor quality of the evidence, no conclusions may be drawn about the effect of the other three interventions on drug use, or of either intervention on health-related outcomes

Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris

Objective: There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA). Methods: In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR. Results: Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p,0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p,0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p,0.01. Conclusion: Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that th

Evolutionary history of the OmpR/IIIA family of signal transduction two component systems in Lactobacillaceae and Leuconostocaceae

<p>Abstract</p> <p>Background</p> <p>Two component systems (TCS) are signal transduction pathways which typically consist of a sensor histidine kinase (HK) and a response regulator (RR). In this study, we have analyzed the evolution of TCS of the OmpR/IIIA family in <it>Lactobacillaceae </it>and <it>Leuconostocaceae</it>, two families belonging to the group of lactic acid bacteria (LAB). LAB colonize nutrient-rich environments such as foodstuffs, plant materials and the gastrointestinal tract of animals thus driving the study of this group of both basic and applied interest.</p> <p>Results</p> <p>The genomes of 19 strains belonging to 16 different species have been analyzed. The number of TCS encoded by the strains considered in this study varied between 4 in <it>Lactobacillus helveticus </it>and 17 in <it>Lactobacillus casei</it>. The OmpR/IIIA family was the most prevalent in <it>Lactobacillaceae </it>accounting for 71% of the TCS present in this group. The phylogenetic analysis shows that no new TCS of this family has recently evolved in these <it>Lactobacillaceae </it>by either lineage-specific gene expansion or domain shuffling. Furthermore, no clear evidence of non-orthologous replacements of either RR or HK partners has been obtained, thus indicating that coevolution of cognate RR and HKs has been prevalent in <it>Lactobacillaceae</it>.</p> <p>Conclusions</p> <p>The results obtained suggest that vertical inheritance of TCS present in the last common ancestor and lineage-specific gene losses appear as the main evolutionary forces involved in their evolution in <it>Lactobacillaceae</it>, although some HGT events cannot be ruled out. This would agree with the genomic analyses of <it>Lactobacillales </it>which show that gene losses have been a major trend in the evolution of this group.</p

Protective Effector Memory CD4 T Cells Depend on ICOS for Survival

Memory CD4 T cells play a vital role in protection against re-infection by pathogens as diverse as helminthes or influenza viruses. Inducible costimulator (ICOS) is highly expressed on memory CD4 T cells and has been shown to augment proliferation and survival of activated CD4 T cells. However, the role of ICOS costimulation on the development and maintenance of memory CD4 T cells remains controversial. Herein, we describe a significant defect in the number of effector memory (EM) phenotype cells in ICOS−/− and ICOSL−/− mice that becomes progressively more dramatic as the mice age. This decrease was not due to a defect in the homeostatic proliferation of EM phenotype CD4 T cells in ICOS−/− or ICOSL−/− mice. To determine whether ICOS regulated the development or survival of EM CD4 T cells, we utilized an adoptive transfer model. We found no defect in development of EM CD4 T cells, but long-term survival of ICOS−/− EM CD4 T cells was significantly compromised compared to wild-type cells. The defect in survival was specific to EM cells as the central memory (CM) ICOS−/− CD4 T cells persisted as well as wild type cells. To determine the physiological consequences of a specific defect in EM CD4 T cells, wild-type and ICOS−/− mice were infected with influenza virus. ICOS−/− mice developed significantly fewer influenza-specific EM CD4 T cells and were more susceptible to re-infection than wild-type mice. Collectively, our findings demonstrate a role for ICOS costimulation in the maintenance of EM but not CM CD4 T cells

Proteolytic Activities of Oral Bacteria on ProMMP-9 and the Effect of Synthetic Proteinase Inhibitors

Tissue reactions to bacteria lead to proinflammatory reactions involving matrix metalloproteinases (MMPs). Synthetic protease inhibitors may offer new possibilities to regulate bacterial proteases. We investigated proteolytic activities of certain periodontal bacteria, their effects on the latent proMMP-9, and the effects of synthetic MMP inhibitors and a serine protease inhibitor Pefabloc. The strains studied were Porphyromonas gingivalis, Prevotella intermedia, Peptostreptoccus micros, Prevotella nigrescens, Fusobacterium nucleatum, and 5 Aggregatibacter actinomycetemcomitans serotypes. Their gelatinolytic activities and the effects of certain synthetic MMP inhibitors and Pefabloc were analyzed by zymography. Bacterial effects on proMMP-9 conversion were investigated by Western immunoblot. All investigated periodontal bacteria produced gelatinolytic cell-bound and extracellular proteinases which could fragment latent proMMP-9, suggesting co-operative processing cascades in oral tissue remodeling. A. actinomycetemcomitans produced the weakest gelatinolytic activity. Synthetic proteinase inhibitors exhibited slight but clear reductive effects on the bacterial proteolytic activities. We conclude that targeted anti-proteolytic treatment modalities against bacterial-host proteolytic cascades can be developed

Th17-related cytokines: new players in the control of chronic intestinal inflammation

Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD) in man, are thought to be caused by an excessive and poorly controlled immune response that is directed against components of the normal microflora. The exact sequence of events by which this pathological process is triggered and maintained is not fully understood, but studies in experimental models of IBD and data emerging from recent clinical trials indicate that T cell-derived cytokines are crucial mediators of the tissue damage. Although CD and UC have been traditionally considered two typical examples of T helper (Th)1 or Th2-associated disease respectively, it is now known that CD- and UC-related inflammation is also marked by enhanced production of cytokines made by a distinct subset of Th cells, termed Th17 cells. Th17 cytokines can have both tissue-protective and inflammatory effects in the gut and there is evidence that Th17 cells can alter their cytokine program according to the stimuli received and convert into Th1-producing cells. These novel findings have contributed to advancing our understanding of mechanisms of gut tissue damage and open new avenues for development of therapeutic strategies in IBD

Context, cognition and communication in language

Questions pertaining to the unique structure and organisation of language have a long history in the field of linguistics. In recent years, researchers have explored cultural evolutionary explanations, showing how language structure emerges from weak biases amplified over repeated patterns of learning and use. One outstanding issue in these frameworks is accounting for the role of context. In particular, many linguistic phenomena are said to to be context-dependent; interpretation does not take place in a void, and requires enrichment from the current state of the conversation, the physical situation, and common knowledge about the world. Modelling the relationship between language structure and context is therefore crucial for developing a cultural evolutionary approach to language. One approach is to use statistical analyses to investigate large-scale, cross-cultural datasets. However, due to the inherent limitations of statistical analyses, especially with regards to the inadequacy of these methods to test hypotheses about causal relationships, I argue that experiments are better suited to address questions pertaining to language structure and context. From here, I present a series of artificial language experiments, with the central aim being to test how manipulations to context influence the structure and organisation of language. Experiment 1 builds upon previous work in iterated learning and communication games through demonstrating that the emergence of optimal communication systems is contingent on the contexts in which languages are learned and used. The results show that language systems gradually evolve to only encode information that is informative for conveying the intended meaning of the speaker - resulting in markedly different systems of communication. Whereas Experiment 1 focused on how context influences the emergence of structure, Experiments 2 and 3 investigate under what circumstances do manipulations to context result in the loss of structure. While the results are inconclusive across these two experiments, there is tentative evidence that manipulations to context can disrupt structure, but only when interacting with other factors. Lastly, Experiment 4 investigates whether the degree of signal autonomy (the capacity for a signal to be interpreted without recourse to contextual information) is shaped by manipulations to contextual predictability: the extent to which a speaker can estimate and exploit contextual information a hearer uses in interpreting an utterance. When the context is predictable, speakers organise languages to be less autonomous (more context-dependent) through combining linguistic signals with contextual information to reduce effort in production and minimise uncertainty in comprehension. By decreasing contextual predictability, speakers increasingly rely on strategies that promote more autonomous signals, as these signals depend less on contextual information to discriminate between possible meanings. Overall, these experiments provide proof-of-concept for investigating the relationship between language structure and context, showing that the organisational principles underpinning language are the result of competing pressures from context, cognition, and communication

Aging and the mucosal immune system in the intestine

Bacterial and viral infections of the gastrointestinal tract are more common in the elderly and represent a major cause of morbidity and mortality. The mucosal immune system provides the first line of defence against pathogens acquired by ingestion and inhalation, but its function is adversely affected in the elderly. This aging-related decline in the immune function is termed immunosenescence and is associated with diminished abilities to generate protective immunity, reduced vaccine efficacy, increased incidence of cancer, inflammation and autoimmunity, and the impaired ability to generate tolerance to harmless antigens. In this review we describe our current understanding of the effects immunosenescence has on the innate and adaptive arms of the mucosal immune system in the intestine. Current estimates suggest that by the year 2050 up to 40 % of the UK population will be over 65 years old, bringing with it important health challenges. A thorough understanding of the mechanisms that contribute to the development of immunosenescence is therefore crucial to help identify novel approaches to improve mucosal immunity in the elderly