Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes.

Gut microbiota has recently been proposed as a crucial environmental factor in the development of metabolic diseases such as obesity and type 2 diabetes, mainly due to its contribution in the modulation of several processes including host energy metabolism, gut epithelial permeability, gut peptide hormone secretion, and host inflammatory state. Since the symbiotic interaction between the gut microbiota and the host is essentially reflected in specific metabolic signatures, much expectation is placed on the application of metabolomic approaches to unveil the key mechanisms linking the gut microbiota composition and activity with disease development. The present review aims to summarize the gut microbial-host co-metabolites identified so far by targeted and untargeted metabolomic studies in humans, in association with impaired glucose homeostasis and/or obesity. An alteration of the co-metabolism of bile acids, branched fatty acids, choline, vitamins (i.e., niacin), purines, and phenolic compounds has been associated so far with the obese or diabese phenotype, in respect to healthy controls. Furthermore, anti-diabetic treatments such as metformin and sulfonylurea have been observed to modulate the gut microbiota or at least their metabolic profiles, thereby potentially affecting insulin resistance through indirect mechanisms still unknown. Despite the scarcity of the metabolomic studies currently available on the microbial-host crosstalk, the data-driven results largely confirmed findings independently obtained from in vitro and animal model studies, putting forward the mechanisms underlying the implication of a dysfunctional gut microbiota in the development of metabolic disorders.

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. CONCLUSIONS These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Genetic redox dysregulation induces behavioural deficits in the adult mouse: an animal model for schizophrenia

Background: Glutathione (GSH), a major cellular redox regulator and antioxidant, is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. The gene of the key GSH-synthesizing enzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, is associated with schizophrenia, suggesting that the deficit in the GSH system is of genetic origin. Using the GCLM knock-out (KO) mouse as model system with 60% decreased brain GSH levels and, thus, strong vulnerability to oxidative stress, we have shown that GSH dysregulation results in abnormal mouse brain morphology (e.g., reduced parvalbumin, PV, immuno-reactivity in frontal areas) and function. Additional oxidative stress, induced by GBR12909 (a dopamine re-uptake inhibitor), enhances morphological changes even further. Aim: In the present study we use the GCLM KO mouse model system, asking now, whether GSH dysregulation also compromises mouse behaviour and cognition. Methods: Male and female wildtype (WT) and GCLM-KO mice are treated with GBR12909 or phosphate buffered saline (PBS) from postnatal day (P) 5 to 10, and are behaviourally tested at P 60 and older. Results: In comparison to WT, KO animals of both sexes are hyperactive in the open field, display more frequent open arm entries on the elevated plus maze, longer float latencies in the Porsolt swim test, and more frequent contacts of novel and familiar objects. Contrary to other reports of animal models with reduced PV immuno-reactivity, GCLM-KO mice display normal rule learning capacity and perform normally on a spatial recognition task. GCLM-KO mice do, however, show a strong deficit in object-recognition after a 15 minutes retention delay. GBR12909 treatment exerts no additional effect. Conclusions: The results suggest that animals with impaired regulation of brain oxidative stress are impulsive and have reduced behavioural control in novel, unpredictable contexts. Moreover, GSH dysregulation seems to induce a selective attentional or stimulus-encoding deficit: despite intensive object exploration, GCLM-KO mice cannot discriminate between novel and familiar objects. In conclusion, the present data indicate that GSH dysregulation may contribute to the manifestation of behavioural and cognitive anomalies that are associated with schizophrenia.

Report on the Special Investigation of the Nutrition Department of the Boone Community School District, For the Period August 30, 2004 through March 31, 2006 and Selected Activity for the period February 28, 2000 through March 31, 2006

Community School District Audit Report - Special Investigation

Perioperative nutrition is still a surgical orphan

Objective: To assess if screening programs and treatment of preoperative malnutrition have been implemented into surgical practice to decrease morbidity. There is strong evidence that postoperative morbidity can be minimized by early identifying and treating patients at nutritional risk before major surgery.The validated nutritional risk score (NRS) is recommended by the European Society of Parenteral and Enteral Nutrition for nutritional screening. It remains unclear whether routine preoperative nutritional assessment and perioperative nutrition is widely implemented.Methods: A survey was conducted in 173 Swiss and Austrian surgical departments. Implementation of nutritional screening, perioperative nutrition, and estimated impact on clinical outcome were assessed. Non-responders were repeatedly contacted by the authors.Results: The overall response rate was 55%, whereby 69% (54/78) of Swiss and 44% (42/95) of Austrian centers responded. Despite 80% and 59% of the responding centers are aware of a reduced complication rate and shortened hospital stay, respectively, only 20% of them implemented routine nutritional screening. Financial (49%) and logistic restrictions (33%) are the predominant reasons against the routine clinical use. Screening is mainly performed either in the outpatient's clinic (52%) or during admission (54%). The NRS is only used by 14%. Instead, various clinical (78%), e.g. BMI and laboratory findings (56%), e.g. albumine, are used. Indication for perioperative nutrition is based on preoperative screening in 49%.While 23% use preoperative nutrition, 68% apply nutritional support pre- and postoperatively. Preoperative nutritional treatment ranged from three days (33%), to five days (31%) and even seven days (20%).Conclusion: Despite malnutrition is well recognized as major risk factor for increased postoperative morbidity, the majority of surgeons are reluctant to implement routine screening and nutritional support. If nutritional assessment is performed, local institutional screening parameters are still preferred. It remains difficult to overcome traditions, and to change surgeon's mind.

Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models.

Abstract Significance: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology. Recent Advances: Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination. Critical Issues: Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication. Future Directions: These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds. Antioxid. Redox Signal. 18, 1428-1443.

Enteral versus parenteral nutrition: comparison of energy metabolism in lean and moderately obese women.

Continuous respiratory-exchange measurements were performed on ten moderately obese and ten lean young women for 1 h before, 3 h during, and 3 h after either parenteral (IV) or intragastric (IG) administration of a nutrient mixture infused at twice the postabsorptive, resting energy expenditure (REE). REE rose significantly from 0.98 +/- 0.02 to 1.13 +/- 0.03 kcal/min (IV) and from 0.99 +/- 0.02 to 1.13 +/- 0.02 kcal/min (IG) in the lean group; from 1.10 +/- 0.02 to 1.27 +/- 0.03 kcal/min (IV) and from 1.11 +/- 0.02 to 1.29 +/- 0.03 (IG) in the obese group. These increases resulted in similar nutrient-induced thermogenesis of 10.0 +/- 0.7% (IV) and 9.3 +/- 0.9% (IG) in the lean group; of 9.2 +/- 0.7% (IV) and 10.1 +/- 0.8% (IG) in the obese. Nutrient utilization was comparable in both groups and in both routes of administration, although the response time to IG feeding was delayed. These results showed no significant difference in both the thermogenic response and nutrient utilization between moderately obese and control groups using acute IV or IG feeding.

RECHERCHE TRANSLATIONNELLE EN NEUROSCIENCES PSYCHIATRIQUES: DE L'ANIMAL MODELE DE SCHIZOPHRENIE A LA DETECTION D'UNE DESORIENTATION SPATIALE, PRATIQUE OU SYMBOLIQUE CHEZ DES PATIENTS

La modélisation, chez l'animal, de maladies psychiatriques telles que la schizophrénie repose sur différentes démarches visant à induire des perturbations cérébrales similaires à celles observées dans la maladie. Nous avons cherché à étudier chez le rat les effets d'une diminution (50%) transitoire en glutathion (GSH) durant le développement (PND 5 à PND 16) à partir de l'implication, chez des adultes, des conséquences de cette perturbation dans des mécanismes fondamentaux de traitement de l'information sensorielle. Cette thèse évalue et documente les déficits de compétences de navigation spatiale dans ce modèle. Nous avons mis en évidence des effets comportementaux à partir de l'identification de différences particulières dans des tâches d'orientation: des difficultés, chez les rats ayant subi un déficit en GSH, à élaborer une représentation globale de l'environnement dans lequel ils se déplacent, difficultés compensées par une attention particulière aux détails visuels le composant. Cette stratégie réactive compensatoire est efficace lorsque les conditions permettent un ajustement continu aux repères visuels environnementaux. Elle ne permet cependant pas des prédictions et des attentes sur ce qui devrait être rencontré et perçu dans une certaine direction, dès qu'une partie des informations visuelles familières disparaît. Il faudrait pour cela une capacité fondée sur une représentation abstraite, à distance des modalités sensorielles qui en ont permis son élaboration. Notre thèse soutient que les déficits, supposés participer à l'émergence de certains symptômes de la maladie, auraient également des conséquences sur l'élaboration de la représentation spatiale nécessaire à des capacités d'orientation effectives et symboliques. - The study of a psychiatric disease such as schizophrenia in an animal model relies on different approaches attempting to replicate brain perturbations similar to those observed in the illness. In the present work, behavioural consequences of a functional deficit in brain connectivity and coordination were assessed in rats with a transitory glutathione (GSH) deficit induced during the postnatal development (PND 5-PND 16) with daily injections of BSO (1- buthionine-(S,R)- sulfoximine). We searched for a theoretical syndrome associating ecologically relevant behavioural adaptive deficits and resulting from the weakening of sensory integration processes. Our results revealed significant and specific deficit of BSO treated rats in spatial orientation tasks designed to test for cognitive mapping abilities. Treated rats behaved as if impaired in the proactive strategies supported by an abstract representation such as a cognitive map. In contrast their performances were preserved whenever the environmental conditions allowed for adaptative reactive strategies, an equivalent of the visual affordances described by Gibson (1958). This supports our thesis that BSO treated rats expressed difficulties in elaborating a global representation of the environment. This deficit was completely - or - partially compensated by the development of an increased attention to the environment's visual details. This compensatory reactive strategy requires a rich environment allowing for continuous adjustment to visual cues. However, such adjustment doesn't allow to predictions and expectancies about what should be met and perceived in a certain direction, when familiar visual spatial cues are missing. Such competencies require orientation based on the use of an abstract spatial representation, independent from the specific sensory modalities that have participated to its elaboration. The impairment of BSO rats such spatial representation could result from a deficit in the integration and organization of perceptual information. Our model leads to the hypothesis that these fundamental deficits might account for certain symptoms of schizophrenia. They would also interfere with in the capacity to elaborate spatial representation necessary for optimal orientation in natural, artificial or symbolic environment.

Animal Industry News, February 2004, Vol. 5, No. 1

Newsletter produced by Iowa Department of Agriculture and Land Stewardship.

Establishment of animal models to analyze the kinetics and distribution of human tumor antigen-specific CD8⁺ T cells.

Many patients develop tumor antigen-specific T cell responses detectable in peripheral blood mononuclear cells (PBMCs) following cancer vaccine. However, measurable tumor regression is observed in a limited number of patients receiving cancer vaccines. There is a need to re-evaluate systemically the immune responses induced by cancer vaccines. Here, we established animal models targeting two human cancer/testis antigens, NY-ESO-1 and MAGE-A4. Cytotoxic T lymphocyte (CTL) epitopes of these antigens were investigated by immunizing BALB/c mice with plasmids encoding the entire sequences of NY-ESO-1 or MAGE-A4. CD8(+) T cells specific for NY-ESO-1 or MAGE-A4 were able to be detected by ELISPOT assays using antigen presenting cells pulsed with overlapping peptides covering the whole protein, indicating the high immunogenicity of these antigens in mice. Truncation of these peptides revealed that NY-ESO-1-specific CD8(+) T cells recognized D(d)-restricted 8mer peptides, NY-ESO-181-88. MAGE-A4-specific CD8(+) T cells recognized D(d)-restricted 9mer peptides, MAGE-A4265-273. MHC/peptide tetramers allowed us to analyze the kinetics and distribution of the antigen-specific immune responses, and we found that stronger antigen-specific CD8(+) T cell responses were required for more effective anti-tumor activity. Taken together, these animal models are valuable for evaluation of immune responses and optimization of the efficacy of cancer vaccines.

Genome Biology and Evolution of the Animal Kingdom

Estudi realitzat a partir d’una estada a la Institut J.W. Jenkinson Laboratory for Evolution and Development of the University of Oxford, Regne Unit, entre 2010 i 2012. He estat membre del laboratori del Professor Peter W.H. Holland com a becari post-doctoral Beatriu de Pinós des de setembre de 2010 al setembre de 2012. El nostre projecte de recerca se centra en l'anàlisi genòmic comparatiu del Regne Animal, tot explorant el contingut dels genomes a través de totes les branques de l'arbre dels animals. Totes les referències a les meves publicacions durant aquest post-doc es poden trobar a http://about.me/jordi_paps. Crec que el nombre i la qualitat dels resultats del meu post-doc, un total de 8 publicacions incloent dos articles a la prestigiosa revista Nature, són prova de l'èxit d'aquest post-doc. Prof Peter W. H. Holland (Departament de Zoologia de la Universitat d'Oxford) i jo som coautors de tres articles de genòmica comparativa, resultats directes d'aquest projecte: 1) comparació de families gèniques entre vertebrats invertebrats (Briefings in Functional Genomics), 2) el genoma de l'ostra (publicat a la revista Nature), i 3) els genomes de 6 platihelmints paràsits (acceptat també a Nature). A més, tenim altres 2 treballs en preparació. Un d'ells analitza l'evolució, expressió i funció dels gens Hox al a la tènia Hymenolepis. El perfil fi d'aquests gens clau del desenvolupament esclareix els canvis d'estil de vida dels organismes. A més, durant aquest últim post-doc he participat en diverses col•laboracions, incloent anàlisi de gens d'envelliment a cucs plans, un estudi sobre la filogènia del grup Gastrotricha, una revisió de l'evolució phylum Platyhelminthes, així com un capítol d'un llibre sobre l'evolució dels animals bilaterals. Finalment, gràcies a la beca Beatriu de Pinós, el Prof. Peter W.H. Holland m'ha convidat a formar part del seu equip com un investigador post-doctoral en el seu projecte ERC Advance actual sobre duplicacions genòmiques.