Chieh Jason Chou

Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice

Recent data suggest that the gut microbiota plays a significant role in fat accumulation. However, it is not clear whether gut microbiota is involved in the pathophysiology of type 2 diabetes. To assess this issue, we modulated gut microbiota via antibiotics administration in two different mouse models with insulin resistance. Results from dose‐determination studies showed that a combination of norfloxacin and ampicillin, at a dose of 1g/L, maximally suppressed the numbers of cecal aerobic and anaerobic bacteria in ob/ob mice. After a 2‐wk intervention with the antibiotic combination, both ob/ob and diet‐induced obese and insulin‐resistant mice showed a significant improvement in fasting glycemia and oral glucose tolerance. The improved glycemic control was independent of food intake or adiposity because pair‐fed ob/ob mice were as glucose intolerant as the control ob/ob mice. Reduced liver triglycerides and increased liver glycogen correlated with improved glucose tolerance in the treated mice. Concomitant reduction of plasma lipopolysaccharides and increase of adiponectin further supported the antidiabetic effects of the antibiotic treatment in ob/ob mice. In summary, modulation of gut microbiota ameliorated glucose tolerance of mice by altering the expression of hepatic and intestinal genes involved in inflammation and metabolism, and by changing the hormonal, inflammatory, and metabolic status of the host.—Membrez, M., Blancher, F., Jaquet, M., Bibiloni, R., Cani, P. D., Burcelin, R. G., Corthesy, I., Macé, K., Chou, C. J. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 22, 2416–2426 (2008)

Gut decontamination with norfloxacin and ampicillin enhances insulin sensitivity in mice.

Recent data suggest that gut microbiota plays a significant role in fat accumulation. However, it is not clear whether gut microbiota is involved in the pathophysiology of type-2 diabetes. To address this issue, we modulated gut microbiota with two combinations of antibiotics in two different mouse models with insulin resistance. Treatment with norfloxacin and ampicillin for 2 weeks reduced the cecal bacterial DNA below the level of detection in ob/ob, diet-induced obese and insulin resistance (DIO) mice, and significantly improved fasting glycemia and oral glucose tolerance of the treated animals. The enhanced insulin sensitivity was independent of food intake or adiposity because pair-fed ob/ob mice were as glucose intolerant as the untreated ob/ob mice. The reduced liver triglycerides, increased liver glycogen and improved glucose tolerance in the treated mice indicate broad impacts on metabolism by gut decontamination. The treatment with non-absorbable antibiotics polymyxin B and neomycin significantly modified cecal microbiota profile in the DIO mice, and the modified intestinal microbiota was associated with a gradual reduction in glycemia during a washout period. In summary, modulation of gut microbiota ameliorated glucose intolerance in mice and altered the hormonal, inflammatory and metabolic status of the host.

High fat diet drives obesity regardless the composition of gut microbiota in mice

The gut microbiota is involved in many aspects of host physiology but its role in body weight and glucose metabolism remains unclear. Here we studied the compositional changes of gut microbiota in diet-induced obesity mice that were conventionally raised or received microbiota transplantation. In conventional mice, the diversity of the faecal microbiota was weakly associated with 1st week weight gain but transferring the microbiota of mice with contrasting weight gain to germfree mice did not change obesity development or feed efficiency of recipients regardless whether the microbiota was taken before or after 10 weeks high fat (HF) feeding. Interestingly, HF-induced glucose intolerance was influenced by microbiota inoculation and improved glucose tolerance was associated with a low Firmicutes to Bacteroidetes ratio. Transplantation of Bacteroidetes rich microbiota compared to a control microbiota ameliorated glucose intolerance caused by HF feeding. Altogether, our results demonstrate that gut microbiota is involved in the regulation of glucose metabolism and the abundance of Bacteroidetes significantly modulates HF-induced glucose intolerance but has limited impact on obesity in mice. Our results suggest that gut microbiota is a part of complex aetiology of insulin resistance syndrome, individual microbiota composition may cause phenotypic variation associated with HF feeding in mice.

Consequences of Exchanging Carbohydrates for Proteins in the Cholesterol Metabolism of Mice Fed a High-fat Diet

Consumption of low-carbohydrate, high-protein, high-fat diets lead to rapid weight loss but the cardioprotective effects of these diets have been questioned. We examined the impact of high-protein and high-fat diets on cholesterol metabolism by comparing the plasma cholesterol and the expression of cholesterol biosynthesis genes in the liver of mice fed a high-fat (HF) diet that has a high (H) or a low (L) protein-to-carbohydrate (P/C) ratio. H-P/C-HF feeding, compared with L-P/C-HF feeding, decreased plasma total cholesterol and increased HDL cholesterol concentrations at 4-wk. Interestingly, the expression of genes involved in hepatic steroid biosynthesis responded to an increased dietary P/C ratio by first down-regulation (2-d) followed by later up-regulation at 4-wk, and the temporal gene expression patterns were connected to the putative activity of SREBF1 and 2. In contrast, Cyp7a1, the gene responsible for the conversion of cholesterol to bile acids, was consistently up-regulated in the H-P/C-HF liver regardless of feeding duration. Over expression of Cyp7a1 after 2-d and 4-wk H-P/C-HF feeding was connected to two unique sets of transcription regulators. At both time points, up-regulation of the Cyp7a1 gene could be explained by enhanced activations and reduced suppressions of multiple transcription regulators. In conclusion, we demonstrated that the hypocholesterolemic effect of H-P/C-HF feeding coincided with orchestrated changes of gene expressions in lipid metabolic pathways in the liver of mice. Based on these results, we hypothesize that the cholesterol lowering effect of high-protein feeding is associated with enhanced bile acid production but clinical validation is warranted. (246 words)

Gut Microbiota, Obesity and Diabetes

The growing epidemic of obesity is no longer restricted to developed countries. In 2005, the World Health Organization alerted that there were approximately 400 million obese adults worldwide, and approximately 20 million children worldwide were overweight. Obesity is a complex health issue with serious consequences such as type 2 diabetes, cardiovascular diseases, and others. Behavioral, genetic and environmental factors have been addressed as contributing factors for overweight and obesity. Recent evidence indicates that the community of microorganisms that dwell in the gut, known as the gut microbiota, can influence nutrient absorption and energy storage. The microbiotic composition has been shown to differ between obese and lean mice and humans alike, suggesting that modulation of the gut microbiotic composition offers a new avenue for the treatment of obesity and overweight. This review revises the available scientific evidence supporting these speculations. Recent results obtained from studies focusing on the contributions of gut microbiota to diabetes are also summarized in this review.

Resolving microbial membership using Abundance and Variability In Taxonomy ( ‘AVIT )

Development of NGS has revolutionized the analysis in microbial ecology contributing to our deeper understanding of microbiota in health and disease. However, the quality, quantity and confidence of summarized taxonomic abundances are in need of further scrutiny due to sample dependent and independent effects. In this article we introduce ‘AVIT (Abundance and Variability In Taxonomy), an unbiased method to enrich for assigned members of microbial communities. As opposed to using a priori thresholds, ‘AVIT uses inherent abundance and variability of taxa in a dataset to determine the inclusion or rejection of each taxa for further downstream analysis. Using in-vitro and in-vivo studies, we benchmarked performance and parameterized ‘AVIT to establish a framework for investigating the dynamic range of microbial community membership in clinically relevant scenarios.

The Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism

Summary The circadian clock and associated feeding rhythms have a profound impact on metabolism and the gut microbiome. To what extent microbiota reciprocally affect daily rhythms of physiology in the host remains elusive. Here, we analyzed transcriptome and metabolome profiles of male and female germ-free mice. While mRNA expression of circadian clock genes revealed subtle changes in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated with rhythmic physiology. Strikingly, the absence of the microbiome attenuated liver sexual dimorphism and sex-specific rhythmicity. The resulting feminization of male and masculinization of female germ-free animals is likely caused by altered sexual development and growth hormone secretion, associated with differential activation of xenobiotic receptors. This defines a novel mechanism by which the microbiome regulates host metabolism.

Transcriptomics-driven lipidomics (TDL) identifies the microbiome-regulated targets of ileal lipid metabolism

The gut microbiome and lipid metabolism are both recognized as essential components in the maintenance of metabolic health. The mechanisms involved are multifactorial and (especially for microbiome) poorly defined. A strategic approach to investigate the complexity of the microbial influence on lipid metabolism would facilitate determination of relevant molecular mechanisms for microbiome-targeted therapeutics. E. coli is associated with obesity and metabolic syndrome and we used this association in conjunction with gnotobiotic models to investigate the impact of E. coli on lipid metabolism. To address the complexities of the integration of the microbiome and lipid metabolism, we developed transcriptomics-driven lipidomics (TDL) to predict the impact of E. coli colonization on lipid metabolism and established mediators of inflammation and insulin resistance including arachidonic acid metabolism, alterations in bile acids and dietary lipid absorption. A microbiome-related therapeutic approach targeting these mechanisms may therefore provide a therapeutic avenue supporting maintenance of metabolic health.Integrative Lipidomics: Microbiome regulation of lipid metabolismMicrobes multifactorially impact host lipid metabolism bearing a significant impact in health and disease. A team led by Mojgan Masoodi and Scott Parkinson at Nestlé Institute of Health Sciences (NIHS) developed an integrative data driven approach for predictive lipidomics investigations of host-microbial impacts on lipid metabolism. Results of in-vivo studies with germ-free mice inoculated with E. coli and in-vitro studies demonstrated the multifactorial nature of the impact of E. coli on arachidonic acid metabolism in the ileum and altered host inflammation and lipid absorption. The findings provide insights into understanding the host-microbiome interactions and identifying microbiome-related solutions for maintaining health and tackling disease. The systems approach presented is applicable to investigate broad range of microbiome dependent and independent alterations in host lipid metabolism.

Prof. Ángel Ballabriga (1920–2008)

Research in Pediatrics of the Hospital Vall d’Hebron in Barcelona. He published more than 200 articles in high level national and international pediatric journals. His investigative work centered principally on nutrition, neonatology and the development of the brain; his works on the metabolic system of the newborn, the myelinization of the brain, and the composition of the retina are especially outstanding. His excellent worldwide reputation enabled him to organize in 1980 the 16th International Congress of Pediatrics and the 7th European Congress of Perinatal Medicine in Barcelona. He was also presented with a number of awards, among which were an award from the International Pediatric Association and the honorary degree of Doctor Honoris Causa from the universities of Valladolid and Lisbon. It is also important to mention his collaboration over several decades as a member of the Annales Nestlé Editorial Committee where his great professionalism and his advanced vision of the events clearly contributed to the international prestige that Annales Nestlé has today. We would not like to finish these lines without mentioning his extraordinary personality. To those who had the opportunity to know him personally, he was a very affectionate and cultural person, and a great conversationalist. It is difficult to briefly outline the exceptional scientific and human path of Prof. Ángel Ballabriga. In his youth his strong personality was forged as a consequence of the difficulties he encountered; at the age of 17 he was mobilized during the Spanish Civil War, damaging his left knee, and being sent inland to a concentration camp. After the Civil War he studied medicine in Barcelona; he graduated in 1943 and completed his doctorate degree in 1946. He complemented his pediatric training by working in hospitals with Profs. Glanzmann (Bern), Wallgren (Stockholm), Lelong (Paris) and Smith (Boston). From 1958 to 1965 he was Director of the Premature Babies’ Centre of the Provincial Maternity Hospital of Barcelona where his efforts were significant in diminishing the level of neonatal mortality. In 1965 his work acquired greater significance when he was named Director of the Children’s Clinic of the Hospital Vall d’Hebron in Barcelona. There, he created a welfare model based on the autonomous functioning of sub-specialties that had positive repercussions on both the diagnostic and therapeutic levels. In 1976 he became an extraordinary Professor of Pediatrics of the Autonomous University of Barcelona, carrying out an enormous educational workload, not only for post-doctorate students but also in specialist training. In 1988 he was named Honorary Professor of Pediatrics and, finally, during 1992–1996 became Director of the Unit of Biomedical

Pr. Ángel Ballabriga (1920–2008)

recherches biomédicales en pédiatrie de l’Hôpital Vall d’Hebron à Barcelone. Il a publié plus de 200 articles dans des revues pédiatriques nationales et internationales de haut niveau. Ses recherches ont été principalement centrées sur la nutrition, la néonatalogie et le développement cérébral. Ses travaux sur le système métabolique du nouveau-né, la myélinisation du cerveau et la composition de la rétine sont exceptionnels. Son excellente réputation mondiale lui a permis d’organiser en 1980 le 16 ème Congrès international de pédiatrie et le 7 ème Congrès européen de médecine périnatale à Barcelone. Il a également reçu plusieurs distinctions, dont un prix de l’International Pediatric Association et le grade universitaire honoraire de Doctor Honoris Causa des universités de Valladolid et de Lisbonne. Il est également important de mentionner sa collaboration pendant plusieurs décennies au titre de membre du comité de rédaction des Annales Nestlé, où son grand professionnalisme et sa vision élevée des événements ont manifestement contribué au prestige international actuel de cette publication. Nous ne voudrions pas terminer ces lignes sans mentionner son extraordinaire personnalité. Ceux qui ont eu la chance de le connaître personnellement savent combien il était attentif aux autres, cultivé et un brillant causeur. Il est difficile de résumer en quelques mots l’exceptionnelle trajectoire scientifique et humaine du Pr. Ángel Ballabriga. Dans sa jeunesse, sa forte personnalité s’est forgée sous le poids des difficultés qu’il a rencontrées. Mobilisé à l’âge de 17 ans lors de la guerre civile espagnole, il est blessé au genou droit et est interné dans un camp de concentration à l’arrière. Après la guerre civile, il étudie la médecine à Barcelone et obtient un premier diplôme en 1943, puis son doctorat en 1946. Il termine sa formation pédiatrique en travaillant dans divers hôpitaux avec les Pr. Glanzmann (Berne), Wallgren (Stockholm), Lelong (Paris) et Smith (Boston). De 1958 à 1965, il dirige le Centre des prématurés de la Maternité provinciale de Barcelone, où la mortalité néonatale diminue significativement grâce à ses efforts. En 1965, l’importance de ses travaux s’accroît avec sa nomination au poste de Directeur de la Clinique d’enfants de l’hôpital Vall d’Hebron à Barcelone. Il y crée un modèle de soins basé sur le fonctionnement autonome de sous-spécialités, dont les répercussions sont positives tant au plan diagnostique que thérapeutique. En 1976, il devient professeur de pédiatrie extraordinaire à l’Université autonome de Barcelone, assurant une charge didactique colossale, non seulement auprès d’étudiants en post-doctorat, mais encore pour la formation de spécialistes. En 1988, il est nommé Professeur honoraire de pédiatrie et, enfin, de 1992 à 1996, Directeur de l’Unité de