Project description:We illustrate an approach for integrating preclinical gnotobiotic animal models with human studies to understand the contributions of perturbed gut microbiota development to childhood undernutrition, and to identify new microbiota-directed therapeutic concepts/leads. Combining metabolomic and proteomic analyses of serially collected plasma samples with metagenomic analyses of serially collected fecal samples, we characterized the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned to moderate acute malnutrition (MAM) after standard treatment. Gnotobiotic mice were subsequently colonized with a defined consortium of bacterial strains representing different stages of microbiota development in healthy children from Bangladesh. Administering different combinations of Bangladeshi complementary food ingredients to colonized mice and germ-free controls revealed diet-dependent changes in representation and metabolism of targeted weaning-phase strains, including accompanying increases in branched-chain amino acids, plus diet- and colonization-dependent augmentation of IGF-1/mTOR signaling. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes were subsequently examined in gnotobiotic mice colonized with post-SAM MAM microbiota and in gnotobiotic piglets colonized with a defined consortium of targeted age- and growth-discriminatory bacteria. Finally, ar andomized, double-blind study revealed a lead MDCF that affected the representation of targeted bacterial taxa and increased levels of biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function.
Project description:Anorexia is a common symptom among cancer patients and contributes to malnutrition and insufficient food intake. In cancer-induced anorexia, food intake regulation in the hypothalamus appears to be impaired. A negative energy balance persists and accelerates muscle wasting and malnutrition. Moreover, it strongly affects mortality and survival in these patients. Here, we show that the neuropeptide Y system (NPY) appears to fail to respond adequately to changes in energy balance during cancer cachexia. In addition, we investigate the connection between serotonin and NPY release in hypothalamic cell lines. Lewis Lung tumour cells were intramuscularly inoculated 6w old male C57BL/6 mice. Body weight and food intake were measured 3 times a week. On day 10, 14 and 17 hypothalamus was dissected and used for gene expression profiling.
Project description:Anorexia is a common symptom among cancer patients and contributes to malnutrition and insufficient food intake. In cancer-induced anorexia, food intake regulation in the hypothalamus appears to be impaired. A negative energy balance persists and accelerates muscle wasting and malnutrition. Moreover, it strongly affects mortality and survival in these patients. Here, we show that the neuropeptide Y system (NPY) appears to fail to respond adequately to changes in energy balance during cancer cachexia. In addition, we investigate the connection between serotonin and NPY release in hypothalamic cell lines. Hypothalamic neuronal cells mHypoE-46 (serotonin sensitive cells) and mHypoA-2/12 (serotonin unresponsive cells) were used to study the effect of serotonin on messenger NPY expression and NPY excretion.
Project description:Dietary restriction (DR), reduced food intake while avoiding malnutrition, profoundly extends lifespan in most model and non-model organisms. Both chronic (i.e. life-long) and acute (i.e. late-onset) DR have been shown to improve cognitive performance in aged mice compared to animals with an unrestricted access to food (ad libitium feeding; AL). Yet so far, quantitative analyses of the molecular dynamics in the brain of DR fed animals have been limited. Here we performed single-nuclei sequencing (Nuc-seq) of whole hippocampus isolated from young (5 months) and old (24 months) AL fed animals, as well as old chronic DR (DR started at 3 months) and acute DR (aDR) mice.
Project description:<p>The PROVIDE study (Dhaka, Bangladesh) is a randomized clinical trial platform which evaluated the efficacy of delayed-dose oral rotavirus vaccine as well as the benefit of an injectable polio vaccine replacing one dose of oral polio vaccine. This rigorous infrastructure supported the additional examination of hypotheses of vaccine underperformance. Primary and secondary efficacy and immunogenicity measures for rotavirus and polio vaccines were measured, as well as the impact of maternal and childhood malnutrition, environmental enteropathy, and additional exploratory variables.</p> <p>This study has been conducted to test the role of epigenetics in malnutrition, specifically the genome-wide role of histone modifications, which are known to provide a precise signature of metabolic state and immune system function.</p>
Project description:Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production, and retards growth. In order to identify new molecules involved in such changes, we conducted DNA microarray analysis for liver samples of rats fed isoenergetic low protein diet for 8 hours, and identified fibroblast growth factor 21 (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0.05, FDR<0.001). In addition, amino acid deprivation from the culture media increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0.01). Thus, it was suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. Using transgenic mice, FGF21 has also been shown to promote a growth hormone-resistant state and suppress IGF-I. Therefore, to further determine whether the up-regulation of Fgf21 under protein malnutrition causes hepatic steatosis and growth retardation following decrease in IGF-I, we fed isoenergetic low protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration of mice fed the low-protein diet. Meanwhile, Fgf21-KO mice showed greater epididymal white adipose tissue weight as well as hepatic triglyceride and cholesterol levels under protein malnutrition (P<0.05). Taken together, we showed that protein deprivation directly increases Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression under protein malnutrition. Furthermore, up-regulated FGF21 rather appears to have a protective effect against obesity and hepatic steatosis in protein malnourished animals. Livers of rats from 2 groups (control (15P) or low-protain (5P) diet fed groups), total of 6 samples (3 replicates for each group) were analyzed.
Project description:The adaptable transcriptional response to changes in food availability not only ensures animal survival, but also permits progressing with embryonic development. Interestingly, the central nervous system is preferentially protected to periods of malnutrition, a phenomenon known as ‘brain sparing’. However, the mechanisms that mediates this genetic response remains poorly understood. To get a better understanding of this, we used Drosophila melanogaster as a genetic model, analysing the transcriptional response of larval neural stem cells (neuroblasts) and glial cells of the blood-brain barrier during nutrient restriction using the targeted DamID technique.
Project description:The mechanisms underlying natural variation in lifespan and ageing rate remain largely unknown. We performed microarray experiment to characterise genome-wide expression patterns of a long-lived, natural variant of Drosophila melanogaster resulting from selection for starvation resistance (SR) and compare it with normal-lived control flies (C). We sampled adult females at two time points representing middle age (90% survival) and old age (10% survival) respectively, in three adult diets (malnutrition, optimal food, and overfeeding).