Project description:EMG produced TPA metagenomics assembly of the Gut microbial metabolism shifts towards a more toxic profile with supplementary iron in a kinetic model of the human large intestine (TIM2_iron_study) data set
Project description:Bariatric surgeries remain the most effective treatments for sustained weight loss and remission of type 2 diabetes. In addition to decreased body weight and improved glucose regulation, these procedures also dramatically increase secretion of several gut hormones including GLP-1. Despite these benefits, there are deleterious side effects to these procedures that include an increased incidence of iron-deficiency related anemias. The transcription factor HIF2a is heavily expressed in the duodenum and regulates the molecular machinery of iron absorption from the lumen. Lower iron levels after both gastric bypass and sleeve gastrectomy procedures occur despite dramatic upregulation of HIF2a signaling in the duodenum and are likely the result of increased hepcidin levels. Low iron diets also stimulate increased HIF2a signaling in the duodenum and produce effects similar to bariatric surgery that include reduced body weight/fat, improved glucose regulation and increased secretion of the GLP-1. Gut-specific deletion of VHL results in a constitutive upregulation of HIF2a signaling in the small intestine and produces a dramatic phenotype that includes reduced body weight/fat, improved glucose tolerance and increased GLP-1 secretion from the intestine. These data demonstrate an important role of HIF2a signaling in the duodenum to regulate multiple aspects of systemic metabolism and gut hormone secretion pointing towards critical cross-talk between the systems that regulate iron and other aspects of systemic physiology important to prevalent metabolic diseases.
Project description:Bariatric surgeries remain the most effective treatments for sustained weight loss and remission of type 2 diabetes. In addition to decreased body weight and improved glucose regulation, these procedures also dramatically increase secretion of several gut hormones including GLP-1. Despite these benefits, there are deleterious side effects to these procedures that include an increased incidence of iron-deficiency related anemias. The transcription factor HIF2a is heavily expressed in the duodenum and regulates the molecular machinery of iron absorption from the lumen. Lower iron levels after both gastric bypass and sleeve gastrectomy procedures occur despite dramatic upregulation of HIF2a signaling in the duodenum and are likely the result of increased hepcidin levels. Low iron diets also stimulate increased HIF2a signaling in the duodenum and produce effects similar to bariatric surgery that include reduced body weight/fat, improved glucose regulation and increased secretion of the GLP-1. Gut-specific deletion of VHL results in a constitutive upregulation of HIF2a signaling in the small intestine and produces a dramatic phenotype that includes reduced body weight/fat, improved glucose tolerance and increased GLP-1 secretion from the intestine. These data demonstrate an important role of HIF2a signaling in the duodenum to regulate multiple aspects of systemic metabolism and gut hormone secretion pointing towards critical cross-talk between the systems that regulate iron and other aspects of systemic physiology important to prevalent metabolic diseases.
Project description:Iron is an essential metal for both animals and microbiota, and neonates and infants of humans and animals, in general, are at the risk of iron insufficient. However, excess dietary iron usually causes negative impacts on the host and microbiota. This study aimed to investigate over-loaded dietary iron supplementation on growth performance, the distribution pattern of iron in the gut lumen and the host, intestinal microbiota, and intestine gene expression profile of piglets. Sixty healthy weaning piglets were randomly assigned to six groups: fed with diets supplemented with ferrous sulfate monohydrate at the dose of 50ppm (Fe50 group), 100ppm (Fe100 group), 200ppm (Fe200 group), 500ppm (Fe500 group), and 800ppm (Fe800) for three weeks. The results indicated that increasing iron had no effects on growth performance but increased diarrheal risk and iron deposition in intestinal digesta, tissues of intestine and liver, and serum. High iron also reduced serum iron-binding capacity, apolipoprotein, and immunoglobin A. The RNA-sequencing analysis revealed that iron changed colonic gene expression profile, such as interferon gamma-signal transducer and activator of transcription 2 based anti-virus and bacteria gene network. Increasing iron also shifted cecal and colonic microbiota, such as reducing alpha diversity, Clostridiales and Lactobacillus reuteri, and increasing Lactobacillus and Lactobacillus amylovorus. Collectively, this study demonstrated that high dietary iron increased diarrheal incidence, changed intestinal immune response-associated gene expression, and shifts gut microbiota. The results would enhance our knowledge of iron effects on the gut and microbiome in piglets, and further contribute to understanding these aspects in humans.
Project description:Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells. The gene expression profiles were measured on 6 batches each of control and melphalan-treated RPMI8226 and RPMI8226-LR5 cells using Illumina Human HT-12 v3 Expression BeadChip (Illumina, San Diego, CA), which enables genome-wide expression analysis (more than 47 000 transcripts) of 24 samples in parallel on a single microarray.
Project description:Entamoeba histolytica is the parasite causing amoebiasis, an infectious disease targeting the intestine and liver of humans. The molecules involved in amoeba adaptation to different iron conditions during the invasive process are unknown. To investigate the effects of iron availability on gene expression in E. histolytica, we determined by microarray experiments the gene expression profile of parasites grown in the presence of different iron concentrations. Conditions included low amounts of iron, iron starvation and iron starvation supplemented with hemoglobin (Hb). Genes encoding important proteins involved in iron metabolism, reported in other organism such as bacteria, were identified for the first time in E. histolytica. The influence of iron on the amount of these transcripts was confirmed by quantitative real-time PCR and their protein products were analyzed by Western blots
Project description:Obesity is an independent risk factor for colorectal cancer (CRC) although the underlying mechanisms have not been elucidated. Dietary nutrients play a key role in both the prevention and promotion of CRC. While iron is an essential nutrient, excess iron is associated with carcinogenesis. Unlike the systemic compartment, the intestinal lumen lacks an efficient system to regulate iron. In conditions when dietary iron malabsorption and intestinal inflammation co-exist, greater luminal iron is associated with increased intestinal inflammation and a shift in the gut microbiota to more pro-inflammatory strains. However, treatments designed to reduce luminal, including diet restriction and chelation, are associated with lower intestinal inflammation and the colonization of protective gut microbes. Obesity is associated with inflammation-induced, hepcidin-mediated, iron metabolism dysfunction characterized by iron deficiency and dietary iron malabsorption. Obesity is also linked to intestinal inflammation. Currently, there is a fundamental gap in understanding how altered iron metabolism impacts CRC risk in obesity.
The investigator’s objective is to conduct a crossover controlled feeding trial of: 1) a "Typical American" diet with "high" heme/non-heme iron", 2) a "Typical American" diet with "low" iron, and 3) a Mediterranean diet with "high" non heme iron and examine effects on colonic and systemic inflammation and the gut microbiome.
Project description:This a model from the article:
Systems analysis of iron metabolism: the network of iron pools and fluxes
Tiago JS Lopes, Tatyana Luganskaja, Maja Vujic-Spasic, Matthias W Hentze, Martina U Muckenthaler, Klaus Schumann and Jens G Reich
BMC Systems Biology2010, Aug 13;4(1):112.
20704761,
Abstract:
Background
Every cell of the mammalian organism needs iron in numerous oxido-reductive processes as well as for transport and storage of oxygen. The versatility of ionic iron makes it a toxic entity which can catalyze the production of radicals that damage vital membranous and macromolecular assemblies in the cell. The mammalian organism maintains therefore a complex regulatory network of iron uptake, excretion and intra-body distribution. Intracellular regulation in different cell types is intertwined with a global hormonal signaling structure. Iron deficiency as well as excess of iron are frequent and serious human disorders. They can affect every cell, but also the organism as a whole.
Results
Here, we present a kinematic model of the dynamic system of iron pools and fluxes. It is based on ferrokinetic data and chemical measurements in C57BL6 wild-type mice maintained on iron-deficient, iron-adequate, or iron-loaded diet. The tracer iron levels in major tissues and organs (16 compartment) were followed for 28 days. The evaluation resulted in a whole-body model of fractional clearance rates. The analysis permits calculation of absolute flux rates in the steady-state, of iron distribution into different organs, of tracer-accessible pool sizes and of residence times of iron in the different compartments in response to three states of iron-repletion induced by the dietary regime.
Conclusions
This mathematical model presents a comprehensive physiological picture of mice under three different diets with varying iron contents. The quantitative results reflect systemic properties of iron metabolism: dynamic closedness, hierarchy of time scales, switch-over response and dynamics of iron storage in parenchymal organs. Therefore, we could assess which parameters will change under dietary perturbations and study in quantitative terms when those changes take place.
This model corresponds to the Iron Loaded condition - Mice
This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team.For more information see the terms of use.To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.
Project description:Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells.
Project description:Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling. Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells. To investigate large scale alterations in gene expression accompanying melphalan resistance, we used the multiple myeloma cell line RPMI8226 and its melphalan-resistant derivative LR5. The stable isotope labeling by amino acids in cell culture (SILAC) approach.