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1.
Cell Host Microbe ; 26(4): 463-477.e8, 2019 10 09.
Article in English | MEDLINE | ID: mdl-31585844

ABSTRACT

Dramatic increases in processed food consumption represent a global health threat. Maillard reaction products (MRPs), which are common in processed foods, form upon heat-induced reaction of amino acids with reducing sugars and include advanced glycation end products with deleterious health effects. To examine how processed foods affect the microbiota, we fed gnotobiotic mice, colonized with 54 phylogenetically diverse human gut bacterial strains, defined sugar-rich diets containing whey as the protein source or a matched amino acid mixture. Whey or ϵ-fructoselysine, an MRP in whey and many processed foods, selectively increases Collinsella intestinalis absolute abundance and induces Collinsella expression of genomic loci directing import and metabolism of ϵ-fructoselysine to innocuous products. This locus is repressed by glucose in C. aerofaciens, whose abundance decreases with whey, but is not repressed in C. intestinalis. Identifying gut organisms responding to and degrading potentially harmful processed food components has implications for food science, microbiome science, and public health.


Subject(s)
Actinobacteria/metabolism , Fast Foods/analysis , Food Safety , Glycation End Products, Advanced/metabolism , Lysine/analogs & derivatives , Actinobacteria/genetics , Animals , Food Quality , Gastrointestinal Microbiome , Germ-Free Life , Humans , Lysine/metabolism , Maillard Reaction , Mice , Mice, Inbred C57BL , Whey Proteins/metabolism
2.
Endocrinology ; 158(8): 2441-2452, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28637315

ABSTRACT

Prenatal undernutrition and low birth weight are associated with risk of type 2 diabetes and obesity. Prenatal caloric restriction results in low birth weight, glucose intolerance, obesity, and reduced plasma bile acids (BAs) in offspring mice. Because BAs can regulate systemic metabolism and glucose homeostasis, we hypothesized that BA supplementation could prevent diet-induced obesity and glucose intolerance in this model of developmental programming. Pregnant dams were food restricted by 50% from gestational days 12.5 to 18.5. Offspring of both undernourished (UN) and control (C) dams given unrestricted diets were weaned to high-fat diets with or without supplementation with 0.25% w/w ursodeoxycholic acid (UDCA), yielding four experimental groups: C, UN, C + UDCA, and UN + UDCA. Glucose homeostasis, BA composition, liver and intestinal gene expression, and microbiota composition were analyzed in the four groups. Although UDCA supplementation ameliorated diet-induced obesity in C mice, there was no effect in UN mice. UDCA similarly lowered fasting insulin, and improved glucose tolerance, pyruvate tolerance, and liver steatosis in C, but not UN, animals. BA composition differed significantly, and liver and ileal expression of genes involved in BA metabolism (Cyp7b1, Shp) were differentially induced by UDCA in C vs UN animals. Bacterial taxa in fecal microbiota correlated with treatment groups and metabolic parameters. In conclusion, prenatal undernutrition alters responsiveness to the metabolic benefits of BA supplementation, with resistance to the weight-lowering and insulin-sensitizing effects of UDCA supplementation. Our findings suggest that BA metabolism may be a previously unrecognized contributor to developmentally programmed diabetes risk.


Subject(s)
Bile Acids and Salts/pharmacology , Glucose/metabolism , Insulin Resistance/physiology , Malnutrition , Prenatal Nutritional Physiological Phenomena , Animals , Bile Acids and Salts/blood , Bile Acids and Salts/chemistry , Blood Glucose , Diet, High-Fat , Female , Male , Mice , Mice, Inbred ICR , Pregnancy , Prenatal Exposure Delayed Effects , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/pharmacology
3.
Cell Rep ; 7(3): 918-31, 2014 May 08.
Article in English | MEDLINE | ID: mdl-24746820

ABSTRACT

Both strands of human mtDNA are transcribed in continuous, multigenic units that are cleaved into the mature rRNAs, tRNAs, and mRNAs required for respiratory chain biogenesis. We sought to systematically identify nuclear-encoded proteins that contribute to processing of mtRNAs within the organelle. First, we devised and validated a multiplex MitoString assay that quantitates 27 mature and precursor mtDNA transcripts. Second, we applied MitoString profiling to evaluate the impact of silencing each of 107 mitochondrial-localized, predicted RNA-binding proteins. With the resulting data set, we rediscovered the roles of recently identified RNA-processing enzymes, detected unanticipated roles of known disease genes in RNA processing, and identified new regulatory factors. We demonstrate that one such factor, FASTKD4, modulates the half-lives of a subset of mt-mRNAs and associates with mtRNAs in vivo. MitoString profiling may be useful for diagnosing and deciphering the pathogenesis of mtDNA disorders.


Subject(s)
DNA, Mitochondrial/metabolism , Mitochondria/genetics , RNA Processing, Post-Transcriptional/genetics , RNA/metabolism , Cell Line , Genomics , HEK293 Cells , Humans , Mitochondria/metabolism , Mitochondrial Diseases/genetics , Mitochondrial Diseases/metabolism , Mitochondrial Diseases/pathology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , RNA Interference , RNA, Mitochondrial , RNA, Small Interfering/metabolism , RNA-Binding Proteins/antagonists & inhibitors , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism
4.
Genome Biol ; 12(6): R56, 2011 Jun 20.
Article in English | MEDLINE | ID: mdl-21689454

ABSTRACT

BACKGROUND: Mounting evidence suggests a major role for epigenetic feedback in Plasmodium falciparum transcriptional regulation. Long non-coding RNAs (lncRNAs) have recently emerged as a new paradigm in epigenetic remodeling. We therefore set out to investigate putative roles for lncRNAs in P. falciparum transcriptional regulation. RESULTS: We used a high-resolution DNA tiling microarray to survey transcriptional activity across 22.6% of the P. falciparum strain 3D7 genome. We identified 872 protein-coding genes and 60 putative P. falciparum lncRNAs under developmental regulation during the parasite's pathogenic human blood stage. Further characterization of lncRNA candidates led to the discovery of an intriguing family of lncRNA telomere-associated repetitive element transcripts, termed lncRNA-TARE. We have quantified lncRNA-TARE expression at 15 distinct chromosome ends and mapped putative transcriptional start and termination sites of lncRNA-TARE loci. Remarkably, we observed coordinated and stage-specific expression of lncRNA-TARE on all chromosome ends tested, and two dominant transcripts of approximately 1.5 kb and 3.1 kb transcribed towards the telomere. CONCLUSIONS: We have characterized a family of 22 telomere-associated lncRNAs in P. falciparum. Homologous lncRNA-TARE loci are coordinately expressed after parasite DNA replication, and are poised to play an important role in P. falciparum telomere maintenance, virulence gene regulation, and potentially other processes of parasite chromosome end biology. Further study of lncRNA-TARE and other promising lncRNA candidates may provide mechanistic insight into P. falciparum transcriptional regulation.


Subject(s)
Plasmodium falciparum/genetics , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Telomere/metabolism , Transcriptome , Base Sequence , Binding Sites/genetics , Chromosomes , Gene Expression Regulation, Developmental , Genes, Protozoan , Genetic Loci , Genome, Protozoan , Humans , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Open Reading Frames/genetics , Plasmodium falciparum/metabolism , Pseudogenes , Sequence Alignment , Transcription Factors/metabolism , Transcription, Genetic
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