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Title: The effects of micronutrient deficiencies on bacterial species from the human gut microbiota

Abstract

Micronutrient deficiencies afflict two billion people. And while the impact of these imbalances on host biology has been studied extensively, much less is known about their effects on the developing or adult gut microbiota. Thus, we established a community of 44 cultured, sequenced human gut-derived bacterial species in gnotobiotic mice and fed the animals a defined, micronutrient-sufficient diet, followed by a derivative diet devoid of vitamin A, folate, iron or zinc, followed by return to the sufficient diet. Acute vitamin A deficiency had the largest effect on community structure and meta-transcriptome, with Bacteroides vulgatus, a prominent responder, increasing its abundance in the absence of vitamin A, and manifesting transcriptional changes involving various metabolic pathways. Applying retinol selection to a library of 30,300 B. vulgatus transposon mutants revealed that disruption of acrR abrogated retinol sensitivity. Genetic complementation studies, microbial RNA-Seq, and transcription factor binding assays disclosed that AcrR functions as a repressor of an adjacent AcrAB-TolC efflux system plus other members of its regulon. Retinol efflux measurements in wild-type, acrR-mutant, and complemented acrR mutant strains, plus treatment with a pharmacologic inhibitor of the efflux system, revealed that AcrAB-TolC is a determinant of retinol and bile acid sensitivity. We associated acute vitaminmore » A deficiency with altered bile acid metabolism in vivo, raising the possibility that retinol, bile acid metabolites, and AcrAB-TolC interact to influence the fitness of B. vulgatus and perhaps other microbiota members. This type of preclinical model can help develop mechanistic insights about and more effective treatment strategies for micronutrient deficiencies.« less

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [3];  [4];  [5]; ORCiD logo [5]; ORCiD logo [5]; ORCiD logo [6]; ORCiD logo [6];  [4]; ORCiD logo [5]
  1. Washington Univ. School of Medicine, St. Louis, MO (United States). Center for Genome Sciences and Systems Biology, Center for Gut Microbiome and Nutrition Research
  2. Washington Univ. School of Medicine, St. Louis, MO (United States). Center for Genome Sciences and Systems Biology
  3. Russian Academy of Sciences (RAS), Moscow (Russian Federation). A.A. Kharkevich Inst. for Information Transmission Problems; Sanford Burnham Prebys Medical Discovery Inst., La Jolla, CA (United States)
  4. Sanford Burnham Prebys Medical Discovery Inst., La Jolla, CA (United States)
  5. Washington Univ. School of Medicine, St. Louis, MO (United States). Center for Genome Sciences and Systems Biology, Center for Gut Microbiome and Nutrition Researc
  6. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Chemical Sciences Division
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1394231
DOE Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article
Journal Name:
Science Translational Medicine
Additional Journal Information:
Journal Volume: 9; Journal Issue: 390; Journal ID: ISSN 1946-6234
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Hibberd, Matthew C., Wu, Meng, Rodionov, Dmitry A., Li, Xiaoqing, Cheng, Jiye, Griffin, Nicholas W., Barratt, Michael J., Giannone, Richard J., Hettich, Robert L., Osterman, Andrei L., and Gordon, Jeffrey I. The effects of micronutrient deficiencies on bacterial species from the human gut microbiota. United States: N. p., 2017. Web. doi:10.1126/scitranslmed.aal4069.
Hibberd, Matthew C., Wu, Meng, Rodionov, Dmitry A., Li, Xiaoqing, Cheng, Jiye, Griffin, Nicholas W., Barratt, Michael J., Giannone, Richard J., Hettich, Robert L., Osterman, Andrei L., & Gordon, Jeffrey I. The effects of micronutrient deficiencies on bacterial species from the human gut microbiota. United States. doi:10.1126/scitranslmed.aal4069.
Hibberd, Matthew C., Wu, Meng, Rodionov, Dmitry A., Li, Xiaoqing, Cheng, Jiye, Griffin, Nicholas W., Barratt, Michael J., Giannone, Richard J., Hettich, Robert L., Osterman, Andrei L., and Gordon, Jeffrey I. Wed . "The effects of micronutrient deficiencies on bacterial species from the human gut microbiota". United States. doi:10.1126/scitranslmed.aal4069.
@article{osti_1394231,
title = {The effects of micronutrient deficiencies on bacterial species from the human gut microbiota},
author = {Hibberd, Matthew C. and Wu, Meng and Rodionov, Dmitry A. and Li, Xiaoqing and Cheng, Jiye and Griffin, Nicholas W. and Barratt, Michael J. and Giannone, Richard J. and Hettich, Robert L. and Osterman, Andrei L. and Gordon, Jeffrey I.},
abstractNote = {Micronutrient deficiencies afflict two billion people. And while the impact of these imbalances on host biology has been studied extensively, much less is known about their effects on the developing or adult gut microbiota. Thus, we established a community of 44 cultured, sequenced human gut-derived bacterial species in gnotobiotic mice and fed the animals a defined, micronutrient-sufficient diet, followed by a derivative diet devoid of vitamin A, folate, iron or zinc, followed by return to the sufficient diet. Acute vitamin A deficiency had the largest effect on community structure and meta-transcriptome, with Bacteroides vulgatus, a prominent responder, increasing its abundance in the absence of vitamin A, and manifesting transcriptional changes involving various metabolic pathways. Applying retinol selection to a library of 30,300 B. vulgatus transposon mutants revealed that disruption of acrR abrogated retinol sensitivity. Genetic complementation studies, microbial RNA-Seq, and transcription factor binding assays disclosed that AcrR functions as a repressor of an adjacent AcrAB-TolC efflux system plus other members of its regulon. Retinol efflux measurements in wild-type, acrR-mutant, and complemented acrR mutant strains, plus treatment with a pharmacologic inhibitor of the efflux system, revealed that AcrAB-TolC is a determinant of retinol and bile acid sensitivity. We associated acute vitamin A deficiency with altered bile acid metabolism in vivo, raising the possibility that retinol, bile acid metabolites, and AcrAB-TolC interact to influence the fitness of B. vulgatus and perhaps other microbiota members. This type of preclinical model can help develop mechanistic insights about and more effective treatment strategies for micronutrient deficiencies.},
doi = {10.1126/scitranslmed.aal4069},
journal = {Science Translational Medicine},
issn = {1946-6234},
number = 390,
volume = 9,
place = {United States},
year = {2017},
month = {5}
}

Works referenced in this record:

GAGE: generally applicable gene set enrichment for pathway analysis
journal, January 2009


Inhibitors of Efflux Pumps in Pseudomonas a eruginosa Potentiate the Activity of the Fluoroquinolone Antibacterial Levofloxacin
journal, December 1999

  • Renau, Thomas E.; Léger, Roger; Flamme, Eric M.
  • Journal of Medicinal Chemistry, Vol. 42, Issue 24
  • DOI: 10.1021/jm9904598

Analysis of microsamples of human faeces: a non-invasive approach to study the bioavailability of fat-soluble bioactive compounds
journal, May 2015

  • Hernandez-Alvarez, E.; Pérez-Sacristán, B. I.; Blanco-Navarro, I.
  • European Journal of Nutrition, Vol. 54, Issue 8
  • DOI: 10.1007/s00394-015-0939-5

A novel transcriptional regulator of L-arabinose utilization in human gut bacteria
journal, October 2015

  • Chang, Changsoo; Tesar, Christine; Li, Xiaoqing
  • Nucleic Acids Research
  • DOI: 10.1093/nar/gkv1005

Fecal Microbial Community Structure Is Stable over Time and Related to Variation in Macronutrient and Micronutrient Intakes in Lactating Women
journal, August 2015

  • Carrothers, Janae M.; York, Mara A.; Brooker, Sarah L.
  • The Journal of Nutrition, Vol. 145, Issue 10
  • DOI: 10.3945/jn.115.211110

Structure of the AcrAB–TolC multidrug efflux pump
journal, April 2014

  • Du, Dijun; Wang, Zhao; James, Nathan R.
  • Nature, Vol. 509, Issue 7501
  • DOI: 10.1038/nature13205

Molecular cloning and characterization of acrA and acrE genes of Escherichia coli.
journal, October 1993


Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial
journal, November 2011


Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children
journal, February 2016


Enzymes catalysing the hydrolysis of retinyl esters
journal, October 1993


Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis
journal, November 2010


Ultrafast and memory-efficient alignment of short DNA sequences to the human genome
journal, January 2009


Fat and vitamin intakes during pregnancy have stronger relations with a pro-inflammatory maternal microbiota than does carbohydrate intake
journal, October 2016


clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters
journal, May 2012

  • Yu, Guangchuang; Wang, Li-Gen; Han, Yanyan
  • OMICS: A Journal of Integrative Biology, Vol. 16, Issue 5
  • DOI: 10.1089/omi.2011.0118

Dramatic performance of Clostridium thermocellum explained by its wide range of cellulase modalities
journal, February 2016


Nutrition meets the microbiome: micronutrients and the microbiota: Nutrition meets the microbiome
journal, May 2016

  • Biesalski, Hans K.
  • Annals of the New York Academy of Sciences, Vol. 1372, Issue 1
  • DOI: 10.1111/nyas.13145

Identifying Genetic Determinants Needed to Establish a Human Gut Symbiont in Its Habitat
journal, September 2009


Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist
journal, February 2013


Homeostasis of retinol in lecithin: Retinol acyltransferase gene knockout mice fed a high retinol diet
journal, June 2008


The Epidemiology of Global Micronutrient Deficiencies
journal, January 2015

  • Bailey, Regan L.; West Jr., Keith P.; Black, Robert E.
  • Annals of Nutrition and Metabolism, Vol. 66, Issue 2
  • DOI: 10.1159/000371618

DanteR: an extensible R-based tool for quantitative analysis of -omics data
journal, July 2012


RegPredict: an integrated system for regulon inference in prokaryotes by comparative genomics approach
journal, June 2010

  • Novichkov, P. S.; Rodionov, D. A.; Stavrovskaya, E. D.
  • Nucleic Acids Research, Vol. 38, Issue Web Server
  • DOI: 10.1093/nar/gkq531

Transcriptional Regulation of Central Carbon and Energy Metabolism in Bacteria by Redox-Responsive Repressor Rex
journal, December 2011

  • Ravcheev, D. A.; Li, X.; Latif, H.
  • Journal of Bacteriology, Vol. 194, Issue 5
  • DOI: 10.1128/JB.06412-11

Predicting a Human Gut Microbiota's Response to Diet in Gnotobiotic Mice
journal, May 2011


Survival of Germfree Rats without Vitamin A
journal, February 1969


Regulators of Gut Motility Revealed by a Gnotobiotic Model of Diet-Microbiome Interactions Related to Travel
journal, September 2015


WebLogo: A Sequence Logo Generator
journal, May 2004

  • Crooks, Gavin E.; Hon, Gary; Chandonia, John-Marc
  • Genome Research, Vol. 14, Issue 6, p. 1188-1190
  • DOI: 10.1101/gr.849004

Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides
journal, October 2015


Dissecting the in Vivo Metabolic Potential of Two Human Gut Acetogens
journal, May 2010

  • Rey, Federico E.; Faith, Jeremiah J.; Bain, James
  • Journal of Biological Chemistry, Vol. 285, Issue 29
  • DOI: 10.1074/jbc.M110.117713

Active efflux of bile salts by Escherichia coli.
journal, April 1997


Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice
journal, March 2011

  • Goodman, A. L.; Kallstrom, G.; Faith, J. J.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 15
  • DOI: 10.1073/pnas.1102938108

Bypassing the periplasm: Reconstitution of the AcrAB multidrug efflux pump of Escherichia coli
journal, June 1999

  • Zgurskaya, H. I.; Nikaido, H.
  • Proceedings of the National Academy of Sciences, Vol. 96, Issue 13
  • DOI: 10.1073/pnas.96.13.7190

Maternal and child undernutrition: global and regional exposures and health consequences
journal, January 2008


Childhood undernutrition, the gut microbiota, and microbiota-directed therapeutics
journal, June 2016


Molecular cloning of the genes for lipid A disaccharide synthase and UDP-N-acetylglucosamine acyltransferase in Escherichia coli.
journal, October 1986


Structure of the Tripartite Multidrug Efflux Pump AcrAB-TolC Suggests an Alternative Assembly Mode
journal, January 2015


IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering
journal, August 2009

  • Ma, Ze-Qiang; Dasari, Surendra; Chambers, Matthew C.
  • Journal of Proteome Research, Vol. 8, Issue 8
  • DOI: 10.1021/pr900360j

QIIME allows analysis of high-throughput community sequencing data
journal, April 2010

  • Caporaso, J. Gregory; Kuczynski, Justin; Stombaugh, Jesse
  • Nature Methods, Vol. 7, Issue 5
  • DOI: 10.1038/nmeth.f.303

The Impact of a Consortium of Fermented Milk Strains on the Gut Microbiome of Gnotobiotic Mice and Monozygotic Twins
journal, October 2011


Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD
journal, February 2016


The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals
journal, January 1996


The SEED and the Rapid Annotation of microbial genomes using Subsystems Technology (RAST)
journal, November 2013

  • Overbeek, Ross; Olson, Robert; Pusch, Gordon D.
  • Nucleic Acids Research, Vol. 42, Issue D1
  • DOI: 10.1093/nar/gkt1226

MyriMatch:  Highly Accurate Tandem Mass Spectral Peptide Identification by Multivariate Hypergeometric Analysis
journal, February 2007

  • Tabb, David L.; Fernando, Christopher G.; Chambers, Matthew C.
  • Journal of Proteome Research, Vol. 6, Issue 2
  • DOI: 10.1021/pr0604054

Mucosal Glycan Foraging Enhances Fitness and Transmission of a Saccharolytic Human Gut Bacterial Symbiont
journal, November 2008


Hepcidin and the Iron-Infection Axis
journal, November 2012


Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
journal, December 2014


Persistent gut microbiota immaturity in malnourished Bangladeshi children
journal, June 2014

  • Subramanian, Sathish; Huq, Sayeeda; Yatsunenko, Tanya
  • Nature, Vol. 510, Issue 7505
  • DOI: 10.1038/nature13421

Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice
journal, May 2016

  • Planer, Joseph D.; Peng, Yangqing; Kau, Andrew L.
  • Nature, Vol. 534, Issue 7606
  • DOI: 10.1038/nature17940