Effects of microbiota-directed foods in gnotobiotic animals and undernourished children

Autor: Ishita Mostafa, Hao Wei Chang, Robert L. Hettich, Matthew C. Hibberd, Robert Y. Chen, Sathish Subramanian, Nuzhat Choudhury, M Munirul Islam, Vanderlene L. Kung, Clay F. Semenkovich, Aleksandr A. Arzamasov, Siddarth Venkatesh, Sayeeda Huq, Richard J. Giannone, Martin Meier, Mustafa Mahfuz, Andrei L. Osterman, Christopher S. Sawyer, Bernard Henrissat, Imteaz Mahmud, Larry D. Spears, Iqbal Hossain, Christopher B. Newgard, Shafiqul Alam Sarker, Michael J. Muehlbauer, Richard D. Head, Dmitry A. Rodionov, Michael Talcott, Jeffrey I. Gordon, Olga Ilkayeva, Tahmeed Ahmed, Jiye Cheng, Semen A. Leyn, Michael J. Barratt, David O'Donnell, Jeanette L. Gehrig, Carrie A. Cowardin
Přispěvatelé: Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), King Abdulaziz University, Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, Duke University Medical Center, Department of Theoretical Physics and Astronomy [St Petersburg], Herzen State Pedagogical University of Russia, Sanford Burnham Prebys Medical Discovery Institute, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), United States Department of Health & Human Services National Institutes of Health (NIH) - USA GM007200 P30 DK052574 P30 CA91842 UL1TR002345Washington University Musculoskeletal Research Center NIH P30 AR057235Russian Science Foundation (RSF) 14-14-00289 19-14-00305Thought Leader Award from Agilent Technologies United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P30CA091842United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Advancing Translational Sciences (NCATS) UL1TR002345 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) P30AR057235 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) P30DK056341 P30DK020579 P30DK052574United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) T32GM007200
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Science (New York, N.y.)
Science
Science, 2019, 365 (6449), ⟨10.1126/science.aau4732⟩
Science, American Association for the Advancement of Science, 2019, 365 (6449), ⟨10.1126/science.aau4732⟩
ISSN: 1095-9203
0036-8075
DOI: 10.1126/science.aau4732⟩
Popis: To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM. INTRODUCTION There is a dimension to post-natal human development that involves assembly of microbial communities in different body habitats, including the gut. Children with acute malnutrition have impaired development of their gut microbiota, leaving them with communities that appear younger (more immature) than those of chronologically age-matched healthy individuals. Current therapeutic foods given to children with acute malnutrition have not been formulated based on knowledge of how they affect the developmental biology of the gut microbiota. Moreover, they are largely ineffective in ameliorating the long-term sequelae of malnutrition that include persistent stunting, neurodevelopmental abnormalities, and immune dysfunction. RATIONALE Repairing microbiota immaturity and determining the degree to which such repair restores healthy growth requires identification of microbial targets that are not only biomarkers of community assembly but also mediators of various aspects of growth. Identifying ingredients in complementary foods, consumed during the transition from exclusive milk feeding to a fully weaned state, that increase the representation and expressed beneficial functions of growth-promoting bacterial taxa in the developing microbiota could provide an effective, affordable, culturally acceptable, and sustainable approach to treatment. RESULTS Metabolomic and proteomic analyses of serially collected plasma samples were combined with metagenomic analyses of serially collected fecal samples from Bangladeshi children with severe acute malnutrition (SAM) treated with standard therapy. The results provided a readout of their biological features as they transitioned from SAM to a state of persistent moderate acute malnutrition (MAM) with accompanying persistent microbiota immaturity. Significant correlations were identified between levels of plasma proteins, anthropometry, plasma metabolites, and the representation of bacteria in their microbiota. Gnotobiotic mice were subsequently colonized with a defined consortium of bacterial strains that represent various phases of microbiota development in healthy Bangladeshi children. Administration of different combinations of Bangladeshi complementary food ingredients to colonized mice and germ-free controls revealed diet-dependent increases in the abundance and changes in the metabolic activities of targeted weaning-phase strains as well as diet- and colonization-dependent augmentation of growth-promoting host signaling pathways. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes were subsequently examined in gnotobiotic mice colonized with immature microbiota from children with post-SAM MAM and in gnotobiotic piglets colonized with a defined consortium of targeted age- and growth-discriminatory taxa. A randomized, double-blind study of standard therapy versus various MDCF prototypes emerging from these preclinical models, conducted in Bangladeshi children with MAM, identified a lead MDCF that increased levels of biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function toward a state resembling healthy children. Using an approach inspired by statistical methods applied to financial markets, we show in the accompanying paper by Raman et al. that this lead MDCF was most effective in repairing the microbiota. CONCLUSION These findings demonstrate the translatability of results obtained from pre-clinical gnotobiotic animal models to humans, directly support the hypothesis that healthy microbiota development is causally linked to healthy growth, illustrate an approach for treating childhood undernutrition, and with the capacity to deliberately reconfigure immature microbiota, suggest a means to decipher how elements of the gut microbial community operate to regulate various host systems involved in healthy growth. Overview of therapeutic food discovery and testing. The approach used for integrating preclinical gnotobiotic animal models with human studies to understand the contributions of perturbed gut microbiota development to childhood malnutrition and to identify MDCFs.
Databáze: OpenAIRE
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