title: Bacterial nutrient foraging in a mouse model of enteral nutrient deprivation: insight into the gut origin of sepsis.
abstract: Total parenteral nutrition (TPN) leads to a shift in small intestinal microbiota with a characteristic dominance of Proteobacteria This study examined how metabolomic changes within the small bowel support an altered microbial community in enterally deprived mice. C57BL/6 mice were given TPN or enteral chow. Metabolomic analysis of jejunal contents was performed by liquid chromatography/mass spectrometry (LC/MS). In some experiments, leucine in TPN was partly substituted with [13C]leucine. Additionally, jejunal contents from TPN-dependent and enterally fed mice were gavaged into germ-free mice to reveal whether the TPN phenotype was transferrable. Small bowel contents of TPN mice maintained an amino acid composition similar to that of the TPN solution. Mass spectrometry analysis of small bowel contents of TPN-dependent mice showed increased concentration of13C compared with fed mice receiving saline enriched with [13C]leucine. [13C]leucine added to the serosal side of Ussing chambers showed rapid permeation across TPN-dependent jejunum, suggesting increased transmucosal passage. Single-cell analysis by fluorescence in situ hybridization (FISH)-NanoSIMS demonstrated uptake of [13C]leucine by TPN-associated bacteria, with preferential uptake by Enterobacteriaceae Gavage of small bowel effluent from TPN mice into germ-free, fed mice resulted in a trend toward the proinflammatory TPN phenotype with loss of epithelial barrier function. TPN dependence leads to increased permeation of TPN-derived nutrients into the small intestinal lumen, where they are predominately utilized by Enterobacteriaceae The altered metabolomic composition of the intestinal lumen during TPN promotes dysbiosis.
authors: Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, Michigan; mralls@med.umich.edu.
authors: Matthew W
authors: MW
authors: Ralls
authors: Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, Michigan.
authors: Farokh R
authors: FR
authors: Demehri
authors: Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, Michigan.
authors: Yongjia
authors: Y
authors: Feng
authors: Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, Michigan.
authors: Sasha
authors: S
authors: Raskind
authors: Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, Michigan.
authors: Chunhai
authors: C
authors: Ruan
authors: Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Research Network Chemistry Meets Microbiology, University of Vienna, Vienna, Austria.|Large-Instrument Facility for Advanced Isotope Research, University of Vienna, Vienna, Austria; and.
authors: Arno
authors: A
authors: Schintlmeister
authors: Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Research Network Chemistry Meets Microbiology, University of Vienna, Vienna, Austria.
authors: Alexander
authors: A
authors: Loy
authors: Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Research Network Chemistry Meets Microbiology, University of Vienna, Vienna, Austria.
authors: Buck
authors: B
authors: Hanson
authors: Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Research Network Chemistry Meets Microbiology, University of Vienna, Vienna, Austria.
authors: David
authors: D
authors: Berry
authors: Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors: Charles F
authors: CF
authors: Burant
authors: Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, Michigan.
authors: Daniel H
authors: DH
authors: Teitelbaum
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology; D007583:Jejunum / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D010289:Parenteral Nutrition, Total; D018805:Sepsis / Q000378:metabolism* / Q000382:microbiology
keywords: NanoSIMS; epithelial barrier function; metabolome; microbiota; nutrient foraging; total parenteral nutrition