The gut microbiota modulates host energy and lipid metabolism in mice[S]

The gut microbiota has recently been identified as an environmental factor that may promote metabolic diseases. To investigate the effect of gut microbiota on host energy and lipid metabolism, we compared the serum metabolome and the lipidomes of serum, adipose tissue, and liver of conventionally raised (CONV-R) and germ-free mice. The serum metabolome of CONV-R mice was characterized by increased levels of energy metabolites, e.g., pyruvic acid, citric acid, fumaric acid, and malic acid, while levels of cholesterol and fatty acids were reduced. We also showed that the microbiota modified a number of lipid species in the serum, adipose tissue, and liver, with its greatest effect on triglyceride and phosphatidylcholine species. Triglyceride levels were lower in serum but higher in adipose tissue and liver of CONV-R mice, consistent with increased lipid clearance. Our findings show that the gut microbiota affects both host energy and lipid metabolism and highlights its role in the development of metabolic diseases.

[1]  J. Exton Signaling through phosphatidylcholine breakdown. , 1990, The Journal of biological chemistry.

[2]  L. Fulton,et al.  Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. , 2008, Cell host & microbe.

[3]  A. Gotto,et al.  The plasma lipoproteins: structure and metabolism. , 1978, Annual review of biochemistry.

[4]  Elaine Holmes,et al.  Probiotic Modulation of Symbiotic Gut Microbial–host Metabolic Interactions in a Humanized Microbiome Mouse Model , 2022 .

[5]  C. Larkin,et al.  Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats. , 1983, Laboratory animal science.

[6]  C. W. Moss,et al.  Production of hydrocinnamic acid by clostridia. , 1970, Applied microbiology.

[7]  Elaine Holmes,et al.  A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model , 2007, Molecular systems biology.

[8]  I. Mattila,et al.  Factors affecting the conversion of apple polyphenols to phenolic acids and fruit matrix to short-chain fatty acids by human faecal microbiota in vitro , 2008, European journal of nutrition.

[9]  J. Girard,et al.  Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. , 2008, The Journal of clinical investigation.

[10]  F. Shanahan,et al.  The gut flora as a forgotten organ , 2006, EMBO reports.

[11]  K. McCoy,et al.  Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. , 2007, Seminars in immunology.

[12]  J. Nicholson,et al.  Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics , 2002, Nature Medicine.

[13]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[14]  Marko Sysi-Aho,et al.  A Systems Biology Strategy Reveals Biological Pathways and Plasma Biomarker Candidates for Potentially Toxic Statin-Induced Changes in Muscle , 2006, PloS one.

[15]  J. Gordon,et al.  Molecular analysis of commensal host-microbial relationships in the intestine. , 2001, Science.

[16]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[17]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[18]  S. Young,et al.  Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia. , 1987, The Journal of clinical investigation.

[19]  S. Levenson,et al.  Response of germfree, conventional, conventionalized and E. coli monocontaminated mice to starvation. , 1968, Journal of NutriLife.

[20]  Y. Benjamini,et al.  Controlling the false discovery rate in behavior genetics research , 2001, Behavioural Brain Research.

[21]  T. Midtvedt Microbial bile acid transformation. , 1974, The American journal of clinical nutrition.

[22]  D. Vance Role of phosphatidylcholine biosynthesis in the regulation of lipoprotein homeostasis , 2008, Current opinion in lipidology.

[23]  F. Bäckhed,et al.  Obesity alters gut microbial ecology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  F. Bäckhed,et al.  Host-Bacterial Mutualism in the Human Intestine , 2005, Science.

[25]  Julian L Griffin,et al.  High Resolution 1H NMR-based Metabolomics Indicates a Neurotransmitter Cycling Deficit in Cerebral Tissue from a Mouse Model of Batten Disease* , 2005, Journal of Biological Chemistry.

[26]  M. Barker,et al.  Partial least squares for discrimination , 2003 .

[27]  Les Dethlefsen,et al.  The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S rRNA Sequencing , 2008, PLoS biology.

[28]  Ting Wang,et al.  The gut microbiota as an environmental factor that regulates fat storage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Borén,et al.  The assembly and secretion of apolipoprotein B-containing lipoproteins. , 1999, Current opinion in lipidology.

[30]  J. Gordon,et al.  How host-microbial interactions shape the nutrient environment of the mammalian intestine. , 2002, Annual review of nutrition.

[31]  P. Turnbaugh,et al.  Microbial ecology: Human gut microbes associated with obesity , 2006, Nature.

[32]  Olli Simell,et al.  Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes , 2008, The Journal of experimental medicine.

[33]  Jeffrey I. Gordon,et al.  Mechanisms underlying the resistance to diet-induced obesity in germ-free mice , 2007, Proceedings of the National Academy of Sciences.

[34]  R. Tukey,et al.  Human UDP-glucuronosyltransferases: metabolism, expression, and disease. , 2000, Annual review of pharmacology and toxicology.

[35]  R. Knight,et al.  Evolution of Mammals and Their Gut Microbes , 2008, Science.

[36]  M. Armstrong,et al.  The hydrophobic-hydrophilic balance of bile salts. Inverse correlation between reverse-phase high performance liquid chromatographic mobilities and micellar cholesterol-solubilizing capacities. , 1982, Journal of lipid research.

[37]  E. N. Bergman Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. , 1990, Physiological reviews.

[38]  Z. Ramadan,et al.  Top-down systems biology integration of conditional prebiotic modulated transgenomic interactions in a humanized microbiome mouse model , 2008, Molecular systems biology.

[39]  W. R. Wikoff,et al.  Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites , 2009, Proceedings of the National Academy of Sciences.

[40]  Jeffrey I. Gordon,et al.  Reciprocal Gut Microbiota Transplants from Zebrafish and Mice to Germ-free Recipients Reveal Host Habitat Selection , 2006, Cell.

[41]  John Turk,et al.  Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver , 2009, Cell.

[42]  S. D. Jong SIMPLS: an alternative approach to partial least squares regression , 1993 .

[43]  G. Abrams,et al.  Effect of the Normal Microbial Flora on Gastrointestinal Motility.∗ , 1967, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[44]  Haifeng Lu,et al.  Symbiotic gut microbes modulate human metabolic phenotypes , 2008, Proceedings of the National Academy of Sciences.

[45]  T. Hashimoto,et al.  PEROXISOMAL β-OXIDATION AND PEROXISOME PROLIFERATOR–ACTIVATED RECEPTOR α: An Adaptive Metabolic System , 2001 .

[46]  B. Kowalski,et al.  Partial least-squares regression: a tutorial , 1986 .

[47]  T Hashimoto,et al.  Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. , 2001, Annual review of nutrition.

[48]  Elaine Holmes,et al.  Systemic multicompartmental effects of the gut microbiome on mouse metabolic phenotypes , 2008, Molecular systems biology.

[49]  Rob Knight,et al.  Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation , 2009, Proceedings of the National Academy of Sciences.