Expanding role of gut microbiota in lipid metabolism

Purpose of review This article highlights recent advances in the emerging role that gut microbiota play in modulating metabolic phenotypes, with a particular focus on lipid metabolism. Recent findings Accumulating data from both human and animal studies demonstrate that intestinal microbes can affect host lipid metabolism through multiple direct and indirect biological mechanisms. These include a variety of signaling molecules produced by gut bacteria that have potent effects on hepatic lipid and bile metabolism and on reverse cholesterol transport, energy expenditure, and insulin sensitivity in peripheral tissues. Additionally, host genetic factors can modulate the abundance of bacterial taxa, which can subsequently affect various metabolic phenotypes. Proof of causality for identified microbial associations with host lipid-related phenotypes has been demonstrated in several animal studies, but remains a challenge in humans. Ultimately, selective manipulation of the gut microbial ecosystem for intervention will first require a better understanding of which specific bacteria, or alternatively, which bacterial metabolites, are appropriate targets. Summary Recent discoveries have broad implications for elucidating bacterially mediated pathophysiological mechanisms that alter lipid metabolism and other related metabolic traits. From a clinical perspective, this newly recognized endocrine organ system can be targeted for therapeutic benefit of dyslipidemia and cardiometabolic diseases.

[1]  Brian J. Bennett,et al.  Comparative Genome-Wide Association Studies in Mice and Humans for Trimethylamine N-Oxide, a Proatherogenic Metabolite of Choline and L-Carnitine , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[2]  G. Tsujimoto,et al.  The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43 , 2013, Nature Communications.

[3]  Lucie Geurts,et al.  Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity , 2013, Proceedings of the National Academy of Sciences.

[4]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[5]  Alison S. Waller,et al.  Genomic variation landscape of the human gut microbiome , 2012, Nature.

[6]  D. Sinderen,et al.  Gut microbiota composition correlates with diet and health in the elderly , 2012, Nature.

[7]  J. Clemente,et al.  Diet Drives Convergence in Gut Microbiome Functions Across Mammalian Phylogeny and Within Humans , 2011, Science.

[8]  V. Tremaroli,et al.  FXR is a molecular target for the effects of vertical sleeve gastrectomy , 2014, Nature.

[9]  J. Auwerx,et al.  TGR5-mediated bile acid sensing controls glucose homeostasis. , 2009, Cell metabolism.

[10]  Fredrik H. Karlsson,et al.  Gut metagenome in European women with normal, impaired and diabetic glucose control , 2013, Nature.

[11]  Eleazar Eskin,et al.  Genetic and environmental control of host-gut microbiota interactions , 2015, Genome research.

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

[13]  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.

[14]  F. Bäckhed,et al.  Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits , 2014, Cell.

[15]  J. Clemente,et al.  Human gut microbiome viewed across age and geography , 2012, Nature.

[16]  Richard A. Flavell,et al.  Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity , 2012, Nature.

[17]  Brian J. Bennett,et al.  Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation* , 2014, The Journal of Biological Chemistry.

[18]  W. D. de Vos,et al.  Modulation of Mucosal Immune Response, Tolerance, and Proliferation in Mice Colonized by the Mucin-Degrader Akkermansia muciniphila , 2011, Front. Microbio..

[19]  Katherine H. Huang,et al.  A framework for human microbiome research , 2012, Nature.

[20]  Richard G. Lee,et al.  The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance. , 2015, Cell Reports.

[21]  J. Auwerx,et al.  Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation , 2006, Nature.

[22]  S. Hazen,et al.  Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis , 2015, Cell.

[23]  Angela C. Poole,et al.  Human Genetics Shape the Gut Microbiome , 2014, Cell.

[24]  M. McCarthy,et al.  Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice , 2006, Proceedings of the National Academy of Sciences.

[25]  E. Balskus,et al.  Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme , 2012, Proceedings of the National Academy of Sciences.

[26]  E. Zoetendal,et al.  Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. , 2012, Gastroenterology.

[27]  Brian J. Bennett,et al.  Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease , 2011, Nature.

[28]  Brian J. Bennett,et al.  Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis[S] , 2015, Journal of Lipid Research.

[29]  Brian J. Bennett,et al.  Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. , 2013, Cell metabolism.

[30]  D. Gevers,et al.  The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids , 2015, Circulation research.

[31]  F. Bushman,et al.  Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes , 2011, Science.

[32]  George M. Weinstock,et al.  Genomic approaches to studying the human microbiota , 2012, Nature.

[33]  S. Sandhu,et al.  Aerobic degradation of choline by Proteus mirabilis: enzymatic requirements and pathway. , 1986, Canadian journal of microbiology.

[34]  J. Petrosino,et al.  Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders , 2013, Cell.

[35]  Cecilia Jernberg,et al.  Long-term impacts of antibiotic exposure on the human intestinal microbiota. , 2010, Microbiology.

[36]  M. Blaser,et al.  Antibiotics in early life and obesity , 2015, Nature Reviews Endocrinology.

[37]  Qiang Feng,et al.  A metagenome-wide association study of gut microbiota in type 2 diabetes , 2012, Nature.

[38]  J. Clemente,et al.  Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice , 2013, Science.

[39]  Laxman Yetukuri,et al.  The gut microbiota modulates host energy and lipid metabolism in mice[S] , 2010, Journal of Lipid Research.

[40]  S. Dowell,et al.  The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids* , 2003, The Journal of Biological Chemistry.

[41]  F. Bushman,et al.  Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis , 2013, Nature Medicine.

[42]  G. Macfarlane,et al.  Bacteria, colonic fermentation, and gastrointestinal health. , 2012, Journal of AOAC International.

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