Obesity and the Microbiota Herbert Tilg, Alexander R. Moschen, Arthur Kaser  Gastroenterology  Volume 136, Issue 5, Pages 1476-1483 (May 2009) DOI: 10.1053/j.gastro.2009.03.030 Copyright © 2009 AGA Institute Terms and Conditions

Figure 1 Several pathways have been identified regarding how the gut microbiota might influence host energy metabolism. (1) Absence of the microbiota in germ-free mice is associated with an increased activity of phosphorylated AMP-activated protein kinase (AMPK) in the liver and the muscle. (2) The gut microbiome contains myriad fermentation enzymes. Therefore otherwise poorly digestible complex carbohydrates can be made accessible. (3) Released monosaccharides are absorbed and activate key transcription factors such as carbohydrate responsive element binding protein (ChREBP). (4) Some of the breakdown products are metabolized to short chain fatty acids (SCFA). SCFA such as propionate and acetate are ligands for the G-protein coupled receptors Gpr41 and Gpr42. Activation of Gpr41 by its ligands induces gut-derived hormones such as peptide YY (PYY) by enteroendocrine cells, and affects the host's energy harvest from the diet. (5) Moreover, the microbiota suppresses epithelial expression of fasting-induced adipocyte factor (Fiaf), which functions as a circulating LPL inhibitor and therefore is an important regulator of peripheral fat storage. Gastroenterology 2009 136, 1476-1483DOI: (10.1053/j.gastro.2009.03.030) Copyright © 2009 AGA Institute Terms and Conditions

Figure 2 Genetic and diet-induced obesity are associated with alterations of (i) the composition and (ii) the functional properties of the gut microbiota. (A) Leptin-deficient ob/ob mice rapidly gain weight. Development of obesity correlates with a shift in the abundance of the 2 dominating divisions, the Bacteroidetes and the Firmicutes. Compared to lean ob/+ or +/+ littermates, obesity was associated with a 50% reduction in Bacteroidetes and a proportional division-wide increase in Firmicutes. Moreover, ob/ob mice showed an increase in environmental gene tags that matched Archaea, methanogenic microorganisms that might promote bacterial fermentation by removing one of its end products, namely hydrogen (H2). The metagenomic analysis of the obese gut microbiome revealed an increase in glycoside hydrolases, capable of breaking down otherwise indigestible alimentary polysaccharides. Furthermore, the obese microbiome showed enrichment for transport proteins and fermentation enzymes further processing breakdown products. As a consequence, ob/ob mice have an increased capacity to harvest energy from their diet. (B) The interrelationship between diet, intestinal microbial ecology, and energy homeostasis was investigated in a mouse model of diet-induced obesity.28 The microbiota of mice fed a high-fat/high-sugar prototypic Western diet was compared with the microbiota of mice receiving a low-fat/high-polysaccharide diet. Again, as in the ob/ob model, the Western diet was associated with an increased body weight, a lower relative abundance of Bacteroidetes, and a higher relative abundance of Firmicutes. However, unlike in the ob/ob model this shift was not division-wide. The overall diversity of the Western diet-associated gut microbiota dropped dramatically. The reason was a bloom in a single class of the Firmicutes—the Mollicutes. The Western diet gut microbiome was enriched for genes involved in import and fermentation of simple sugars and host glycans, enriched for genes for beta-fructosidases, and depleted for genes involved in motility. Gastroenterology 2009 136, 1476-1483DOI: (10.1053/j.gastro.2009.03.030) Copyright © 2009 AGA Institute Terms and Conditions