An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease  Frank J. Gonzalez, Changtao Jiang, Andrew D. Patterson  Gastroenterology  Volume 151, Issue 5, Pages 845-859 (November 2016) DOI: 10.1053/j.gastro.2016.08.057 Copyright © 2016 AGA Institute Terms and Conditions

Figure 1 Levels of pantothenic acid in the urine of mice that were treated with tempol. Pantothenic acid is converted to 4’phosphopantothenate, which is a precursor for synthesis of coenzyme A (CoA) and is required for the β-oxidation of fatty acids in mitochondria. Gastroenterology 2016 151, 845-859DOI: (10.1053/j.gastro.2016.08.057) Copyright © 2016 AGA Institute Terms and Conditions

Figure 2 Bile acids are synthesized in the liver and intestine to produce FXR agonist and antagonist. In the liver, CDCA is synthesized and then conjugated with taurine to produce taurochenodeoxycholic acid (TCDCA), or hydroxylated to produce α-MCA, which also can be conjugated with taurine to produce T-α-MCA (not shown). UDCA, an isomer of CDCA, is made and hydroxylated to produce β-MCA, which then is conjugated with taurine to yield T-β-MCA. TCDCA and T-β-MCA and some of their free unconjugated forms are exported to the intestine. In the intestine, T-β-MCA, an FXR antagonist, can be deconjugated to taurine and β-MCA by bacterial BSH. CDCA resulting from TCDCA deconjugation is an FXR agonist. The concentrations of CDCA, T-β-MCA, and other bile acids in the lower small intestine likely determine the extent of FXR signaling in ileal epithelial cells. Gastroenterology 2016 151, 845-859DOI: (10.1053/j.gastro.2016.08.057) Copyright © 2016 AGA Institute Terms and Conditions

Figure 3 The role of gut bacterial and intestinal FXR in tempol-induced weight loss. Cholesterol is converted to T-β-MCA, which is secreted into the intestine. In the lower small intestine of mice, it is hydrolyzed to β-MCA and taurine by BSH. When mice are administered tempol, the levels of Lactobacillus and BSH activity are decreased, resulting in increased T-β-MCA that inhibits FXR in the ilium epithelial cells. This results in lower obesity and insulin resistance. Chol, cholesterol. Gastroenterology 2016 151, 845-859DOI: (10.1053/j.gastro.2016.08.057) Copyright © 2016 AGA Institute Terms and Conditions

Figure 4 The role FXR signaling and ceramides in the modulation of metabolic disease. In obese mice, a bile acid agonist produced in the liver constitutively stimulates FXR in the ileum, resulting in increased production of ceramides. Ceramides then cause lipid toxicity in the liver through increased endoplasmic reticulum stress and increased fatty acid synthesis as a result of elevated SREBP-1 signaling. Ceramides also impair adipose function through increased endoplasmic reticulum stress, resulting in a decrease in the ratio of beige to white adipocytes. In the presence of the FXR antagonist Gly-MCA, ceramide levels are decreased, resulting in decreased hepatic lipid synthesis and steatosis, and increased adipose beiging. FA, fatty acid. Gastroenterology 2016 151, 845-859DOI: (10.1053/j.gastro.2016.08.057) Copyright © 2016 AGA Institute Terms and Conditions

Figure 5 Potential mechanism by which ceramides increase NAFLD. Ceramides enter the cell and incorporate into the endoplasmic reticulum (ER) and mitochondrial membranes, causing increased ER stress and mitochondrial permeability, respectively. Mitochondrial damage can give rise to increased reactive oxygen species (ROS) and cause apoptosis. Through a mechanism that still is unclear, ceramides can activate SREBP-1c, leading to increased fatty acid synthesis and NAFLD. Gastroenterology 2016 151, 845-859DOI: (10.1053/j.gastro.2016.08.057) Copyright © 2016 AGA Institute Terms and Conditions