腸内細菌代謝産物の腸管保護作用に関する研究

広島大学(Hiroshima University)博士(農学)Doctor of Agriculturedoctora

Diet-Induced Obese Mice and Leptin-Deficient Lepob/ob Mice Exhibit Increased Circulating GIP Levels Produced by Different Mechanisms.

As glucose-dependent insulinotropic polypeptide (GIP) possesses pro-adipogenic action, the suppression of the GIP hypersecretion seen in obesity might represent a novel therapeutic approach to the treatment of obesity. However, the mechanism of GIP hypersecretion remains largely unknown. In the present study, we investigated GIP secretion in two mouse models of obesity: High-fat diet-induced obese (DIO) mice and leptin-deficient Lepob/ob mice. In DIO mice, plasma GIP was increased along with an increase in GIP mRNA expression in the lower small intestine. Despite the robust alteration in the gut microbiome in DIO mice, co-administration of maltose and the α-glucosidase inhibitor (α-GI) miglitol induced the microbiome-mediated suppression of GIP secretion. The plasma GIP levels of Lepob/ob mice were also elevated and were suppressed by fat transplantation. The GIP mRNA expression in fat tissue was not increased in Lepob/ob mice, while the expression of an interleukin-1 receptor antagonist (IL-1Ra) was increased. Fat transplantation suppressed the expression of IL-1Ra. The plasma IL-1Ra levels were positively correlated with the plasma GIP levels. Accordingly, although circulating GIP levels are increased in both DIO and Lepob/ob mice, the underlying mechanisms differ, and the anti-obesity actions of α-GIs and leptin sensitizers may be mediated partly by the suppression of GIP secretion

Nutritional signaling via free fatty acid receptors

Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs’ carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis. In particular, recent studies have shown that the administration of selective agonists of G protein-coupled receptor (GPR) 40 and GPR120 improved glucose metabolism and systemic metabolic disorders. Furthermore, the anti-inflammation and energy metabolism effects of short chain FAs have been linked to the activation of GPR41 and GPR43. In this review, we summarize recent progress in research on FFAs and their physiological roles in the regulation of energy metabolism

Dietary Combination of Fish Oil and Soy beta-Conglycinin Inhibits Fat Accumulation and Reduces Blood Glucose Levels by Altering Gut Microbiome Composition in Diabetic/Obese KK-Ay Mice

Dietary fish oil containing n-3 polyunsaturated fatty acids provides health benefits by lowering lipid levels in the liver and serum. beta-Conglycinin (beta CG) is a major constituent protein in soybean with many physiological effects, such as lowering blood triglyceride levels, preventing obesity and diabetes, and improving hepatic lipid metabolism. However, the combined effects of fish oil and beta CG remain unclear. Here, we investigated the effects of a dietary combination of fish oil and beta CG on lipid and glucose parameters in diabetic/obese KK-Ay mice. KK-Ay mice were divided into three groups: control, fish oil, and fish oil + beta CG; these groups were fed a casein-based diet containing 7% (w/w) soybean oil, a casein-based diet containing 2% (w/w) soybean oil and 5% (w/w) fish oil, and a beta CG-based diet containing 2% (w/w) soybean oil and 5% (w/w) fish oil, respectively. The effects of the dietary combination of fish oil and beta CG on blood biochemical parameters, adipose tissue weight, expression levels of fat-and glucose metabolism -related genes, and cecal microbiome composition were evaluated. The total white adipose tissue weight (p < 0.05), levels of total serum cholesterol (p < 0.01), triglyceride (p < 0.01), and blood glucose (p < 0.05), and expression levels of fatty acid synthesis-related genes (including Fasn (p < 0.05) and Acc (p < 0.05)), and glucose metabolism-related genes (such as Pepck (p < 0.05)) were lower in the fish oil and fish oil + beta CG groups than in the control group. Furthermore, the relative abundance of Bacteroidaceae and Coriobacteriaceae differed significantly between the fish oil + beta CG and control groups. These findings suggest that dietary intake of fish oil + beta CG may prevent obesity and diabetes, alleviate lipid abnormalities, and alter the gut microbiome composition in diabetic/obese KK-Ay mice. Further research is needed to build on this study to evaluate the health benefits of major components of Japanese food

Involvement of Gut Microbial Metabolites Derived from Diet on Host Energy Homeostasis

Due to the excess energy intake, which is a result of a high fat and high carbohydrate diet, dysfunction of energy balance leads to metabolic disorders such as obesity and type II diabetes mellitus (T2DM). Since obesity can be a risk factor for various diseases, including T2DM, hypertension, hyperlipidemia, and metabolic syndrome, novel prevention and treatment are expected. Moreover, host diseases linked to metabolic disorders are associated with changes in gut microbiota profile. Gut microbiota is affected by diet, and nutrients are used as substrates by gut microbiota for produced metabolites, such as short-chain and long-chain fatty acids, that may modulate host energy homeostasis. These free fatty acids are not only essential energy sources but also signaling molecules via G-protein coupled receptors (GPCRs). Some GPCRs are critical for metabolic functions, such as hormone secretion and immune function in various types of cells and tissues and contribute to energy homeostasis. The current studies have shown that GPCRs for gut microbial metabolites improved host energy homeostasis and systemic metabolic disorders. Here, we will review the association between diet, gut microbiota, and host energy homeostasis

Characterization of the glycoproteins of bat-derived influenza viruses

Recently found bat-derived influenza viruses (BatlVs) have hemagglutinin (HA) and neuraminidase (NA) gene segments distinct from those of previously known influenza A viruses. However, pathogenicities of these BatlVs remain unknown since infectious virus strains have not been isolated yet. To gain insight into the biological properties of BatlVs, we generated vesicular stomatitis viruses (VSVs) pseudotyped with the BatIV HA and NA. We found that VSVs pseudotyped with BatIV HAs and NAs efficiently infected particular bat cell lines but not those derived from primates, and that proteolytic cleavage with a trypsinlike protease was necessary for HA-mediated virus entry. Treatment of the susceptible bat cells with some enzymes and inhibitors revealed that BatIV HAs might recognize some cellular glycoproteins as receptors rather than the sialic acids used for the other known influenza viruses. These data provide fundamental information on the mechanisms underlying the cellular entry and host restriction of BatIVs. (C) 2016 Elsevier Inc. All rights reserved

A polymorphism of the TIM-1 IgV domain: Implications for the susceptibility to filovirus infection

Filoviruses, including Ebola and Marburg viruses, cause severe hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Human T-cell immunoglobulin and mucin domain 1 (TIM-I) is one of the host proteins that have been shown to promote filovirus entry into cells. In this study, we cloned TIM-1 genes from three different African green monkey kidney cell lines (Vero E6, COS-I, and BSC-1) and found that TIM-1 of Vero E6 had a 23-amino acid deletion and 6 amino acid substitutions compared with those of COS-1 and BSC-1. Interestingly, Vero E6 TIM-I had a greater ability to promote the infectivity of vesicular stomatitis viruses pseudotyped with filovirus glycoproteins than COS-1-derived TIM-I. We further found that the increased ability of Vero E6 TIM-1 to promote virus infectivity was most likely due to a single amino acid difference between these TIM-1s. These results suggest that a polymorphism of the TIM-I molecules is one of the factors that influence cell susceptibility to filovirus infection, providing a new insight into the molecular basis for the filovirus host range. (C) 2014 Elsevier Inc. All rights reserved