S P E C I A L
F E A T U R E E d i t o r i a l
Gut Microbiome, Obesity-Related Comorbidities, and Low-Grade Chronic Inflammation Giovanni Tarantino Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, 80131 Naples, Italy; and Istituro Nazionale Tumori Pascale Foundation, Cancer Research Center of Mercogliano, 83013 Mercogliano Avellino, Italy
O
besity is a complex disease appearing as a polygenic condition affected by environmental factors (mainly, but not only, diet and physical activity). The combination of genotype and epigenetic modifications explains the association of susceptibility to obesity with dietary patterns and sedentary lifestyle. The rising incidence of obesity (in the form of total and/or visceral adiposity) in Western countries is associated with various obesity-related health complications, including— beyond the most prominent conditions of coronary artery disease and cancer, type 2 diabetes mellitus, obstructive sleep apnea syndrome (OSAS), chronic kidney disease, osteoarthritis, and cognitive impairment—the well-recognized nonalcoholic fatty liver disease (NAFLD). Recent evidence suggests that adipose tissue is an endocrine/metabolic organ secreting the so-called adipocytokines, among which the most important are TNF-␣, IL-6, adiponectin, and leptin. The imbalanced production of pro- and anti-inflammatory adipokines secreted from fat contributes to the pathogenesis of obesity-related NAFLD. Modulation of those interactions may provide exciting pharmacological targets for the treatment of NAFLD. For example, in patients with obesity-related NAFLD, serum levels of leptin are increased, and the liver becomes refractory to the “antisteatotic” effects of leptin (1). Consequently, the external administration of leptin is of scarce therapeutic value in patients with NAFLD. TNF-␣, a proinflammatory adipokine, interferes with insulin signaling by inducing serine phosphorylation of insulin receptor substrate-1 and inducing insulin resistance and consequently favors NAFLD progression. Neutralization of TNF-␣ activity might improve NAFLD in human beings. IL-6 is a polyvalent cytokine with proin-
flammatory and pro-oncogenic activity that is a predictor marker of insulin resistance and coronary artery disease (2). Initially, this cytokine was considered hepatoprotective because it reduces oxidative stress and prevents mitochondrial dysfunction in animal models (3). IL-6, contextually with TNF-␣, suppresses adiponectin levels (4). Adiponectin is an adipocytokine with anti-inflammatory properties, and it decreases in subjects with increased liver fat concentration (5). Treatment of cells with proinflammatory cytokines such as TNF-␣ and IL-1 or with bacterial products such as lipopolysaccharide (LPS) leads to the activation of a specific-IKK complex that phosphorylates IB and thereby tags it for ubiquitination and degradation by the proteasome (6). The degradation of IB thus allows nuclear factor-B (NF-B) to translocate into the nucleus where it can act as a transcription factor that up-regulates IL-6 production and secretion. IL-6 works locally through paracrine and/or endocrine mechanisms to activate IL-6 signaling in the liver. IL-6 is known to induce insulin resistance in hepatocytes (7). Hepatic production of IL-6 also provides a further pathogenic link to extrahepatic organs such as muscle. NF-B target genes are not upregulated in transgenic mouse muscle, but IL-6 target genes are, including suppressor of cytokine signaling and signal transducer and activator of transcription proteins. These genes are reversed during IL-6 neutralization, which is consistent with the pathogenic involvement of IL-6. Activation of NF-B leads to a severe syndrome of muscle wasting, surprisingly without insulin resistance (8). Fat mass in overweight/obese subjects has a primary role in determining low-grade chronic inflammation and, in turn, insulin resistance and ectopic lipid storage within the liver.
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received April 16, 2014. Accepted May 1, 2014.
Abbreviations: LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; NF-B, nuclear factor-B; OSAS, obstructive sleep apnea syndrome.
For article see page 2575
doi: 10.1210/jc.2014-2074
J Clin Endocrinol Metab, July 2014, 99(7):2343–2346
jcem.endojournals.org
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Microbiome and Obesity
The confounding effect of visceral obesity colors the findings of much of the published data investigating IL-6 in OSAS. A number of case control studies favor an independent effect of OSAS on IL-6 levels (9), whereas other researchers show some criticism of this interpretation (10). Clearly, inflammation is an adaptive and energyconsuming process, in response to rich fat-calorie content of diet, with adiponectin being one of the most critical signals to reducing an inflammatory response. Adiponectin levels in NAFLD patients were generally low. Its expression is lower by one-third in NAFLD patients, lending credence to the hypothesis that adiponectin deficiency is a cornerstone mechanism in determining the more severe form of NAFLD, ie, nonalcoholic steatohepatitis. Some animal-based studies have demonstrated that exogenous adiponectin lessens hepatic inflammation by decreasing hepatic expression of TNF-␣ and depletes lipid accumulation. Inflammatory mediators that are biosynthesized in the liver and increased in NAFLD patients include C- reactive protein, IL-6, fibrinogen, and plasminogen activator inhibitor-1. Furthermore, fat in the liver represents a site beyond adipose tissue that independently contributes to synthesis of inflammatory mediators. However, it appears that most efforts should center upon individuating the complex interplay between organs of production for this cytoadipokine network, ie, visceral fat, liver, and gut. Recent findings point out a possible role for components of the microbiota in influencing body weight, possibly determining more efficient calorie extraction from the diet (11). The intestinal bacteria population inhabits a complex environment, and its composition differs throughout the gut. It is necessary to distinguish at least three different types of microbiota: the luminal microbiota, within the intestinal lumen; the mucosal microbiota that adheres to the intestinal wall; and the fecal microbiota, excreted in feces. In mice, the intestinal flora partly accounts for body fat deposition (12). Although the relative contribution varies considerably according to body composition, organisms in the Bacteroidetes and Firmicutes phyla collectively represent nearly 90% of the microbiota composition. Interestingly, obese subjects have a higher proportion of Firmicutes to Bacteroidetes than lean subjects (13). Intestinal microbiota has been found to have an important role in energy harvesting and fat storage. Germ-free mice are protected from diet-induced weight gain (14) due to the involvement of gut flora in the fermentation of polysaccharides to monosaccharides and in the metabolism of short-chain fatty acids (15). The microbiota can also enhance the lipoprotein lipase activity because it reduces the expression of the fasting-induced adipocyte factor in the intestinal epithelium, resulting in
J Clin Endocrinol Metab, July 2014, 99(7):2343–2346
enhanced free fatty acid storage in adipocytes (14). But, apart from the aforementioned mechanism in the development of obesity, Gram-negative intestinal bacteria producing an endotoxin, ie, LPS that constitutes the outer membrane, elicit not only an inflammatory/immune response, but also insulin resistance (16). It is noteworthy that a high-fat diet stimulates LPS production in mice, and its passage through the intestinal wall may be fat-dependent. The subsequent endotoxemia induces weight gain, intrahepatic triglyceride accumulation, and hepatic insulin resistance, leading to increased expression of Toll-like receptor 4 and proinflammatory cytokine (IL-1, IL-6, TNF␣, and plasminogen activator inhibitor-1) in adipose tissue, muscle, and liver (17). Moreover, the bacterial flagellin can also play a role in inflammation/immunity, engaging its specific Toll-like receptor 5 receptor on the surface of the gut. Indeed, in an animal model, a diet with a high concentration in palm oil induces weight gain and increased liver triglyceride concentration, decreases gut microbial diversity, and leads to a higher Firmicutes/Bacteroidetes ratio compared to a diet that is high in polyunsaturated fatty acid (18). This correlation between intestinal dysbiosis and lipid accumulation in the liver is further confirmed by the finding that the fecal microbiota of women following a choline-deficient diet, inducing steatosis, varies during choline depletion and correlates with changes in liver fat concentration showing modifications in Gammaproteobacteria and Erysipelotrichi populations (19). The gut microflora inhibits angiopoietin-related protein 4 leading to continuous expression of lipoprotein lipase, which results in increased uptake of fatty acids and accumulation of triglycerides in adipocytes and enhanced hepatic triglyceride storage (20). Additionally, variations of the gut microbiota composition, resembling those seen after prebiotic (special form of dietary fiber) treatment or weight loss after caloric restriction (21), have also been found among obese individuals who have undergone gastric bypass surgery (22). Some intriguing hypotheses could be that these changes may be associated with a more balanced secretion of gastrointestinal hormones, ie, gastric inhibitory polypeptide and glucagon-like peptide-1; a modulation of the activity of the endocannabinoid system; an improved leptin sensitivity; a minor conversion of nondigestible carbohydrates (fibers) into short-chain fatty acids; or a decreased local alcohol production. Some of these processes, ameliorating insulin resistance, reduce the risk of the NAFLD worsening. But, a key role could be played by the restoration of a correct enterohepatic circulation of bile acids, which are required for efficient absorption of dietary fat and fat-soluble vitamins, and are involved in the control of
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 28 August 2014. at 10:11 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2074
high-density lipoprotein and very low-density lipoprotein. Furthermore, a correct secondary bile acid metabolism, the regulation of bile acid synthesis, and the equilibrium of lipid peroxidation are central to maintaining the intestinal barrier function and the luminal environment, ultimately leading to decreased bacterial translocation. Summarizing, intestinal microbiota may act as a triggering factor linking low-grade inflammation to high-fat diet-induced metabolic syndrome (23), as a consequence of or independently from interventions, as clearly evident in the accompanying study (24). In the paper by Ortiz et al (24), published in this edition of the JCEM, the authors analyzed the translocation of bacterial DNA, qualitatively detected and identified in blood samples by broad-range PCR, and of the prokaryote 16SrRNA gene. They demonstrate that the translocation of bacterial products into the blood of morbidly obese patients characterizes a subgroup of patients who are not able to reduce their systemic inflammatory cytokine levels (IL-6, TNF␣, IL-2, and interferon-␥) after following a massive weight reduction protocol consisting of a modified fasting period followed by bariatric surgery. By virtue of these findings, our understanding of the role of microbial communities is improved, mainly in the light of identifying possible molecular targets related to metabolism regulation. Another merit of this study lies in the blood-based analysis of the gut microbiota. In fact, this method avoids multiple molecular procedures, including quantitative PCR for total fecal bacteria or for more specific genera and even specific strains (eg, Firmicutes, Bacteroidetes, Bifidobacterium spp., Lactobacillus spp., Roseburia spp., Eubacterium rectale/Clostridium coccoides group, and Bacteroides-Prevotella spp.), barcoded pyrosequencing, and phylogenetic microarrays of 16S rRNA able to generate comprehensive microbial community profiles. Although animal models have led to striking and unequivocal findings regarding the role of gut microbiota in host energy metabolism, this research in humans opens the scenario to other approaches that are more easily applicable, including selection of diet constituents or administration of probiotic/prebiotic-inducing/modifying flora composition, with the aim to improve gut barrier function and alleviate inflammation and insulin resistance associated with obesity. Conclusively, given the high prevalence of excess body weight in many populations, better elucidating mechanisms inducing/maintaining obesity are crucial to lessen obesity-related risks, which are an important public health problem in several countries. Lifestyle intervention trials and bariatric surgery offer compelling evidence for the reversibility of insulin resistance by weight loss, although genetic assets can exceed these favorable changes. Accordingly, this intriguing study casts some doubts about the absolute necessity for weight loss
jcem.endojournals.org
2345
in obese patients to reduce the inflammation and the obesity-related comorbidities.
Acknowledgments Address all correspondence and requests for reprints to: Giovanni Tarantino, Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: [email protected], or [email protected]. Disclosure Summary: This author has nothing to disclose.
References 1. Huang XD, Fan Y, Zhang H, et al. Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease. World J Gastroenterol. 2008;14:2888 –2893. 2. Kopp HP, Kopp CW, Festa A, et al. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler Thromb Vasc Biol. 2003;23:1042–1047. 3. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379 –1383. 4. Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3–L1 adipocytes. Biochem Biophys Res Commun. 2003; Feb 21;301(4):1045–50. 5. Kolak M, Westerbacka J, Velagapudi VR, et al. Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes. 2007; 56:1960 –1968. 6. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621– 663. 7. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes. 2003;52:2784 –2789. 8. Cai D, Frantz JD, Tawa NE Jr, et al. IKK/NF-B activation causes severe muscle wasting in mice. Cell. 2004;119:285–298. 9. Arnardottir ES, Maislin G, Schwab RJ, et al. The interaction of obstructive sleep apnea and obesity on the inflammatory markers C-reactive protein and interleukin-6: the Icelandic Sleep Apnea Cohort. Sleep. 2012;35:921–932. 10. Mehra R, Storfer-Isser A, Kirchner HL, et al. Soluble interleukin 6 receptor: a novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med. 2006;166:1725–1731. 11. Blaut M, Klaus S. Intestinal microbiota and obesity. Handb Exp Pharmacol. 2012;209:251–273. 12. Flint HJ. Obesity and the gut microbiota. J Clin Gastroenterol. 2011;45:S128 —S132. 13. Krznari Z, Vraneši Bender D, Kunovi A, Kekez D, Stimac D. Gut microbiota and obesity. Dig Dis. 2012;30:196 –200. 14. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101:15718 –15723. 15. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. 16. Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol. 2012;18: 2609 –2618.
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17. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–1772. 18. de Wit N, Derrien M, Bosch-Vermeulen H, et al. Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. Am J Physiol Gastrointest Liver Physiol. 2012;303:G589 — G599. 19. Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology. 2011;140:976 –986. 20. Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care. 2010; 33:2277–2284.
J Clin Endocrinol Metab, July 2014, 99(7):2343–2346
21. Santacruz A, Marcos A, Wärnberg J, et al. Interplay between weight loss and gut microbiota composition in overweight adolescents. Obesity (Silver Spring). 2009;17:1906 –1915. 22. Osto M, Abegg K, Bueter M, le Roux CW, Cani PD, Lutz TA. Roux-en-Y gastric bypass surgery in rats alters gut microbiota profile along the intestine. Physiol Behav. 2013;119:92–96. 23. DiBaise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc. 2008;83:460 – 469. 24. Ortiz S, Zapater P, Estrada JL, et al. Bacterial DNA translocation holds increased insulin resistance and systemic inflammatory levels in morbid obese patients. J Clin Endocrinol Metab. 2014;99:2575– 2583.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 28 August 2014. at 10:11 For personal use only. No other uses without permission. . All rights reserved.
F E A T U R E E d i t o r i a l
Gut Microbiome, Obesity-Related Comorbidities, and Low-Grade Chronic Inflammation Giovanni Tarantino Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, 80131 Naples, Italy; and Istituro Nazionale Tumori Pascale Foundation, Cancer Research Center of Mercogliano, 83013 Mercogliano Avellino, Italy
O
besity is a complex disease appearing as a polygenic condition affected by environmental factors (mainly, but not only, diet and physical activity). The combination of genotype and epigenetic modifications explains the association of susceptibility to obesity with dietary patterns and sedentary lifestyle. The rising incidence of obesity (in the form of total and/or visceral adiposity) in Western countries is associated with various obesity-related health complications, including— beyond the most prominent conditions of coronary artery disease and cancer, type 2 diabetes mellitus, obstructive sleep apnea syndrome (OSAS), chronic kidney disease, osteoarthritis, and cognitive impairment—the well-recognized nonalcoholic fatty liver disease (NAFLD). Recent evidence suggests that adipose tissue is an endocrine/metabolic organ secreting the so-called adipocytokines, among which the most important are TNF-␣, IL-6, adiponectin, and leptin. The imbalanced production of pro- and anti-inflammatory adipokines secreted from fat contributes to the pathogenesis of obesity-related NAFLD. Modulation of those interactions may provide exciting pharmacological targets for the treatment of NAFLD. For example, in patients with obesity-related NAFLD, serum levels of leptin are increased, and the liver becomes refractory to the “antisteatotic” effects of leptin (1). Consequently, the external administration of leptin is of scarce therapeutic value in patients with NAFLD. TNF-␣, a proinflammatory adipokine, interferes with insulin signaling by inducing serine phosphorylation of insulin receptor substrate-1 and inducing insulin resistance and consequently favors NAFLD progression. Neutralization of TNF-␣ activity might improve NAFLD in human beings. IL-6 is a polyvalent cytokine with proin-
flammatory and pro-oncogenic activity that is a predictor marker of insulin resistance and coronary artery disease (2). Initially, this cytokine was considered hepatoprotective because it reduces oxidative stress and prevents mitochondrial dysfunction in animal models (3). IL-6, contextually with TNF-␣, suppresses adiponectin levels (4). Adiponectin is an adipocytokine with anti-inflammatory properties, and it decreases in subjects with increased liver fat concentration (5). Treatment of cells with proinflammatory cytokines such as TNF-␣ and IL-1 or with bacterial products such as lipopolysaccharide (LPS) leads to the activation of a specific-IKK complex that phosphorylates IB and thereby tags it for ubiquitination and degradation by the proteasome (6). The degradation of IB thus allows nuclear factor-B (NF-B) to translocate into the nucleus where it can act as a transcription factor that up-regulates IL-6 production and secretion. IL-6 works locally through paracrine and/or endocrine mechanisms to activate IL-6 signaling in the liver. IL-6 is known to induce insulin resistance in hepatocytes (7). Hepatic production of IL-6 also provides a further pathogenic link to extrahepatic organs such as muscle. NF-B target genes are not upregulated in transgenic mouse muscle, but IL-6 target genes are, including suppressor of cytokine signaling and signal transducer and activator of transcription proteins. These genes are reversed during IL-6 neutralization, which is consistent with the pathogenic involvement of IL-6. Activation of NF-B leads to a severe syndrome of muscle wasting, surprisingly without insulin resistance (8). Fat mass in overweight/obese subjects has a primary role in determining low-grade chronic inflammation and, in turn, insulin resistance and ectopic lipid storage within the liver.
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received April 16, 2014. Accepted May 1, 2014.
Abbreviations: LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; NF-B, nuclear factor-B; OSAS, obstructive sleep apnea syndrome.
For article see page 2575
doi: 10.1210/jc.2014-2074
J Clin Endocrinol Metab, July 2014, 99(7):2343–2346
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 28 August 2014. at 10:11 For personal use only. No other uses without permission. . All rights reserved.
2343
2344
Tarantino
Microbiome and Obesity
The confounding effect of visceral obesity colors the findings of much of the published data investigating IL-6 in OSAS. A number of case control studies favor an independent effect of OSAS on IL-6 levels (9), whereas other researchers show some criticism of this interpretation (10). Clearly, inflammation is an adaptive and energyconsuming process, in response to rich fat-calorie content of diet, with adiponectin being one of the most critical signals to reducing an inflammatory response. Adiponectin levels in NAFLD patients were generally low. Its expression is lower by one-third in NAFLD patients, lending credence to the hypothesis that adiponectin deficiency is a cornerstone mechanism in determining the more severe form of NAFLD, ie, nonalcoholic steatohepatitis. Some animal-based studies have demonstrated that exogenous adiponectin lessens hepatic inflammation by decreasing hepatic expression of TNF-␣ and depletes lipid accumulation. Inflammatory mediators that are biosynthesized in the liver and increased in NAFLD patients include C- reactive protein, IL-6, fibrinogen, and plasminogen activator inhibitor-1. Furthermore, fat in the liver represents a site beyond adipose tissue that independently contributes to synthesis of inflammatory mediators. However, it appears that most efforts should center upon individuating the complex interplay between organs of production for this cytoadipokine network, ie, visceral fat, liver, and gut. Recent findings point out a possible role for components of the microbiota in influencing body weight, possibly determining more efficient calorie extraction from the diet (11). The intestinal bacteria population inhabits a complex environment, and its composition differs throughout the gut. It is necessary to distinguish at least three different types of microbiota: the luminal microbiota, within the intestinal lumen; the mucosal microbiota that adheres to the intestinal wall; and the fecal microbiota, excreted in feces. In mice, the intestinal flora partly accounts for body fat deposition (12). Although the relative contribution varies considerably according to body composition, organisms in the Bacteroidetes and Firmicutes phyla collectively represent nearly 90% of the microbiota composition. Interestingly, obese subjects have a higher proportion of Firmicutes to Bacteroidetes than lean subjects (13). Intestinal microbiota has been found to have an important role in energy harvesting and fat storage. Germ-free mice are protected from diet-induced weight gain (14) due to the involvement of gut flora in the fermentation of polysaccharides to monosaccharides and in the metabolism of short-chain fatty acids (15). The microbiota can also enhance the lipoprotein lipase activity because it reduces the expression of the fasting-induced adipocyte factor in the intestinal epithelium, resulting in
J Clin Endocrinol Metab, July 2014, 99(7):2343–2346
enhanced free fatty acid storage in adipocytes (14). But, apart from the aforementioned mechanism in the development of obesity, Gram-negative intestinal bacteria producing an endotoxin, ie, LPS that constitutes the outer membrane, elicit not only an inflammatory/immune response, but also insulin resistance (16). It is noteworthy that a high-fat diet stimulates LPS production in mice, and its passage through the intestinal wall may be fat-dependent. The subsequent endotoxemia induces weight gain, intrahepatic triglyceride accumulation, and hepatic insulin resistance, leading to increased expression of Toll-like receptor 4 and proinflammatory cytokine (IL-1, IL-6, TNF␣, and plasminogen activator inhibitor-1) in adipose tissue, muscle, and liver (17). Moreover, the bacterial flagellin can also play a role in inflammation/immunity, engaging its specific Toll-like receptor 5 receptor on the surface of the gut. Indeed, in an animal model, a diet with a high concentration in palm oil induces weight gain and increased liver triglyceride concentration, decreases gut microbial diversity, and leads to a higher Firmicutes/Bacteroidetes ratio compared to a diet that is high in polyunsaturated fatty acid (18). This correlation between intestinal dysbiosis and lipid accumulation in the liver is further confirmed by the finding that the fecal microbiota of women following a choline-deficient diet, inducing steatosis, varies during choline depletion and correlates with changes in liver fat concentration showing modifications in Gammaproteobacteria and Erysipelotrichi populations (19). The gut microflora inhibits angiopoietin-related protein 4 leading to continuous expression of lipoprotein lipase, which results in increased uptake of fatty acids and accumulation of triglycerides in adipocytes and enhanced hepatic triglyceride storage (20). Additionally, variations of the gut microbiota composition, resembling those seen after prebiotic (special form of dietary fiber) treatment or weight loss after caloric restriction (21), have also been found among obese individuals who have undergone gastric bypass surgery (22). Some intriguing hypotheses could be that these changes may be associated with a more balanced secretion of gastrointestinal hormones, ie, gastric inhibitory polypeptide and glucagon-like peptide-1; a modulation of the activity of the endocannabinoid system; an improved leptin sensitivity; a minor conversion of nondigestible carbohydrates (fibers) into short-chain fatty acids; or a decreased local alcohol production. Some of these processes, ameliorating insulin resistance, reduce the risk of the NAFLD worsening. But, a key role could be played by the restoration of a correct enterohepatic circulation of bile acids, which are required for efficient absorption of dietary fat and fat-soluble vitamins, and are involved in the control of
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 28 August 2014. at 10:11 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2074
high-density lipoprotein and very low-density lipoprotein. Furthermore, a correct secondary bile acid metabolism, the regulation of bile acid synthesis, and the equilibrium of lipid peroxidation are central to maintaining the intestinal barrier function and the luminal environment, ultimately leading to decreased bacterial translocation. Summarizing, intestinal microbiota may act as a triggering factor linking low-grade inflammation to high-fat diet-induced metabolic syndrome (23), as a consequence of or independently from interventions, as clearly evident in the accompanying study (24). In the paper by Ortiz et al (24), published in this edition of the JCEM, the authors analyzed the translocation of bacterial DNA, qualitatively detected and identified in blood samples by broad-range PCR, and of the prokaryote 16SrRNA gene. They demonstrate that the translocation of bacterial products into the blood of morbidly obese patients characterizes a subgroup of patients who are not able to reduce their systemic inflammatory cytokine levels (IL-6, TNF␣, IL-2, and interferon-␥) after following a massive weight reduction protocol consisting of a modified fasting period followed by bariatric surgery. By virtue of these findings, our understanding of the role of microbial communities is improved, mainly in the light of identifying possible molecular targets related to metabolism regulation. Another merit of this study lies in the blood-based analysis of the gut microbiota. In fact, this method avoids multiple molecular procedures, including quantitative PCR for total fecal bacteria or for more specific genera and even specific strains (eg, Firmicutes, Bacteroidetes, Bifidobacterium spp., Lactobacillus spp., Roseburia spp., Eubacterium rectale/Clostridium coccoides group, and Bacteroides-Prevotella spp.), barcoded pyrosequencing, and phylogenetic microarrays of 16S rRNA able to generate comprehensive microbial community profiles. Although animal models have led to striking and unequivocal findings regarding the role of gut microbiota in host energy metabolism, this research in humans opens the scenario to other approaches that are more easily applicable, including selection of diet constituents or administration of probiotic/prebiotic-inducing/modifying flora composition, with the aim to improve gut barrier function and alleviate inflammation and insulin resistance associated with obesity. Conclusively, given the high prevalence of excess body weight in many populations, better elucidating mechanisms inducing/maintaining obesity are crucial to lessen obesity-related risks, which are an important public health problem in several countries. Lifestyle intervention trials and bariatric surgery offer compelling evidence for the reversibility of insulin resistance by weight loss, although genetic assets can exceed these favorable changes. Accordingly, this intriguing study casts some doubts about the absolute necessity for weight loss
jcem.endojournals.org
2345
in obese patients to reduce the inflammation and the obesity-related comorbidities.
Acknowledgments Address all correspondence and requests for reprints to: Giovanni Tarantino, Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: [email protected], or [email protected]. Disclosure Summary: This author has nothing to disclose.
References 1. Huang XD, Fan Y, Zhang H, et al. Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease. World J Gastroenterol. 2008;14:2888 –2893. 2. Kopp HP, Kopp CW, Festa A, et al. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler Thromb Vasc Biol. 2003;23:1042–1047. 3. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379 –1383. 4. Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3–L1 adipocytes. Biochem Biophys Res Commun. 2003; Feb 21;301(4):1045–50. 5. Kolak M, Westerbacka J, Velagapudi VR, et al. Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes. 2007; 56:1960 –1968. 6. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621– 663. 7. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes. 2003;52:2784 –2789. 8. Cai D, Frantz JD, Tawa NE Jr, et al. IKK/NF-B activation causes severe muscle wasting in mice. Cell. 2004;119:285–298. 9. Arnardottir ES, Maislin G, Schwab RJ, et al. The interaction of obstructive sleep apnea and obesity on the inflammatory markers C-reactive protein and interleukin-6: the Icelandic Sleep Apnea Cohort. Sleep. 2012;35:921–932. 10. Mehra R, Storfer-Isser A, Kirchner HL, et al. Soluble interleukin 6 receptor: a novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med. 2006;166:1725–1731. 11. Blaut M, Klaus S. Intestinal microbiota and obesity. Handb Exp Pharmacol. 2012;209:251–273. 12. Flint HJ. Obesity and the gut microbiota. J Clin Gastroenterol. 2011;45:S128 —S132. 13. Krznari Z, Vraneši Bender D, Kunovi A, Kekez D, Stimac D. Gut microbiota and obesity. Dig Dis. 2012;30:196 –200. 14. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101:15718 –15723. 15. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. 16. Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol. 2012;18: 2609 –2618.
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2346
Tarantino
Microbiome and Obesity
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