Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2019 Feb 1.
Published in final edited form as: JPEN J Parenter Enteral Nutr. 2018 Feb;42(2):279–295. doi: 10.1002/jpen.1121

Proceedings of the 2017 ASPEN Research Workshop— Gastric Bypass: Role of the Gut

Ajay Kumar Jain 1, Carel W le Roux 2, Puneet Puri 3, Ali Tavakkoli 4, Nana Gletsu-Miller 5, Blandine Laferrère 6, Richard Kellermayer 7, John K DiBaise 8, Robert G Martindale 9, Bruce M Wolfe 9
PMCID: PMC5955776  NIHMSID: NIHMS922260  PMID: 29443403

Abstract

The goal of the NIH funded A.S.P.E.N. 2017 research workshop (RW) “Gastric Bypass: Role of the Gut”, was to focus on the exciting research evaluating gut-derived signals in modulating outcomes post bariatric surgery. Though gastric bypass surgery has undoubted positive effects, the mechanistic basis of improved outcomes cannot be solely explained by caloric restriction.

Emerging data suggest that bile acid metabolic pathways, luminal contents, energy balance, gut mucosal integrity as well as the gut microbiota are significantly modulated post bariatric surgery and may be responsible for the variable outcomes, each of which were rigorously evaluated.

The RW served as a timely and novel academic meeting that brought together clinicians and researchers across the scientific spectrum, fostering a unique venue for inter-disciplinary collaboration among investigators.

It promoted engaging discussion and evolution of new research hypothesis and ideas, driving the development of novel ameliorative, therapeutic and non-surgical interventions targeting obesity and its co-morbidities.

Importantly, a critical evaluation of the current knowledge regarding gut modulated signaling post bariatric surgery, potential pitfalls and lacunae were thoroughly addressed.

Introduction

Obesity is a global health problem and its ameliorative strategies remain a major research focus1,2. Though several interventions have been trialed, the mainstay of current therapy anchors on lifestyle modification inclusive of nutrition and exercise35. While clinically meaningful weight loss may be achieved with lifestyle intervention, such weight loss is generally not sustained and its efficacy in modulating comorbidities has been questioned6. Thus, there remains an ongoing need for effective and durable therapeutic options, including bariatric surgery.

With surgical advances patients with obesity tend to have significant improvement in obesity related co-morbidities with gastric bypass surgery. While several variations for such bariatric surgery are in practice, one of the earliest was the Roux-en-Y gastric bypass (RYGB)7. Post-surgery improvement in most organ systems affected by obesity have been noted8.

In keeping with significant health benefits, the number of patients undergoing bariatric surgery has reached unprecedented levels, with over 300,000 bariatric surgery procedures being undertaken annually9,10. Given the remarkable success, the underlying mechanisms leading to improved outcomes after bariatric surgery are the focus of a burgeoning field of research that may lead to novel non-surgical interventions.

Recent data suggests that post-surgery improvement may not merely be an effect of weight loss; there may be a significant influence of altered gut derived signals in modulating the disease pathology. Alterations in gut anatomy also induce adaptive changes to the morphology of the gut, which affect the absorption of macro and micronutrients. The mechanisms responsible for metabolic and nutritional outcomes following gastric bypass were reviewed as part of the workshop and presented by each faculty member.

(I) Overview of Enterohepatic Circulation, Gut Microbiota and Metabolic Pathways Relevant to the Gut-liver Axis: (Ajay K Jain)

Gastric Bypass FXR and Bile Acids

Emerging studies suggest that bile acid metabolic pathways are disrupted with bariatric surgery with significant alterations to the finely regulated enterohepatic bile acid circulation11,12. Bile acids, traditionally considered as toxic agents have emerged as major signaling molecules maintaining several homeostatic pathways involved in insulin, glucose metabolism, lipid regulation as well as regulators of hepatic steatosis13,14. Marked increases in serum bile acids and its sub-fractions have been noted post RYGB in comparison to weight matched controls12,15. New research provides evidence that enteral bile acid treatment activates the nuclear receptor, Farnesoid X Receptor (FXR) in gut epithelial cells16,17. Such activation stimulates the production of the growth factor, Fibroblast Growth Factor – 19 (FGF19). FGF19 is subsequently delivered via the portal system to the liver and is known to modulate bile acid, glucose and lipid metabolism18,19. In fact, intravenously delivered FGF19 has been shown to reverse or prevent diabetes, improve glycemic control and reduced hepatic steatosis and triglyceride levels2022. FGF19 thus functions as a secretory signal from the gut to the liver, regulating bile acid synthesis23.

This seems to provide evidence that hepatic bile acid synthesis; glucose and lipid metabolism is modulated via gut FXR signaling2426. Indeed, higher levels of FXR and FGF19 have been noted several months post RYGB in human subjects27.

Both large animal studies and human studies have shown that exogenously delivered FXR agonist improve glycemic control, lipid metabolism and hepatic steatosis28,29. Additionally surgical procedures involving ileal transposition (where sections of the ileum are inserted into the jejunum), result in a significant increase in bile acids levels, improvement in body mass and obesity related co-morbidities30.

A postulated mechanism has been a short circuiting of the normal enterohepatic circulation brought about by the altered anatomy, as the ileum is the primary site of bile acid absorption. Improved glycemic regulation, reduced hepatic steatosis, increased bile acid levels, as well as weight loss have been noted in animal models with biliary diversion31,32. The recapitulation of the benefits of gastric bypass using such procedure raises the thought provoking idea that anatomic alteration during bariatric surgery may explain some of the mechanistic basis of improved outcomes. However, while this data is encouraging it has also been noted that there are differences in post prandial bile acids after RYGB or Vertical sleeve gastrectomy (VSG) which points to a differential enterohepatic signaling based on the type of surgery33,34.

Further exploration of such bile acid regulated key signaling pathways with a potential for pharmacological and nutritional intervention was a major focus of the 2017 RW.

Gastric Bypass and role of Glucagon Like Peptide-1 (GLP-1) and TGR5 axis

A further mechanistic link is again through bile acid regulated pathways. Bile acids activate TGR5 – a cell surface G-protein-coupled receptor35. TGR5 is known to be present in the intestines, brown adipose tissue and the liver36. There is an increase in intracellular cAMP upon bile acid stimulation of TGR5 with variable effects dependent on the cell type expressing TGR537. The role of bile acids in regulation of glucose homeostasis is further strengthened by the secretion of GLP-1 upon TGR5 activation38,39.

We now know that plasma GLP-1 rapidly increases after RYGB40. GLP-1 has been implicated in glycemic homeostasis. Along with glucose dependent insulinotropic polypeptide (GIP), GLP-1 is a major gut hormone which enhances the insulin response to nutrient ingestion41. In non-obese individuals with normal glucose tolerance GLP-1 is released in response to nutrient intake. However, this GLP-1 response is significantly diminished in those with obesity42. It is known that post RYGB there in an increased TGR5 signaling12. Given that GLP-1 is secreted from enteroendocrine L cells in the intestine, it is plausible that manipulation of the gastro-intestinal tract as in RYGB alters GLP-1 secretion.

Further highlighting this pathway is data that postoperatively there is enhancement of postprandial GLP-1 response43,44. GLP-1 response is known to be greater after RYGB than after Sleeve Gastrectomy45. Additionally, such increase in GLP-1 response was not noted in calorie restricted obese patients; mimicking the post-surgery diet46 or in obese patients on a low-calorie diet experiencing a similar weight loss. It has also been shown that there is a progressive increase in GLP-1 level during the first year postoperatively with a sustained response noted in some individuals4749.

Given the above data it appears plausible that alterations to GLP-1 and the TGR5-GLP axis, brought about by the surgical procedure of Gastric bypass exert significant beneficial influence and the therapeutic potential needs to be explored.

Gut Microbiota FXR and TGR5

While the bacterial mass in any individual is a small percent of body weight50, the bacterial genome exceeds by several folds the human genome. Ironically this makes us genetically 1% human and 99% bacterial51,52.

When viewed as a whole, this “super gut microbial organism” can perform vital physiologic functions53. These typically benefit the host in educating the mucosal immune system, nutrient extraction from undigested carbohydrates, production of short chain fatty acids, production of vitamins and metabolism of bile acids54,55.

A large human study evaluating fecal microbial colonies in dizygotic and monozygotic twin pairs addressed the role of host genetic factors, adiposity, environment and its influence on the gut microbiota56. Although the human gut microbiota was shared among family members, it was specific for each individual. A comparable co-variation between dizygotic and monozygotic twin pairs excluded difference based on genetic factors. Obesity was associated with intestinal microbiomes showing reduced diversity at a phylum level56.

In rodent studies, delivery of cecal microbiota from ob/ob mice into wild germ free animals resulted in a modest fat gain. Such bacterial transfer also increased food calorie extraction in comparison to animals receiving gut bacteria from lean animal donors57. Several studies evaluating Nonalcoholic steatohepatitis (NASH), have noted improvement in steatosis, glucose intolerance as well as lipid profiles58,59 with exogenous gut bacterial modulation60,61.

These studies further support the belief that gut bacteria modulate and play an important role in human disease. Several rodent and human studies have shown that post RYGB there occurs a restructuring of the gut microbiota62,63. An exogenous transfer of the gut microbes from RYGB mice to un-operated, germ-free mice resulted in significant reduction in fat mass gain as well as less weight gain in comparison to such a transfer from mice that underwent sham surgery64.

Given that gut microbes are intimately involved in gut nutrient processing and their alterations are noted with RYGB, it is reason to believe that altered gut microbiota secondary to gastric bypass influences positive outcomes post RYGB surgery.

(II) Gut Hormones and Bariatric Surgery: (Carel Le Roux)

Gut hormones have been implicated as part of the mechanisms of how bariatric surgery reduces bodyweight and maintains long term weight loss65.

RYGB and VSG might alter signaling from the gut to the hypothalamus and brainstem. Markedly higher postprandial levels of the anorexigenic hormone peptide YY (PYY)66 are noted after both RYGB and VSG, but not after calorie restriction or adjustable gastric banding (AGB)67,68. After a meal, PYY is released from the L cells in the distal small bowel in proportion to consumed calories. It decreases food intake by acting at the arcuate nucleus of the hypothalamus69, and also via vagal afferents ending at the nucleus of the solitary track, thus signaling satiety. PYY has been shown to delay gastric emptying and increase energy expenditure70. Patients with increased PYY after RYGB have more weight loss71,72. Blocking the release of PYY with octreotide increased food intake in humans and rats after RYGB, but not AGB. Mechanistic studies have also shown the physiological importance of PYY in rodent studies. GLP-1 responses are similar to those of PYY after both RYGB and VSG73. GLP‑1 is secreted by the L cells of the small bowel together with PYY, with higher concentrations in the colon and distal ileum. It acts on the GLP‑1 receptors in the hypothalamus, striatum, substantia nigra and brainstem74. In response to a meal the peptide is produced, which decreases food intake via its effects on the brainstem and hypothalamus75. GLP‑1 delays gastric emptying, inhibits the release of glucagon and acts on the pancreas to promote secretion of insulin76. Whether GLP‑1 alone is necessary for VSG-induced weight loss has been questioned. The procedure was effective equally in GLP‑1 receptor wild-type and knockout mice77 but the potential synergy of GLP-1 along with other gut hormones post these operations may hold the key. The rapid nutrient delivery to the distal ileum after RYGB might be responsible for the exaggerated increase of both GLP-1 and PYY levels78. In the absence of a shorter small bowel in VSG, the rise in levels of these gut hormones has been attributed to rapid gastric emptying79. However, this finding is probably just part of the story as nutrient sensing in the proximal segment of the small bowel can produce signal to the distal small bowel to release gut hormones80. Recent data also suggests that post RYGB there is an increase in the post prandial responses for cholecystokinin and glucagon and a decrease in ghrelin and leptin81. It is also known that gut hormones are elevated within days after surgery and remain elevated for at least a decade after RYGB47. However, although they play an important role the gut hormones are only part of the mechanistic explanations for why bariatric surgery is able to reduce weight and maintain weight loss.

(III) Role of Bile Salts and Key Hepatobiliary Receptors in Modulating Gut Structure and Signaling Post Gastric Bypass Surgery (Puneet Puri)

Weight loss in the management of obesity is plagued by the lack of effective long term sustainability and translation into improved outcomes6,82. The most notable obesity related liver condition is nonalcoholic fatty liver disease (NAFLD). More concerning is the fact that NASH, the aggressive phenotype of NAFLD, is emerging as the leading cause of cirrhosis, liver cancer and liver transplantation83,84.

Bariatric surgery remains a very important approach to combat obesity and its co-morbidities85. The benefits of bariatric surgery extend beyond weight loss and are postulated to occur via modulation of glucose and lipid homeostasis, which in turn are also regulated by bile acids86. Given alterations noted in serum bile acid levels following gastric bypass surgery in both human and animal studies12,87, several authors have postulated that the beneficial effects post-surgery are a result, at least in part, due to changes in enterohepatic circulation of bile acids88.

Experimental approaches such as ‘ileal transposition’ or bile diversion have been used in preclinical studies. Ileal transposition studies in rodent models demonstrate diminished food intake, significant weight loss and resolution of the features of the metabolic syndrome89. These improvements are linked to adaptation of the interposed segment as evident by greater length of jejunum-like villi, enhanced mucosal surface area, as well as increase in mRNA expression of transcription factor GATA4/ileal lipid binding protein (GATA4/ILBP)30. Additionally, ileal transposition short-circuits enterohepatic recycling of the bile acids that lead to protective effects against the metabolic syndrome30. Importantly, weight loss alone does not improve the metabolic effects as is seen in rodents with similar weight loss on food restriction, but are observed in surgical weight loss procedures that alter serum bile acids and have been noted to help in the resolution of NASH90.

While data translated from these studies is certainly helpful in defining mechanistic links, it is plausible that additional bile acid pathways are modulated by current bariatric surgery procedures as there is a known variability in the serum bile acid levels based on the kind of surgery performed34,91.

In fact, VSG with gastroduodenal continuity is becoming the preferred surgical option for obesity in recent years92. In addition to weight loss, VSG can produce changes in bile acids and their receptor mediated molecular actions confer the metabolic benefits93. We now know that FXR is “a” target for the beneficial weight-loss dependent and independent effects of VSG, similarly its downstream targets small heterodimer partner (SHP) and indirect entero-hepatic signal FGF15/19 also merit future investigation as potential therapeutic targets94. Further mechanistic insights into bile acid signaling and regulation of entero-hepatic circulation will advance our understanding of bariatric surgery related metabolic benefits. In future, this will allow translation of these metabolic benefits through non- or minimally invasive “bariatric-mimetic” interventions that would bridge the current vast therapeutic gap in patients suffering from obesity and other related comorbidities including NASH95.

(IV) Changes in intestinal metabolism and portal signaling (Ali Tavakkoli)

Mechanisms leading to the anti-diabetic effects of bariatric surgery remain poorly elucidated. Understanding these mechanisms can lead to development of less invasive surgical or medical alternatives that can be offered to a wider patient population. There has been a broad interest in the changes in intestinal function that occurs after RYGB surgery, with studies showing increase in intestinal glucose utilization after surgery96. Furthermore, studies have also shown a decrease in intestinal glucose absorption after RYGB97,98. It has been postulated that these changes in intestinal function, alter fasting and post-prandial portal vein milieu which can alter hepatic glucose handling and lead to the early reduction in hepatic insulin resistance that is seen after bariatric surgery. To support this hypothesis, studies using portal vein infusions in a rodent model, have shown post-infusion changes in expression of hepatic enzymes involved in glucose homeostasis, through a neutrally mediated process that likely involves SGLT3 as a portal glucose sensor97. The authors concluded that the portal vein was not only capable of sensing its glucose levels but responded to it by altering hepatic glucose handling.

The portal vein delivers the intestinal venous drainage to the liver and as such provides a direct communication between the bowel and the liver. The above mentioned studies which show that the portal vein is more than a simple conduit between the bowel and the liver, and the observation that changes in portal vein glucose levels can lead to changes in hepatic pathways involved in glucose homeostasis97,99, through a neutrally mediated pathway, highlight an important role for this structure in post-operative glucose improvement.

To this effect studies have documented a decrease in fasting and post-prandial glucose levels after RYGB surgery in rodents, with associated decrease in hepatic gluconeogenesis and glycolysis. Interestingly, some of these changes are uniquely seen in RYGB and not VSG, which may explain the more potent anti-diabetic effects of RYGB. Further research may provide insights into the mechanistic basic of these responses.

(V) Gut Nutrient Sensing: Gut Remodeling and Adaptation to Gastric Bypass and Effects on Absorption of Macro and Micronutrients (Nana Gletsu-Miller)

Gastric bypass surgery is traditionally considered to be malabsorptive100, however, from the stand point of nutrition this characterization is simplistic. Several mechanisms contribute to the risk of malnutrition observed following RYGB. One major issue is the reduced dietary intake of macro and micronutrients, secondary to decreased energy intake and to food intolerances that develop after surgery101,102. In addition patients decrease their intake of dietary factors that enhance absorption including fat and vitamin C, which leads to decreased bioavailability of nutrients such as vitamin D, iron and copper. Besides changes in dietary intake, anatomical changes result in reduced nutrient bioavailability and intestinal absorption. Resection of the stomach antrum decreases gastric acid secretion103,104 and loss of absorptive surface in the duodenum and proximal jejunum reduces access to nutrient transporters105. At the same time, the adaptive response to changes in the anatomy result in growth of the remaining small intestine, similar to the adaptation of the gut that occurs after resection of the intestine, referred to as short gut syndrome106. The result of these changes is an increase the absorption of some nutrients but not others after RYGB107. Therefore the impact of RYGB on nutritional status is mixed with respect to macro and micronutrients.

Impact on macronutrient status

As aforementioned changes in gut anatomy, accompanied by intestinal hyperplasia106,108 lead to changes in macronutrient absorption. Over the long term, the gut retains or enhances its ability to absorb glucose109, fatty acids110 and amino acids111,112. Elegant studies in rodents and humans demonstrated that gut adaptations can lead to improvements in glucose metabolism, as the intestine assists with glucose disposal from the periphery109. At one and six months post gastric bypass, it has been demonstrated that even though patients decreased their dietary intake of fat, they did not exhibit deficiencies in essential fatty acids113. However, enhanced absorption of amino acids does not compensate for the fact that many patients do not meet the dietary intake of 60 g of protein that is recommended for this population114,115. The evidence supporting this recommendation was rated as low; information on the impact of dietary protein on protein status during surgically-induced weight loss is mostly observational116 and evidence from randomized clinical trials is extremely limited117. This is an important issue since sarcopenia is common after surgery, with patient losing 10 to 28% of lean mass116. The clinical manifestations of a reduction of lean body mass and sarcopenic obesity include decreased energy expenditure118, muscle strength119, and bone density118, adverse outcomes that have the potential to reduce the benefits of surgery over the long term.

Impact on micronutrient status

Unlike macronutrients, patients undergoing RYGB are more vulnerable to deficiencies in micronutrients, primarily minerals and fat soluble vitamins. It has long been appreciated that nutritional complications such as hair loss, bone loss, anemia, fatigue, neuropathies120, and more severe symptoms including bone fractures121, blindness122 and paralysis123, associated with deficiencies in micronutrients can occur following gastric bypass. Unfortunately, the literature regarding the micronutrient status of RYGB is incomplete due to the lack of patient follow-up and nutritional screening. Our best knowledge is that deficiencies in iron, calcium and vitamin D are common, ranging from 25 to 75%120. Deficiencies in vitamins A, B12 and other B vitamins occur less frequently with incidences of around 10%124,125 The mechanisms responsible are complex since obesity per se, prior to surgery, is a risk factor for deficiency in specific nutrients, such as vitamin D126 and iron127. In the obese state, the bioavailability of iron and vitamin D is reduced due to obesity-induced inflammation128 and sequestration in adipose tissue129, respectively. Following surgery, as patients experience weight loss, this alleviates the adverse impact on the nutritional status that is related to obesity130,131. Despite the favorable impact of weight loss, research shows that the nutritional status of vitamin B12, iron, zinc, copper, and calcium worsens after surgery120. This may be due to resection of the stomach and the resulting decrease in gastric acid secretion59,60. Gastric acid is needed to digest the minerals from food, and solubilize them, so that they are bioavailable for absorption. Moreover, to reduce the risk of stomach ulcers after surgery, patients increase their use of proton pump inhibitors132, and hypogastric acidity impairs the absorption of nutrients133. Bypass of the proximal intestine, which is where the majority of the transporters of minerals are located, also contributes to the reduced absorption of iron105, zinc105, and vitamin D134 that has been observed after surgery. It is not clear whether gut adaptation, over the long term, can rescue the defects in intestinal absorption of micronutrients135138.

Strategies for prevention and treatment

The risk of malnutrition following RYGB reduces its safety profile. Adverse outcomes related to function and quality of life139,140 would be reduced if nutritional support of these patients was improved. Therefore patients, practitioners, and other stakeholders need to know the best practices for the treatment and prevention of nutritional deficiencies114. Studies have demonstrated that sufficient intake of protein and iron, can realistically be obtained from diet especially if it is nutrient dense115,141. Use of dietary supplements is also an effective way to manage status of protein142, calcium, iron141,143, and vitamins D115 and B12144 after gastric bypass. For treatment of deficiencies, although clinical trial are limited, data suggest that high-dose supplementation of iron145, vitamins D142,146 and B12 and protein117 is effective. Taken together, since oral ingestion of food and supplements can be used to prevent and treat malnutrition, this suggests that sufficient capacity of the gut remains for digestion and absorption of micronutrients after surgery. However, it has also been advocated for patients to undergo intravenous administration of nutrients, as a second line of therapy114,147. In summary, more research is needed to determine optimum strategies for treatment and prevention of nutritional deficiencies post gastric bypass surgery. This information will improve nutritional outcomes so that more patients can benefit from this life-saving procedure.

(VI) Effect of Microbiota on Digestion and Absorption: Integrity of the Mucosal Barrier (Bruce M. Wolfe)

The extent to which obesity contributes to the development and severity of obesity-related comorbid conditions such as type 2 diabetes, hypertension, dyslipidemia, and obstructive sleep apnea generally increases with the severity of obesity but is highly variable148. There are both genetic and environmental factors which contribute to obesity-related comorbid disease, including certain alterations of the composition of the microbiome. Efforts to determine causality are the subject of ongoing research.

In addition, weight loss is highly variable among people with obesity following interventions including lifestyle intervention, pharmacotherapy, and bariatric surgery/gastric bypass149. Efforts to explain or predict the extent of this variable weight loss following gastric bypass remain largely unknown. While, the NIH multi-center consortium, Longitudinal Assessment of Bariatric Surgery, identified changes in eating behaviors that contribute modestly to this variation150, further research is necessary into the potential contributions by genomic factors as well as changes of the microbiome induced by gastric bypass to identify appropriate candidates. Though mechanisms indicating a direct relationship between gut microbiota changes and response to gastric bypass remain a major focus of research, we know that the gut microbiota in mammals plays an important role in the digestion, absorption, and extraction of energy from ingested nutrients151. The importance of this energy extraction varies among mammalian species. For example, in cows, as much as 70% of total energy extraction from the diet results from fermentation production of short-chain fatty acids. Germ-free mice require approximately 30% greater energy intake in order to achieve comparable growth to normally colonized mice. The contribution from microbiota digestion of nutrients in humans is estimated to represent approximately 10% of total energy, a figure that potentially varies widely.

The mammalian proximal intestine absorbs simple carbohydrates efficiently, especially glucose. Disaccharides are also absorbed and, to a limited extent, polysaccharides. Otherwise indigestible carbohydrates in the proximal intestine pass distally for digestion and metabolism by luminal microbiota. Fermentation in which polysaccharides are metabolized to short-chain fatty acids is an important pathway. Pyruvate is metabolized to acetyl-CoA and ultimately acetate, butyrate and propionate152. Butyrate and acetate are readily absorbed and contribute to energy supply, particularly for enterocytes. Butyrate has been identified as a modifier of cytokine production by CT cells and to enhance the integrity of the intestinal epithelial barrier. Metabolic signaling is also attributed to absorbed butyrate153. Acetate has a role in enhancing the resolution of intestinal inflammation and protection from intestinal pathogens.

In summary, gut microbiota is responsible for the digestion of otherwise indigestible carbohydrates and, to a lesser extent, protein and lipids. The contribution of these processes to total energy supply will vary as functions of dietary intake, microbiome composition, and other factors involved in digestion of nutrients including bile salts, and pancreatic and other enzymes154. One measure of qualitative detection of the microbiota effect on digestion is the production of both methane and hydrogen. These gases are excreted in the breath and may be detected qualitatively if not quantitatively, reflecting bacterial digestion. Since gut anatomy is altered post bariatric surgery there is data confirming an associated change in the microbiota. Whether such change this is a cause or has a major effect post bariatric surgery needs further investigation.

Low levels of chronic inflammation are variably associated with obesity. This low level inflammation is associated with atherosclerosis, insulin resistance, type 2 diabetes as well as non-alcoholic steatohepatitis152. The activation of inflammatory cells in fat stores involves the action of cytokines, chemokines, and acute phase reactants. Triggers of inflammatory cells include adipocyte apoptosis, saturated free fatty acids, ceramides, glucose, and low levels of endotoxemia (LPS).

LPS-binding protein (LPB) serves as a surrogate marker of underlying low-grade endotoxemia induced by LPS from the gut. The absorption of LPS is attributed to increased permeability of the intestinal barrier induced by alterations of the microbiome among other factors. Levels of LPB, BMI, and obstructive sleep apnea have all been shown to be associated in children155. New data also shows that short term decrease in LPS is additionally dependent on the type of the surgical procedure as well as on the glycemic status of a patient156. In mice, a high fat diet induced changes of the microbiome are associated with endotoxemia, suggesting a relationship between diet-induced changes of the microbiome, intestinal permeability to endotoxins, and related systemic inflammation157. This may provide a link between the association of the gut microbiome and cardio/metabolic health158. As changes in the flow of the food stream post bariatric surgery can alter the microbiota, it seem intuitive to believe that these microscopic organisms may prove formidable players in outcomes post such surgery.

Microbiome-obesity research challenges

It is apparent that many associations of the descriptive findings of the microbiome with metabolic phenomena and related human disease have been established including gastric bypass. Most of these studies use feces, which may or may not be an appropriate representation of the composition of the microbiome throughout the intestinal tract. Additional challenges arise from the incomplete status of bacterial genome databases and the high number of polymorphisms. There are species differences among the animal models. Finally, obesity, as noted above, is a heterogeneous condition. Thus, establishing a cause-and-effect relationship and a basis for therapeutic interventions will require sorting out multiple aspects of the relationship of the microbiome to obesity and related comorbid disease. These investigations generate exceedingly large data files which require rapidly evolving skillsets among computational biologists for analyses.

(VII) Gut Microbial Symbiosis and Key Enterocyte Derived Signals Influencing Health and Disease: Microbial Metabolomics (Blandine Laferrère)

We know that specific composition of the gut microbiome associates with pathological conditions such as cardio vascular disease, inflammatory bowel disease or asthma and with certain phenotypes like obesity and insulin resistance159. However, the mechanism by which the gut microbiome maintains health or contributes to diseases is unknown. Metabolomics is the quantitative analysis by mass-spectrometry or nuclear magnetic resonance spectroscopy of large numbers of low molecular weight metabolites, substrates and products in metabolic pathways, in bio specimens (fluids or tissue)160. Identifying metabolomic signatures and circulating biomarkers associated with the metabolism and functions of gut bacteria is an important step to understand the pathways and mechanisms by which the gut microbiome contributes to the development of diseases. These metabolomic biomarkers could also be used to track response to treatment. Discussed below are four examples of targeted metabolomics to the measure circulating biomarkers of microbiome metabolism: short chain fatty acids (SCFA), bile acids, branched chain amino acids (BCAA) and trimethylamine-N-oxide (TMAO), and how they relate to outcomes post bariatric surgery.

SCFA – fuel and anti-carcinogen

The SCFAs are fatty acids with 2 to 6 carbons, bacterial metabolites produced during the colonic fermentation of indigestible oligosaccharides, dietary plant fibers, non-digested proteins and intestinal mucin, that are at the interface between the diet, the microbiota and the host161. SCFA (and medium chain FA) are primarily absorbed through the portal vein during lipid digestion, while long chain fatty acids go through chylomicrons, the lymphatic canal and the subclavian vein. SCFAs have many positive functions. Butyrate is the major energy source for colonocytes162164. SCFAs stimulate the production of the satiety hormones GLP-1 and PYY via activation of the G-protein-coupled receptor FFAR2165,166, a mechanism by which SCFA may modulate food intake167. Propionate is largely metabolized in the liver, and acetate is the main circulating SCFA168. SCFAs play a role in lipid metabolism and inflammation, improve insulin sensitivity and modulate the risk of cardio vascular disease, in part by activation of a subset of G protein-coupled receptors169,170. The administration of inulin-propionate ester, a dietary fiber, to 60 overweight humans reduced body weight, intra-abdominal adipose tissue, liver fat and improved insulin resistance in a 24-weeks randomized clinical trial. The targeted colonic delivery of inulin-propionate increased circulating PYY and GLP-1 concentrations during a test meal and reduced subsequent food intake171. This in vivo data confirm the in vitro stimulation of PYY and GLP-1 from a colonic cell line by butyrate and propionate166. Colonic infusions of SCFA mixtures, in concentrations and ratios similar to the ones reached after fiber intake, increased fat oxidation, energy expenditure and PYY, and decreased lipolysis in overweight/obese men172. The systemic availability and metabolism of colonic-derived SCFAs in healthy subjects has been demonstrated using stable isotopes. The quantification of SCFA production from 13C-labelled fibers in the human colon can be done by measurement of 13C-labelled SCFA concentrations in blood173,174. In that study, the systemic availability of colonic-administered acetate, propionate and butyrate was 36%, 9% and 2%, respectively. Conversion of acetate into butyrate (24%) is the most prevalent interconversion by the colonic microbiota. Little administered acetate was incorporated into cholesterol (<1%) and less than 15% in fatty acids. On average, 6% of colonic propionate was incorporated into glucose. Most of SCFAs excretion occurred via the lungs after oxidation to 13CO2, and almost no SCFAs (less than 0.05%) were excreted into urine. There is no report to our knowledge of levels of circulating SCFA after bariatric surgery. However, fecal SCFA concentration and microbial composition was shown to be altered after biliopancreatic diversion and related to change in metabolism175.

Bile acids and microbiota – symbiotic relationship

Bile acids are synthesized in the liver from cholesterol under the control of key enzymes, stored in the gall bladder and excreted in the intestine upon ingestion of meals high in fat. Historically, their main function is to facilitate the emulsification of dietary fats and the intestinal absorption of lipids and lipophilic vitamins176. Bile acids undergo further transformation by the gut microbial enzymes, including bile salt hydrolase, through deconjugation and dehydroxylation reactions that generate unconjugated and secondary bile acids177. Apart from regulating secondary bile acid metabolism, gut microbiota also reduce the synthesis of bile acids in the liver, by a mechanism involving the suppression of FXR expression in the ileum178. Therefore, the gut microbiota contributes to the diversity and composition of the bile acid pool176,179. The activity of bile salt hydrolase may be modified in colon cancer and or liver disease. In the gut, bile acids control bacterial overgrowth and microbiome composition180182. We also know that bile acids have carcinogenic potential183,184,185. In addition to their role in lipid digestion and as bacteriostatic agents, bile acids signal a variety of systems in the liver and intestine by interaction with multiple nuclear receptors186 and play a role in glucose and lipid metabolism187,188. Dietary factors such as prebiotics play important roles in the growth of intestinal microbiota and bile acids metabolism. Fecal bile acid profiling, as opposed to circulating bile acids, may be a better non-invasive tool to monitor the intestinal environment189. Many studies have shown an increase of circulating bile acids pool after RYGB15,190,191. However, the increased concentration of circulating bile acids and the change in the composition of conjugated bile acids do not seem to parallel the observed GLP-1 rise after the same surgery as noted in some studies191.

Protein and amino acids

Bacterial fermentation of proteins in distal colon can produce ammonia which can act as tumor promotor. Fermentation of aromatic amino acid tyrosine and tryptophan by colonic bacteria can produce phenols and indoles respectively. Phenols, such as p-cresol, may be pro-carcinogen in colon CA192. Essential amino acids, not synthesized in the body, are provided by the diet and de novo biosynthesis by gut bacteria. The intestinal microbiota is involved in the utilization and catabolism of several amino acids originating from the diet and from endogenous proteins. These amino acids can serve as precursors for the synthesis of bacterial products such as SCFAs. Gut bacteria may contribute to the branched chain amino acid (BCAA) signature associated with insulin resistance. Circulating BCAAs have long been associated with obesity and insulin resistance193,194,195,196,197 and can predict future type 2 diabetes198. Their concentration decreases after interventions that improve insulin sensitivity, such as surgical weight loss by RYGB199. Circulating BCAA concentrations are modulated by their metabolism in adipose tissue200 and, perhaps, also by the microbiome201. The altered gut bacterial composition in individuals with obesity and type 2 diabetes may contribute to their dys-metabolism by influencing amino acids and SCFAs bioavailability to the host. Individuals with insulin resistance who have a serum metabolome characterized by increased levels of BCAAs, have a gut microbiome with an enriched biosynthetic potential for BCAAs and deprived of genes encoding bacterial inward transporters (from blood to gut) for these amino acid. Specific bacterial species driving this association were shown to induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs in mice201.

The importance of the TMA/TMAO microbiome-host axis in health and disease

Dietary phosphatidylcholine (lecithin), the major source of choline, is metabolized by intestinal lipases to form glycerophosphocholine, phosphocholine, and choline202. Choline containing nutrients that reach the cecum and the large bowel serve as fuel for intestinal bacteria, producing trimethylamine (TMA). TMA is oxidized to trimethylamine-N-oxide (TMAO) in the liver. TMAO enhances the accumulation of cholesterol in macrophages, the deposition of foam cells in arterial walls and the formation of atherosclerosis, all factors associated with an increased risk of cardiovascular disease and death203,204. Circulating choline can also be oxidized to betaine, a metabolite involved in methylation reactions and detoxification of homocysteine, in the liver and in the kidneys. In humans, elevated plasma concentrations of TMAO, choline and betaine are associated with an increased risk of a major adverse cardiovascular event, even after adjusting for traditional risk factors. The role of the gut microbiota in TMAO production was demonstrated in vivo. The acute rise of circulating TMAO after an oral phosphatidyl challenge can be suppressed with antibiotics205,206. Paradoxically, circulating TMAO levels are elevated after RYGB, a surgery associated with large weight loss, decreased inflammation and cardiovascular risk207.

(VIII) Microbiome Host Mucosal Interactions: The Role of Epigenetics (Richard Kellermayer)

Epigenetics defines molecular mechanisms that influence pre-translational gene expression independently from the genetic code. Epigenetic processes can respond to environmental changes and have been implicated as important participants in the developmental origins of human diseases208. Secondary to environmental plasticity, the host epigenome in mammals carries the potential to communicate with the commensal microbiota through direct and indirect mechanisms209.

With respect to obesity, epigenetic regulation of body composition210 and physical activity211 through prenatal/early life exposures are intense areas of research. Intermediates of energy metabolism are co-factors in epigenetically mediated chromatin, and secondary gene expression modifications. Therefore, gene regulation underlying phenotypic determinants of adult metabolic health may be influenced by maternal and early postnatal diet212. Maternal (by communicating maternal nutritional influences to the emryo) and individual (own) commensal microbiota are inherent participants in this environment-diet associated developmental programming. In fact, early developmental modulation of gut microbial composition leads to lasting metabolic consequences in mammals213. The clinical relevance of these findings is supported by the association of infantile antibiotic exposure and subsequently increased body mass index in children214.

The ongoing importance of microbiome composition in obesity and related comorbidities is underscored by the beneficial effects of fecal microbiota transplantation (FMT) from lean individuals to obese patients with metabolic syndrome215. This therapeutic intervention is intensely being investigated in ongoing obesity related clinical trials216. Importantly, a recent controlled study on FMT from lean donors into obese individuals showed a transient improvement in insulin sensitivity in those recipients who had lower microbiome diversity at baseline (responders)217.

Recent research is also examining the potentially critical role of the microbiome in regards to bariatric surgery outcomes. Murine model experiments indicate that the microbiome plays a critical role in weight gain following transient loss of obesity218. In accordance with this observation, recent human translational research showed consistent increase in the Roseburia genus in patients with successful resolution of diabetes following both RYGB and SG surgery219. Such microbiome changes associated with fecal metabolite alterations, may be relevant for modulating epigenetic mechanisms. Importantly, Roseburia are butyrate producers220. Butyrate can promote epigenetic remodeling in intestinal stem cells by acting as a histone deacetylase inhibitor221. This example signifies the potential for bariatric surgery induced microbiome modification to alter host physiology, which requires intense exploration in the future.

(IX) Gut Microbiota and Obesity: Changes Post Bariatric Surgery – Clinical Perspective (John K. DiBaise)

A better understanding of the mechanisms underlying the effectiveness of bariatric operations is important in order to optimize patient selection and clinical outcomes of these operations, and may result in the development of less invasive, novel treatments. The gut microbiota is now recognized to contribute to host energy harvest, storage and the development of obesity154,222. The relationship between the intestinal microbiota and obesity/adiposity has generated interest into the potential role of this complex microbial community as a contributing factor to the success or failure of bariatric operations.

RYGB anatomical and physiological changes may contribute to dysbiosis

Following RYGB, a variety of environmental, systemic and anatomical changes occur that might directly or indirectly affect the microbial composition of the gut. Reduced gastric size will affect diet composition and acid exposure to the nutrients. Altered nutrient flow due to accelerated transit through the shortened small intestine may affect oxygen and nutrient exposure to the more distal gut. Altered bile acids and mixing of pancreaticobiliary secretions with nutrients will affect gut microbes. Changes in gut hormone production (e.g., GLP-1, PYY) due to altered nutrient exposure in the distal gut, and vagal nerve disruption may also affect gut microbe composition. Finally, other factors that may affect gut microbial populations post-RYGB64 include the occurrence of postoperative complications (some of which may require altered diet and exposure to antibiotics), altered diet (e.g., food intolerances), pre-existing disordered eating behaviors and, potentially, changes in exercise and mood.

Gut microbe changes after RYGB

To date, only a handful of studies have been reported. A small pilot study, using pyrosequencing on fecal samples from morbidly obese individuals, normal weight subjects and patients who had successful weight loss after RYGB showed that RYGB resulted in increased abundances of Gammaproteobacteria and Verrucomicrobia and decreased Clostridia62. Higher numbers of the H2-producing Prevotella and H2-consuming Archaea in the obese subjects were found, suggesting a syntrophic relationship between certain microbes that improves the efficiency of fermentation and contributes to the development of obesity. In a study of 30 obese individuals and 13 lean controls, fecal samples were collected at baseline in all subjects and 3 months and 6 months after RYGB in the obese individuals223. Real-time quantitative PCR was performed to examine seven bacterial groups. After RYGB, Escherichia coli levels were significantly elevated at both 3 and 6 months compared to baseline and lean controls. Faecalibacterium prausnitzii, a bacteria suggested to have anti-inflammatory activity, also increased in abundance after RYGB but only in those individuals who were diabetic preoperatively. The same research group then performed deep sequencing on the same patients and found an increase in richness and diversity of the microbiota after RYGB with 37% of the increased bacteria belonging to Proteobacteria224. Seven dominant genera identified post-surgery, were independent of reduced calorie intake and were associated with markers of anti-inflammation and insulin sensitivity. Using a non-obese rat model comparing RYGB to a sham control, Li et al. performed pyrosequencing and metabolite profiling of fecal samples63. Similar to the studies in humans, they found a 52-fold increase in Proteobacteria (bloom in Enterobacter hormaechei) with smaller decreases in both Firmicutes and Bacteroidetes. Increased oligosaccharide fermentation (and increased short-chain fatty acids), biogenesis of p-cresol, and amine generation were also detected post-RYGB. The same group demonstrated that this shift in microbial composition post-RYGB correlated with an increased cytotoxic environment highlighting a potential long-term cancer risk after RYGB225. It has been shown that RYGB alters the microbiota along the length of the gut but these changes were most substantial in the Roux limb and common channel suggesting that changes in microbes in the small bowel may regulate the beneficial effects post-surgery226. In another study using a mouse model of RYGB and comparing microbial and metabolite changes among two groups of mice following sham surgery with or without caloric restriction64 increases in Proteobacteria (Escherichia), Verrucomicrobia (Akkermansia) and Bacteroidetes (Alistipes) were found. These changes occurred by 1 week post-op, were consistent regardless of diet, were similar with both luminal and mucosal samples, and were detectable along the length of the gut. Moreover, when the authors transplanted the microbiota from all mouse groups into germ-free mice, RYGB feces recipients significantly decreased in body weight compared to the other groups64 providing for the first time empirical support for the claim that the changes in gut microbes post-RYGB contribute to reduced weight/adiposity.

Gut microbe changes after other bariatric operations

Important insight into the role of the gut microbes in the success or failure of RYGB may be obtained by studying changes in gut microbes occurring after other bariatric operations with less drastic alterations in gut anatomy and physiology. Vertical sleeve gastrectomy results in the resection of about 80% of the greater curvature portion of the stomach and causes a restriction of food intake, acceleration of gastric emptying and alteration of gut hormones affecting satiety and appetite. VSG was noted to produce only modest microbial changes compared to RYGB219 but did lead an increase in the Bacteroidetes/Firmicutes ratio and a decrease in Eubacterium rectale, Ruminococcus obeum, Lachnospiraceae bacterium and F. prausnitzii (in those with impaired glucose tolerance only)227. VSG also led to an increase in malabsorption due to loss of energy-rich fatty acids in the stool, impaired bile acid circulation227 and resulted in greater capacity for metabolism of amino acids219. A human study compared gut microbial changes about 9 years after either RYGB or vertical banded gastroplasty (VBG), a predominantly restrictive operation228. They found significant differences in microbe composition between RYGB and obese patients but not between VBG and obesity or VBG and RYGB228. Furthermore, the two operations resulted in alterations of fecal and circulating metabolites in comparison to obese controls. Finally, they investigated a causal link by performing microbiota transplantation of human stool from the three groups into germ free mice. Mice colonized with RYGB and VBG microbiota accumulated 43% and 26% less body fat, respectively, than mice colonized with obese microbiota. Additionally, RYBG colonized mice had lower respiratory quotient than the other groups suggesting a decreased utilization of carbohydrates and an increased utilization of lipids. Finally, results from a retrospective study comparing RYGB and adjustable gastric banding (AGB), another mostly restrictive operation, to lean and obese control subjects found that RYGB and lean patients had higher microbial diversity and evenness than the other groups229. Bacilli, Gammaproteobacteria, and Prevotellaceae were the microbial signatures discriminating RYGB microbiota from lean and obese controls. Gammaproteobacteria and Bacilli also discriminated RYGB from AGB while Flavobacteriia and Porphyromonadacea discriminated AGB subjects from the non-surgical subjects. RYGB had higher butyrate, propionate and branch chain fatty acids230 (saturated fatty acids which have methyl branches on the carbon chain, usually noted in bacteria) than the other groups, implicating fatty acid signaling, which stimulate appetite regulating peptides, as a mechanism of action of RYGB. The available data, while encouraging, are limited by the small number of subjects, relatively short duration of follow-up, lack of standardization for obesity-related comorbidities and medication use, and different techniques used to probe the microbial communities present.

(X) Understanding the Clinical Implications of Therapeutic Bariatric Interventions (Robert G. Martindale)

The numerous potential interventions in the management of obesity are almost limitless today. Endeavors focused at weight loss and metabolic management of obesity using interventions ranging from behavioral modification, to pharmaceutical agents28, to endoscopic devices like intra-gastric balloons231, absorption barriers and various methods of gastric plication to the bariatric surgical procedures make decisions on the optimal choice of weight loss method difficult. Weight management now requires a very individualized approach232. Of these interventions the bariatric surgical procedures are currently the most durable with 20 year outcome data now available for RYGB and BPD and 10 year outcome data for sleeve gastrectomy233,234. Continued follow-up of these patients and well-designed trials have shown the co-morbidities associated with obesity are dramatically decreased following successful weight loss including type 2 DM, obstructive sleep apnea, hypertension, several cancers and even mortality. Although successful in managing weight loss bariatric surgery is not without significant complications which are often ignored or understated by the “business” of bariatric surgery235.

The previous concept of bariatric surgery being a decision between malabsorption procedure and restrictive procedure is very naive and the metabolic changes associated with bariatric surgery are much more complex than ever anticipated. The future is bright for the study and management of obesity with the recent exponential increase in understanding of the complexity of obesity. With “Big Data”, a better understanding of the >30+ peptides involved in appetite control, the importance of bile salts and the microbiome in metabolic regulation has offered a new focus for the metabolic management of obesity236,237. The potential for therapeutic interventions with bile salts or their receptor antagonist30,39,238 has changed the focus and approach to the bariatric patient. Emerging data also points to a rebalancing of satiety signals post-surgery via resensitization of the gut-brain axis which could be a contributor to the improved outcomes239. Mechanistic pathways mediating such signaling remain a major research focus.

Potential answers and approaches to the global obesity crisis are within reach but this will take a concerted effort on not only with the health care professionals but also the general public. Government incentives and sponsored education to all levels of the public focused to draw attention to the problem of obesity will be needed. The importance of major dietary changes and exercise cannot be understated in any successful approach to weight management.

Final Remarks

The theme of the A.S.P.E.N. 2017 RW was to focus on research evaluating the role of the gut gut-derived signals in modulating outcomes post Bariatric Surgery. Gastric Bypass results in significant loss of fat mass. Additionally there is improvement in glucose/insulin signaling, hepatic steatosis and NAFLD, which by far outweigh the benefits of associated weight loss.

Manipulation of the gastro-intestinal tract as in RYGB results in marked increase in bile acids and its sub-fractions, which in gut epithelial cells activate Farnesoid X Receptor (FXR) followed by stimulation of Fibroblast Growth Factor – 19 (FGF19) signaling to liver, thus in turn regulating bile acid synthesis. Additionally GLP-1 rapidly increases after RYGB with favorable lipid and glycemic effects. Furthermore, hepatic and gut nuclear factors as well as bile acid pathways, (specifically FXR, TGR5 and GLP axis), modulated post bariatric surgery, are also known to influence gut microbiota colonization.

Recent data also highlights the importance of applied microbial metabolomics to understand the role of gut microbiome as a mediator between diet and metabolism. Coupling microbial analysis with targeted and untargeted metabolomics analysis of not only circulating metabolites but also stool and gut tissue analysis, coupled with sophisticated statistical methods applied to multi-omics analysis, will allow us to discover mechanistic links and pathways associating microbial metabolism with health and disease. However, the complexity of microbiome metabolism, with multiple cross-talk between bacteria species, represent a challenge to identify novel treatment targets.

Overall, given the remarkable durability, after bariatric surgery in obesity and its related co-morbidities, lessons learned at this workshop point to the irrefutable role of gut derived signals in modulating the post-operative course after bariatric surgery. Efforts exploring this exciting pathway may even lead to novel non-invasive/non-surgical interventions for the worldwide obesity epidemic.

In summary the 2017 ASPEN Research Workshop focused on the novel idea that gut derived signals modulates gastric bypass outcomes. The workshop brought together clinicians and researchers across the scientific spectrum. Such unique interaction and exchange of knowledge between investigators and clinicians greatly promoted an engaging discussion with a great potential for translation of basic findings into clinical practice. Further, the research workshop engaged in direct outreach to other research communities and greatly helped in collaborations across organizations and disciplines.

Acknowledgments

GRANT FUNDING:

Jain AK received funding from the NIH (grant number R13DK109671) as PI for this research workshop. Jain AK is also supported via NIH (grant number K08DK098623). The workshop was additionally funded by the American Society of Parenteral and Enteral Nutrition.

FINANCIAL SUPPORT FOR MANUSCRIPT PREPARATION: None

MAJOR ABBREVIATIONS

FGF19

Fibroblast Growth Factor 19

FXR

Farnesoid X Receptor

SHP

Small heterodimer partner

RYGB

Roux-en-Y gastric bypass

VSG

Vertical sleeve gastrectomy

AGB

Adjustable gastric banding

NASH

Nonalcoholic Steatohepatitis

NAFLD

Non Alcoholic Fatty Liver Disease

References

  • 1.Arena R, Guazzi M, Lianov L, et al. Healthy Lifestyle Interventions to Combat Noncommunicable Disease-A Novel Nonhierarchical Connectivity Model for Key Stakeholders: A Policy Statement From the American Heart Association, European Society of Cardiology, European Association for Cardiovascular Prevention and Rehabilitation, and American College of Preventive Medicine. Mayo Clinic proceedings. 2015 doi: 10.1016/j.mayocp.2015.05.001. [DOI] [PubMed] [Google Scholar]
  • 2.Foster BA, Farragher J, Parker P, Sosa ET. Treatment Interventions for Early Childhood Obesity: A Systematic Review. Academic pediatrics. 2015;15:353–61. doi: 10.1016/j.acap.2015.04.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Rinella ME. Nonalcoholic fatty liver disease: a systematic review. Jama. 2015;313:2263–73. doi: 10.1001/jama.2015.5370. [DOI] [PubMed] [Google Scholar]
  • 4.Dietz WH, Baur LA, Hall K, et al. Management of obesity: improvement of health-care training and systems for prevention and care. Lancet. 2015;385:2521–33. doi: 10.1016/S0140-6736(14)61748-7. [DOI] [PubMed] [Google Scholar]
  • 5.Kelishadi R, Azizi-Soleiman F. Controlling childhood obesity: A systematic review on strategies and challenges. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2014;19:993–1008. [PMC free article] [PubMed] [Google Scholar]
  • 6.Look ARG, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–54. doi: 10.1056/NEJMoa1212914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Torres JC, Oca CF, Garrison RN. Gastric bypass: Roux-en-Y gastrojejunostomy from the lesser curvature. South Med J. 1983;76:1217–21. [PubMed] [Google Scholar]
  • 8.Sasaki A, Nitta H, Otsuka K, et al. Bariatric surgery and non-alcoholic Fatty liver disease: current and potential future treatments. Frontiers in endocrinology. 2014;5:164. doi: 10.3389/fendo.2014.00164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obesity surgery. 2013;23:427–36. doi: 10.1007/s11695-012-0864-0. [DOI] [PubMed] [Google Scholar]
  • 10.Bariatric Surgical Procedures for Obese and Morbidly Obese Patients: A Review of Comparative Clinical and Cost-Effectiveness, and Guidelines. Ottawa (ON): 2014. [PubMed] [Google Scholar]
  • 11.Kuipers F, Groen AK. FXR: the key to benefits in bariatric surgery? Nature medicine. 2014;20:337–8. doi: 10.1038/nm.3525. [DOI] [PubMed] [Google Scholar]
  • 12.Kohli R, Bradley D, Setchell KD, Eagon JC, Abumrad N, Klein S. Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. The Journal of clinical endocrinology and metabolism. 2013;98:E708–12. doi: 10.1210/jc.2012-3736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacological reviews. 2014;66:948–83. doi: 10.1124/pr.113.008201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Jain AK, Wen JX, Blomenkamp KS, et al. Oleanolic Acid Improves Gut Atrophy Induced by Parenteral Nutrition. JPEN Journal of parenteral and enteral nutrition. 2015 doi: 10.1177/0148607115583536. [DOI] [PubMed] [Google Scholar]
  • 15.Patti ME, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity. 2009;17:1671–7. doi: 10.1038/oby.2009.102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–5. doi: 10.1126/science.284.5418.1362. [DOI] [PubMed] [Google Scholar]
  • 17.Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arteriosclerosis, thrombosis, and vascular biology. 2005;25:2020–30. doi: 10.1161/01.ATV.0000178994.21828.a7. [DOI] [PubMed] [Google Scholar]
  • 18.Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell metabolism. 2005;2:217–25. doi: 10.1016/j.cmet.2005.09.001. [DOI] [PubMed] [Google Scholar]
  • 19.Wang L, Lee YK, Bundman D, et al. Redundant pathways for negative feedback regulation of bile acid production. Developmental cell. 2002;2:721–31. doi: 10.1016/s1534-5807(02)00187-9. [DOI] [PubMed] [Google Scholar]
  • 20.Tomlinson E, Fu L, John L, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143:1741–7. doi: 10.1210/endo.143.5.8850. [DOI] [PubMed] [Google Scholar]
  • 21.Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145:2594–603. doi: 10.1210/en.2003-1671. [DOI] [PubMed] [Google Scholar]
  • 22.Huang X, Yang C, Luo Y, Jin C, Wang F, McKeehan WL. FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet induced fatty liver. Diabetes. 2007;56:2501–10. doi: 10.2337/db07-0648. [DOI] [PubMed] [Google Scholar]
  • 23.Li J, Pircher PC, Schulman IG, Westin SK. Regulation of complement C3 expression by the bile acid receptor FXR. The Journal of biological chemistry. 2005;280:7427–34. doi: 10.1074/jbc.M411473200. [DOI] [PubMed] [Google Scholar]
  • 24.Galman C, Arvidsson I, Angelin B, Rudling M. Monitoring hepatic cholesterol 7alpha-hydroxylase activity by assay of the stable bile acid intermediate 7alpha-hydroxy-4-cholesten-3-one in peripheral blood. Journal of lipid research. 2003;44:859–66. doi: 10.1194/jlr.D200043-JLR200. [DOI] [PubMed] [Google Scholar]
  • 25.Lu TT, Makishima M, Repa JJ, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molecular cell. 2000;6:507–15. doi: 10.1016/s1097-2765(00)00050-2. [DOI] [PubMed] [Google Scholar]
  • 26.Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–8. doi: 10.1126/science.284.5418.1365. [DOI] [PubMed] [Google Scholar]
  • 27.Jansen PL, van Werven J, Aarts E, et al. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Digestive diseases. 2011;29:48–51. doi: 10.1159/000324128. [DOI] [PubMed] [Google Scholar]
  • 28.Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65. doi: 10.1016/S0140-6736(14)61933-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Jain AK, Stoll B, Burrin DG, Holst JJ, Moore DD. Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs. American journal of physiology Gastrointestinal and liver physiology. 2012;302:G218–24. doi: 10.1152/ajpgi.00280.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Kohli R, Kirby M, Setchell KD, et al. Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities. American journal of physiology Gastrointestinal and liver physiology. 2010;299:G652–60. doi: 10.1152/ajpgi.00221.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Manfredini G, Ermini M, Scopsi L, Bonaguidi F, Ferrannini E. Internal biliary diversion improves glucose tolerance in the rat. The American journal of physiology. 1985;249:G519–27. doi: 10.1152/ajpgi.1985.249.4.G519. [DOI] [PubMed] [Google Scholar]
  • 32.Pacheco D, de Luis DA, Romero A, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. American journal of surgery. 2007;194:221–4. doi: 10.1016/j.amjsurg.2006.11.015. [DOI] [PubMed] [Google Scholar]
  • 33.Cole AJ, Teigen LM, Jahansouz C, Earthman CP, Sibley SD. The Influence of Bariatric Surgery on Serum Bile Acids in Humans and Potential Metabolic and Hormonal Implications: a Systematic Review. Curr Obes Rep. 2015;4:441–50. doi: 10.1007/s13679-015-0171-x. [DOI] [PubMed] [Google Scholar]
  • 34.Fouladi F, Mitchell JE, Wonderlich JA, Steffen KJ. The Contributing Role of Bile Acids to Metabolic Improvements After Obesity and Metabolic Surgery. Obesity surgery. 2016;26:2492–502. doi: 10.1007/s11695-016-2272-3. [DOI] [PubMed] [Google Scholar]
  • 35.Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR) Biochemical and biophysical research communications. 2002;298:714–9. doi: 10.1016/s0006-291x(02)02550-0. [DOI] [PubMed] [Google Scholar]
  • 36.Staels B, Handelsman Y, Fonseca V. Bile acid sequestrants for lipid and glucose control. Current diabetes reports. 2010;10:70–7. doi: 10.1007/s11892-009-0087-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–9. doi: 10.1038/nature04330. [DOI] [PubMed] [Google Scholar]
  • 38.Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochemical and biophysical research communications. 2005;329:386–90. doi: 10.1016/j.bbrc.2005.01.139. [DOI] [PubMed] [Google Scholar]
  • 39.Jain AK, Sharma A, Arora S, et al. Preserved Gut Microbial Diversity Accompanies Upregulation of TGR5 and Hepatobiliary Transporters in Bile Acid-Treated Animals Receiving Parenteral Nutrition. JPEN Journal of parenteral and enteral nutrition. 2016 doi: 10.1177/0148607116661838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Osto E, Doytcheva P, Corteville C, et al. Rapid and Body Weight-Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1. Circulation. 2015;131:871–81. doi: 10.1161/CIRCULATIONAHA.114.011791. [DOI] [PubMed] [Google Scholar]
  • 41.Drucker DJ. The role of gut hormones in glucose homeostasis. The Journal of clinical investigation. 2007;117:24–32. doi: 10.1172/JCI30076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Faerch K, Torekov SS, Vistisen D, et al. GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study. Diabetes. 2015;64:2513–25. doi: 10.2337/db14-1751. [DOI] [PubMed] [Google Scholar]
  • 43.Falken Y, Hellstrom PM, Holst JJ, Naslund E. Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. The Journal of clinical endocrinology and metabolism. 2011;96:2227–35. doi: 10.1210/jc.2010-2876. [DOI] [PubMed] [Google Scholar]
  • 44.Peterli R, Steinert RE, Woelnerhanssen B, et al. Metabolic and hormonal changes after laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy: a randomized, prospective trial. Obesity surgery. 2012;22:740–8. doi: 10.1007/s11695-012-0622-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Yousseif A, Emmanuel J, Karra E, et al. Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans. Obesity surgery. 2014;24:241–52. doi: 10.1007/s11695-013-1066-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Evans S, Pamuklar Z, Rosko J, et al. Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction. Surgical endoscopy. 2012;26:1086–94. doi: 10.1007/s00464-011-2004-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Dar MS, Chapman WH, 3rd, Pender JR, et al. GLP-1 response to a mixed meal: what happens 10 years after Roux-en-Y gastric bypass (RYGB)? Obesity surgery. 2012;22:1077–83. doi: 10.1007/s11695-012-0624-1. [DOI] [PubMed] [Google Scholar]
  • 48.Tam CS, Berthoud HR, Bueter M, et al. Could the mechanisms of bariatric surgery hold the key for novel therapies? report from a Pennington Scientific Symposium. Obesity reviews: an official journal of the International Association for the Study of Obesity. 2011;12:984–94. doi: 10.1111/j.1467-789X.2011.00902.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Korner J, Inabnet W, Conwell IM, et al. Differential effects of gastric bypass and banding on circulating gut hormone and leptin levels. Obesity. 2006;14:1553–61. doi: 10.1038/oby.2006.179. [DOI] [PubMed] [Google Scholar]
  • 50.Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clinical microbiology reviews. 2007;20:593–621. doi: 10.1128/CMR.00008-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Xu J, Gordon JI. Honor thy symbionts. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:10452–9. doi: 10.1073/pnas.1734063100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Sonnenburg JL, Angenent LT, Gordon JI. Getting a grip on things: how do communities of bacterial symbionts become established in our intestine? Nature immunology. 2004;5:569–73. doi: 10.1038/ni1079. [DOI] [PubMed] [Google Scholar]
  • 53.Aziz Q, Dore J, Emmanuel A, Guarner F, Quigley EM. Gut microbiota and gastrointestinal health: current concepts and future directions. Neurogastroenterol Motil. 2013;25:4–15. doi: 10.1111/nmo.12046. [DOI] [PubMed] [Google Scholar]
  • 54.Esteve E, Ricart W, Fernandez-Real JM. Gut microbiota interactions with obesity, insulin resistance and type 2 diabetes: did gut microbiote co-evolve with insulin resistance? Current opinion in clinical nutrition and metabolic care. 2011;14:483–90. doi: 10.1097/MCO.0b013e328348c06d. [DOI] [PubMed] [Google Scholar]
  • 55.Hur KY, Lee MS. Gut Microbiota and Metabolic Disorders. Diabetes & metabolism journal. 2015;39:198–203. doi: 10.4093/dmj.2015.39.3.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–4. doi: 10.1038/nature07540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.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;444:1027–31. doi: 10.1038/nature05414. [DOI] [PubMed] [Google Scholar]
  • 58.Brunt EM, Tiniakos DG. Histopathology of nonalcoholic fatty liver disease. World journal of gastroenterology: WJG. 2010;16:5286–96. doi: 10.3748/wjg.v16.i42.5286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Singer C, Stancu P, Cosoveanu S, Botu A. Non-alcoholic Fatty liver disease in children. Current health sciences journal. 2014;40:170–6. doi: 10.12865/CHSJ.40.03.03. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Ferolla SM, Armiliato GN, Couto CA, Ferrari TC. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients. 2014;6:5583–99. doi: 10.3390/nu6125583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Hodin CM, Visschers RG, Rensen SS, et al. Total parenteral nutrition induces a shift in the Firmicutes to Bacteroidetes ratio in association with Paneth cell activation in rats. The Journal of nutrition. 2012;142:2141–7. doi: 10.3945/jn.112.162388. [DOI] [PubMed] [Google Scholar]
  • 62.Zhang H, DiBaise JK, Zuccolo A, et al. Human gut microbiota in obesity and after gastric bypass. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:2365–70. doi: 10.1073/pnas.0812600106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Li JV, Ashrafian H, Bueter M, et al. Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut. 2011;60:1214–23. doi: 10.1136/gut.2010.234708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Liou AP, Paziuk M, Luevano JM, Jr, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Science translational medicine. 2013;5:178ra41. doi: 10.1126/scitranslmed.3005687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Tadross JA, le Roux CW. The mechanisms of weight loss after bariatric surgery. Int J Obes (Lond) 2009;33(Suppl 1):S28–32. doi: 10.1038/ijo.2009.14. [DOI] [PubMed] [Google Scholar]
  • 66.Vincent RP, le Roux CW. The satiety hormone peptide YY as a regulator of appetite. J Clin Pathol. 2008;61:548–52. doi: 10.1136/jcp.2007.048488. [DOI] [PubMed] [Google Scholar]
  • 67.Karamanakos SN, Vagenas K, Kalfarentzos F, Alexandrides TK. Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Annals of surgery. 2008;247:401–7. doi: 10.1097/SLA.0b013e318156f012. [DOI] [PubMed] [Google Scholar]
  • 68.le Roux CW, Aylwin SJ, Batterham RL, et al. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Annals of surgery. 2006;243:108–14. doi: 10.1097/01.sla.0000183349.16877.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418:650–4. doi: 10.1038/nature00887. [DOI] [PubMed] [Google Scholar]
  • 70.Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. Am J Physiol Endocrinol Metab. 2007;292:E1062–8. doi: 10.1152/ajpendo.00450.2006. [DOI] [PubMed] [Google Scholar]
  • 71.Meguid MM, Glade MJ, Middleton FA. Weight regain after Roux-en-Y: a significant 20% complication related to PYY. Nutrition. 2008;24:832–42. doi: 10.1016/j.nut.2008.06.027. [DOI] [PubMed] [Google Scholar]
  • 72.Dirksen C, Jorgensen NB, Bojsen-Moller KN, et al. Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. Int J Obes (Lond) 2013;37:1452–9. doi: 10.1038/ijo.2013.15. [DOI] [PubMed] [Google Scholar]
  • 73.Peterli R, Wolnerhanssen B, Peters T, et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial. Annals of surgery. 2009;250:234–41. doi: 10.1097/SLA.0b013e3181ae32e3. [DOI] [PubMed] [Google Scholar]
  • 74.Larsen PJ, Tang-Christensen M, Holst JJ, Orskov C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience. 1997;77:257–70. doi: 10.1016/s0306-4522(96)00434-4. [DOI] [PubMed] [Google Scholar]
  • 75.Suzuki K, Jayasena CN, Bloom SR. Obesity and appetite control. Exp Diabetes Res. 2012;2012:824305. doi: 10.1155/2012/824305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Russell-Jones D, Gough S. Recent advances in incretin-based therapies. Clin Endocrinol (Oxf) 2012;77:489–99. doi: 10.1111/j.1365-2265.2012.04483.x. [DOI] [PubMed] [Google Scholar]
  • 77.Wilson-Perez HE, Chambers AP, Ryan KK, et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency. Diabetes. 2013;62:2380–5. doi: 10.2337/db12-1498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Dirksen C, Damgaard M, Bojsen-Moller KN, et al. Fast pouch emptying, delayed small intestinal transit, and exaggerated gut hormone responses after Roux-en-Y gastric bypass. Neurogastroenterol Motil. 2013;25:346–e255. doi: 10.1111/nmo.12087. [DOI] [PubMed] [Google Scholar]
  • 79.Shah S, Shah P, Todkar J, Gagner M, Sonar S, Solav S. Prospective controlled study of effect of laparoscopic sleeve gastrectomy on small bowel transit time and gastric emptying half-time in morbidly obese patients with type 2 diabetes mellitus. Surg Obes Relat Dis. 2010;6:152–7. doi: 10.1016/j.soard.2009.11.019. [DOI] [PubMed] [Google Scholar]
  • 80.Schirra J, Katschinski M, Weidmann C, et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. The Journal of clinical investigation. 1996;97:92–103. doi: 10.1172/JCI118411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Jacobsen SH, Olesen SC, Dirksen C, et al. Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obesity surgery. 2012;22:1084–96. doi: 10.1007/s11695-012-0621-4. [DOI] [PubMed] [Google Scholar]
  • 82.Obert J, Pearlman M, Obert L, Chapin S. Popular Weight Loss Strategies: a Review of Four Weight Loss Techniques. Current gastroenterology reports. 2017;19:61. doi: 10.1007/s11894-017-0603-8. [DOI] [PubMed] [Google Scholar]
  • 83.Marengo A, Rosso C, Bugianesi E. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. Annu Rev Med. 2016;67:103–17. doi: 10.1146/annurev-med-090514-013832. [DOI] [PubMed] [Google Scholar]
  • 84.Zoller H, Tilg H. Nonalcoholic fatty liver disease and hepatocellular carcinoma. Metabolism. 2016;65:1151–60. doi: 10.1016/j.metabol.2016.01.010. [DOI] [PubMed] [Google Scholar]
  • 85.Golzarand M, Toolabi K, Farid R. The bariatric surgery and weight losing: a meta-analysis in the long- and very long-term effects of laparoscopic adjustable gastric banding, laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy on weight loss in adults. Surgical endoscopy. 2017;31:4331–45. doi: 10.1007/s00464-017-5505-1. [DOI] [PubMed] [Google Scholar]
  • 86.Albaugh VL, Banan B, Ajouz H, Abumrad NN, Flynn CR. Bile acids and bariatric surgery. Mol Aspects Med. 2017;56:75–89. doi: 10.1016/j.mam.2017.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Noel OF, Still CD, Argyropoulos G, Edwards M, Gerhard GS. Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery. J Obes. 2016;2016:4390254. doi: 10.1155/2016/4390254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Kohli R, Myronovych A, Tan BK, et al. Bile Acid Signaling: Mechanism for Bariatric Surgery, Cure for NASH? Digestive diseases. 2015;33:440–6. doi: 10.1159/000371699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Lutz TA, Bueter M. The Use of Rat and Mouse Models in Bariatric Surgery Experiments. Front Nutr. 2016;3:25. doi: 10.3389/fnut.2016.00025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Tomkin GH, Owens D. Obesity diabetes and the role of bile acids in metabolism. J Transl Int Med. 2016;4:73–80. doi: 10.1515/jtim-2016-0018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Kaska L, Sledzinski T, Chomiczewska A, Dettlaff-Pokora A, Swierczynski J. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World journal of gastroenterology: WJG. 2016;22:8698–719. doi: 10.3748/wjg.v22.i39.8698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Stefater MA, Wilson-Perez HE, Chambers AP, Sandoval DA, Seeley RJ. All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr Rev. 2012;33:595–622. doi: 10.1210/er.2011-1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Opozda M, Chur-Hansen A, Wittert G. Changes in problematic and disordered eating after gastric bypass, adjustable gastric banding and vertical sleeve gastrectomy: a systematic review of pre-post studies. Obesity reviews: an official journal of the International Association for the Study of Obesity. 2016;17:770–92. doi: 10.1111/obr.12425. [DOI] [PubMed] [Google Scholar]
  • 94.Ryan KK, Tremaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509:183–8. doi: 10.1038/nature13135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Schwenger KJP, Fischer SE, Jackson TD, Okrainec A, Allard JP. Non-alcoholic Fatty Liver Disease in Morbidly Obese Individuals Undergoing Bariatric Surgery: Prevalence and Effect of the Pre-Bariatric Very Low Calorie Diet. Obesity surgery. 2017 doi: 10.1007/s11695-017-2980-3. [DOI] [PubMed] [Google Scholar]
  • 96.Saeidi N, Meoli L, Nestoridi E, et al. Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science. 2013;341:406–10. doi: 10.1126/science.1235103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Pal A, Rhoads DB, Tavakkoli A. Foregut exclusion disrupts intestinal glucose sensing and alters portal nutrient and hormonal milieu. Diabetes. 2015;64:1941–50. doi: 10.2337/db14-1578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Stearns AT, Balakrishnan A, Tavakkolizadeh A. Impact of Roux-en-Y gastric bypass surgery on rat intestinal glucose transport. American journal of physiology Gastrointestinal and liver physiology. 2009;297:G950–7. doi: 10.1152/ajpgi.00253.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Pal A, Rhoads DB, Tavakkoli A. Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats. PloS one. 2016;11:e0165592. doi: 10.1371/journal.pone.0165592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Mahawar KK, Sharples AJ. Contribution of Malabsorption to Weight Loss After Roux-en-Y Gastric Bypass: a Systematic Review. Obes Surg. 2017;27:2194–206. doi: 10.1007/s11695-017-2762-y. [DOI] [PubMed] [Google Scholar]
  • 101.Miller GD, Norris A, Fernandez A. Changes in nutrients and food groups intake following laparoscopic Roux-en-Y gastric bypass (RYGB) Obes Surg. 2014;24:1926–32. doi: 10.1007/s11695-014-1259-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Boerlage TC, van de Laar AW, Westerlaken S, Gerdes VE, Brandjes DP. Gastrointestinal symptoms and food intolerance 2 years after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Br J Surg. 2017;104:393–400. doi: 10.1002/bjs.10419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Behrns KE, Smith CD, Sarr MG. Prospective evaluation of gastric acid secretion and cobalamin absorption following gastric bypass for clinically severe obesity. Dig Dis Sci. 1994;39:315–20. doi: 10.1007/BF02090203. [DOI] [PubMed] [Google Scholar]
  • 104.Smith CD, Herkes SB, Behrns KE, Fairbanks VF, Kelly KA, Sarr MG. Gastric acid secretion and vitamin B12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity. Ann Surg. 1993;218:91–6. doi: 10.1097/00000658-199307000-00014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Ruz M, Carrasco F, Rojas P, et al. Iron absorption and iron status are reduced after Roux-en-Y gastric bypass. American Journal of Nutrition. 2009;90:527–32. doi: 10.3945/ajcn.2009.27699. [DOI] [PubMed] [Google Scholar]
  • 106.Rubin DC, Levin MS. Mechanisms of intestinal adaptation. Best Pract Res Clin Gastroenterol. 2016;30:237–48. doi: 10.1016/j.bpg.2016.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Cavin JB, Bado A, Le Gall M. Intestinal Adaptations after Bariatric Surgery: Consequences on Glucose Homeostasis. Trends Endocrinol Metab. 2017;28:354–64. doi: 10.1016/j.tem.2017.01.002. [DOI] [PubMed] [Google Scholar]
  • 108.Cavin JB, Voitellier E, Cluzeaud F, et al. Malabsorption and intestinal adaptation after one anastomosis gastric bypass compared with Roux-en-Y gastric bypass in rats. Am J Physiol Gastrointest Liver Physiol. 2016;311:G492–500. doi: 10.1152/ajpgi.00197.2016. [DOI] [PubMed] [Google Scholar]
  • 109.Cavin JB, Couvelard A, Lebtahi R, et al. Differences in Alimentary Glucose Absorption and Intestinal Disposal of Blood Glucose After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy. Gastroenterology. 2016;150:454–64.e9. doi: 10.1053/j.gastro.2015.10.009. [DOI] [PubMed] [Google Scholar]
  • 110.Carswell KA, Vincent RP, Belgaumkar AP, et al. The effect of bariatric surgery on intestinal absorption and transit time. Obes Surg. 2014;24:796–805. doi: 10.1007/s11695-013-1166-x. [DOI] [PubMed] [Google Scholar]
  • 111.Odstrcil EA, Martinez JG, Santa Ana CA, et al. The contribution of malabsorption to the reduction in net energy absorption after long-limb Roux-en-Y gastric bypass. Am J Clin Nutr. 2010;92:704–13. doi: 10.3945/ajcn.2010.29870. [DOI] [PubMed] [Google Scholar]
  • 112.Bojsen-Moller KN, Jacobsen SH, Dirksen C, et al. Accelerated protein digestion and amino acid absorption after Roux-en-Y gastric bypass. Am J Clin Nutr. 2015;102:600–7. doi: 10.3945/ajcn.115.109298. [DOI] [PubMed] [Google Scholar]
  • 113.Forbes R, Gasevic D, Watson EM, et al. Essential Fatty Acid Plasma Profiles Following Gastric Bypass and Adjusted Gastric Banding Bariatric Surgeries. Obes Surg. 2015 Sep 04; doi: 10.1007/s11695-015-1876-3. ed2015. [DOI] [PubMed] [Google Scholar]
  • 114.Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient-2013 update: Cosponsored by american association of clinical endocrinologists, The obesity society, and american society for metabolic & bariatric surgery*. Obesity (Silver Spring) 2013;21(Suppl 1):S1–S27. doi: 10.1002/oby.20461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Moize V, Andreu A, Flores L, et al. Long-term dietary intake and nutritional deficiencies following sleeve gastrectomy or Roux-En-Y gastric bypass in a mediterranean population. J Acad Nutr Diet. 2013;113:400–10. doi: 10.1016/j.jand.2012.11.013. [DOI] [PubMed] [Google Scholar]
  • 116.Ito MK, Goncalves VSS, Faria S, et al. Effect of Protein Intake on the Protein Status and Lean Mass of Post-Bariatric Surgery Patients: a Systematic Review. Obes Surg. 2017;27:502–12. doi: 10.1007/s11695-016-2453-0. [DOI] [PubMed] [Google Scholar]
  • 117.Schollenberger AE, Karschin J, Meile T, Kuper MA, Konigsrainer A, Bischoff SC. Impact of protein supplementation after bariatric surgery: A randomized controlled double-blind pilot study. Nutrition. 2016;32:186–92. doi: 10.1016/j.nut.2015.08.005. [DOI] [PubMed] [Google Scholar]
  • 118.Cardeal Mde A, Faria SL, Faria OP, Facundes M, Ito MK. Diet-induced thermogenesis in postoperatve Roux-en-Y gastric bypass patients with weight regain. Surg Obes Relat Dis. 2016;12:1098–107. doi: 10.1016/j.soard.2016.01.019. [DOI] [PubMed] [Google Scholar]
  • 119.Cole AJ, Kuchnia AJ, Beckman LM, et al. Long-Term Body Composition Changes in Women Following Roux-en-Y Gastric Bypass Surgery. JPEN J Parenter Enteral Nutr. 2017;41:583–91. doi: 10.1177/0148607115625621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120.Gletsu-Miller N, Wright BN. Mineral malnutrition following bariatric surgery. Adv Nutr. 2013;4:506–17. doi: 10.3945/an.113.004341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Nakamura KM, Haglind EG, Clowes JA, et al. Fracture risk following bariatric surgery: a population-based study. Osteoporos Int. 2014;25:151–8. doi: 10.1007/s00198-013-2463-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Eckert MJ, Perry JT, Sohn VY, et al. Incidence of low vitamin A levels and ocular symptoms after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2010;6:653–7. doi: 10.1016/j.soard.2010.02.044. [DOI] [PubMed] [Google Scholar]
  • 123.Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF. Acquired copper deficiency: a potential serious and preventable complication following gastric bypass surgery. Obesity (Silver Spring) 2009;17:827–31. doi: 10.1038/oby.2008.614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124.Toh SY, Zarshenas N, Jorgensen J. Prevalence of nutrient deficiencies in bariatric patients. Nutrition. 2009;25:1150–6. doi: 10.1016/j.nut.2009.03.012. [DOI] [PubMed] [Google Scholar]
  • 125.Weng TC, Chang CH, Dong YH, Chang YC, Chuang LM. Anaemia and related nutrient deficiencies after Roux-en-Y gastric bypass surgery: a systematic review and meta-analysis. BMJ Open. 2015;5:e006964. doi: 10.1136/bmjopen-2014-006964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Lin E, Armstrong-Moore D, Liang Z, et al. Contribution of adipose tissue to plasma 25-hydroxyvitamin d concentrations during weight loss following gastric bypass surgery. Obesity (Silver Spring) 2011;19:588–94. doi: 10.1038/oby.2010.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127.Wright BN, Gletsu-Miller N. Iron nutrition following bariatric surgery. Bariatric Surgical Practice and Patient Care. 2015;10:3–11. [Google Scholar]
  • 128.Tussing-Humphreys LM, Nemeth E, Fantuzzi G, et al. Elevated systemic hepcidin and iron depletion in obese premenopausal females. Obesity (Silver Spring) 2010;18:1449–56. doi: 10.1038/oby.2009.319. [DOI] [PubMed] [Google Scholar]
  • 129.Pramyothin P, Biancuzzo RM, Lu Z, Hess DT, Apovian CM, Holick MF. Vitamin D in adipose tissue and serum 25-hydroxyvitamin D after roux-en-y gastric bypass. Obesity. 2011;19:2228–34. doi: 10.1038/oby.2011.170. [DOI] [PubMed] [Google Scholar]
  • 130.Tussing-Humphreys LM, Nemeth E, Fantuzzi G, et al. Decreased serum hepcidin and improved functional iron status 6 months after restrictive bariatric surgery. Obesity (Silver Spring) 2010;18:2010–6. doi: 10.1038/oby.2009.490. [DOI] [PubMed] [Google Scholar]
  • 131.Anty R, Dahman M, Iannelli A, et al. Bariatric surgery can correct iron depletion in morbidly obese women: a link with chronic inflammation. Obes Surg. 2008;18:709–14. doi: 10.1007/s11695-007-9276-y. [DOI] [PubMed] [Google Scholar]
  • 132.Collares-Pelizaro RVA, Santos JS, Nonino CB, Gaitani CM, Salgado W., Jr Omeprazole Absorption and Fasting Gastrinemia After Roux-en-Y Gastric Bypass. Obes Surg. 2017;27:2303–7. doi: 10.1007/s11695-017-2672-z. [DOI] [PubMed] [Google Scholar]
  • 133.Lam JR, Schneider JL, Quesenberry CP, Corley DA. Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency. Gastroenterology. 2017;152:821–9.e1. doi: 10.1053/j.gastro.2016.11.023. [DOI] [PubMed] [Google Scholar]
  • 134.Schafer AL, Weaver CM, Black DM, et al. Intestinal Calcium Absorption Decreases Dramatically After Gastric Bypass Surgery Despite Optimization of Vitamin D Status. J Bone Miner Res. 2015;30:1377–85. doi: 10.1002/jbmr.2467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135.Vargas-Ruiz AG, Hernandez-Rivera G, Herrera MF. Prevalence of iron, folate, and vitamin B12 deficiency anemia after laparoscopic Roux-en-Y gastric bypass. Obes Surg. 2008;18:288–93. doi: 10.1007/s11695-007-9310-0. [DOI] [PubMed] [Google Scholar]
  • 136.Alexandrou A, Armeni E, Kouskouni E, Tsoka E, Diamantis T, Lambrinoudaki I. Cross-sectional long-term micronutrient deficiencies after sleeve gastrectomy versus Roux-en-Y gastric bypass: a pilot study. Surg Obes Relat Dis. 2014;10:262–8. doi: 10.1016/j.soard.2013.07.014. [DOI] [PubMed] [Google Scholar]
  • 137.Ledoux S, Calabrese D, Bogard C, et al. Long-term evolution of nutritional deficiencies after gastric bypass: an assessment according to compliance to medical care. Ann Surg. 2014;259:1104–10. doi: 10.1097/SLA.0000000000000249. [DOI] [PubMed] [Google Scholar]
  • 138.Gesquiere I, Lannoo M, Augustijns P, Matthys C, Van der Schueren B, Foulon V. Iron deficiency after Roux-en-Y gastric bypass: insufficient iron absorption from oral iron supplements. Obes Surg. 2014;24:56–61. doi: 10.1007/s11695-013-1042-8. [DOI] [PubMed] [Google Scholar]
  • 139.Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric Surgery versus Intensive Medical Therapy for Diabetes – 5-Year Outcomes. N Engl J Med. 2017;376:641–51. doi: 10.1056/NEJMoa1600869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 140.King WC, Chen JY, Belle SH, et al. Use of prescribed opioids before and after bariatric surgery: prospective evidence from a U.S. multicenter cohort study. Surg Obes Relat Dis. 2017 doi: 10.1016/j.soard.2017.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141.Mischler RA, Armah SM, Wright BN, Mattar SG, Rosen AD, Gletsu-Miller N. Influence of diet and supplements on iron status after gastric bypass surgery. Surg Obes Relat Dis. 2016;12:651–8. doi: 10.1016/j.soard.2015.09.007. [DOI] [PubMed] [Google Scholar]
  • 142.Muschitz C, Kocijan R, Haschka J, et al. The Impact of Vitamin D, Calcium, Protein Supplementation, and Physical Exercise on Bone Metabolism After Bariatric Surgery: The BABS Study. J Bone Miner Res. 2016;31:672–82. doi: 10.1002/jbmr.2707. [DOI] [PubMed] [Google Scholar]
  • 143.Brolin RE, Gorman JH, Gorman RC, et al. Prophylactic iron supplementation after Roux-en-Y gastric bypass: a prospective, double-blind, randomized study. Arch Surg. 1998;133:740–4. doi: 10.1001/archsurg.133.7.740. [DOI] [PubMed] [Google Scholar]
  • 144.Boyce SG, Goriparthi R, Clark J, Cameron K, Roslin MS. Can Composite Nutritional Supplement Based on the Current Guidelines Prevent Vitamin and Mineral Deficiency After Weight Loss Surgery? Obes Surg. 2016;26:966–71. doi: 10.1007/s11695-015-1853-x. [DOI] [PubMed] [Google Scholar]
  • 145.Mischler RA, Armah SM, Craig BA, et al. Comparison of oral iron supplement formulations for normalization of iron status following roux-en-y gastric bypass surgery: a randomized trial. Obes Surg. 2017 doi: 10.1007/s11695-017-2858-4. [DOI] [PubMed] [Google Scholar]
  • 146.Luger M, Kruschitz R, Kienbacher C, et al. Vitamin D3 Loading Is Superior to Conventional Supplementation After Weight Loss Surgery in Vitamin D-Deficient Morbidly Obese Patients: a Double-Blind Randomized Placebo-Controlled Trial. Obes Surg. 2017;27:1196–207. doi: 10.1007/s11695-016-2437-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 147.Varma S, Baz W, Badine E, et al. Need for parenteral iron therapy after bariatric surgery. Surg Obes Relat Dis. 2008;4:715–9. doi: 10.1016/j.soard.2008.04.015. [DOI] [PubMed] [Google Scholar]
  • 148.Al-Goblan AS, Al-Alfi MA, Khan MZ. Mechanism linking diabetes mellitus and obesity. Diabetes Metab Syndr Obes. 2014;7:587–91. doi: 10.2147/DMSO.S67400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 149.Courcoulas AP, Christian NJ, O’Rourke RW, et al. Preoperative factors and 3-year weight change in the Longitudinal Assessment of Bariatric Surgery (LABS) consortium. Surg Obes Relat Dis. 2015;11:1109–18. doi: 10.1016/j.soard.2015.01.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 150.Mitchell JE, Christian NJ, Flum DR, et al. Postoperative Behavioral Variables and Weight Change 3 Years After Bariatric Surgery. JAMA Surg. 2016;151:752–7. doi: 10.1001/jamasurg.2016.0395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 151.Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr. 2002;22:283–307. doi: 10.1146/annurev.nutr.22.011602.092259. [DOI] [PubMed] [Google Scholar]
  • 152.Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474:327–36. doi: 10.1038/nature10213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 153.Duca FA, Sakar Y, Lepage P, et al. Replication of obesity and associated signaling pathways through transfer of microbiota from obese-prone rats. Diabetes. 2014;63:1624–36. doi: 10.2337/db13-1526. [DOI] [PubMed] [Google Scholar]
  • 154.Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK. Effects of gut microbes on nutrient absorption and energy regulation. Nutrition in clinical practice: official publication of the American Society for Parenteral and Enteral Nutrition. 2012;27:201–14. doi: 10.1177/0884533611436116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 155.Kheirandish-Gozal L, Peris E, Wang Y, et al. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. The Journal of clinical endocrinology and metabolism. 2014;99:656–63. doi: 10.1210/jc.2013-3327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 156.Clemente-Postigo M, Roca-Rodriguez Mdel M, Camargo A, Ocana-Wilhelmi L, Cardona F, Tinahones FJ. Lipopolysaccharide and lipopolysaccharide-binding protein levels and their relationship to early metabolic improvement after bariatric surgery. Surg Obes Relat Dis. 2015;11:933–9. doi: 10.1016/j.soard.2014.11.030. [DOI] [PubMed] [Google Scholar]
  • 157.Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72. doi: 10.2337/db06-1491. [DOI] [PubMed] [Google Scholar]
  • 158.Hansen TH, Gobel RJ, Hansen T, Pedersen O. The gut microbiome in cardio-metabolic health. Genome Med. 2015;7:33. doi: 10.1186/s13073-015-0157-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 159.Cox LM, Blaser MJ. PATHWAYS IN MICROBE-INDUCED OBESITY. Cell metabolism. 2013;17:883–94. doi: 10.1016/j.cmet.2013.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 160.Issaq HJ, Van QN, Waybright TJ, Muschik GM, Veenstra TD. Analytical and statistical approaches to metabolomics research. J Sep Sci. 2009;32:2183–99. doi: 10.1002/jssc.200900152. [DOI] [PubMed] [Google Scholar]
  • 161.Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environmental microbiology. 2017;19:29–41. doi: 10.1111/1462-2920.13589. [DOI] [PubMed] [Google Scholar]
  • 162.Roediger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 1980;21:793–8. doi: 10.1136/gut.21.9.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 163.Thangaraju M, Cresci GA, Liu K, et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer research. 2009;69:2826–32. doi: 10.1158/0008-5472.CAN-08-4466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 164.Thibault R, Blachier F, Darcy-Vrillon B, de Coppet P, Bourreille A, Segain JP. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis. 2010;16:684–95. doi: 10.1002/ibd.21108. [DOI] [PubMed] [Google Scholar]
  • 165.Tolhurst G, Heffron H, Lam YS, et al. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein–Coupled Receptor FFAR2. Diabetes. 2012;61:364–71. doi: 10.2337/db11-1019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 166.Psichas A, Sleeth ML, Murphy KG, et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. International journal of obesity (2005) 2015;39:424–9. doi: 10.1038/ijo.2014.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Yadav H, Lee J-H, Lloyd J, Walter P, Rane SG. Beneficial Metabolic Effects of a Probiotic via Butyrate-induced GLP-1 Hormone Secretion. The Journal of Biological Chemistry. 2013;288:25088–97. doi: 10.1074/jbc.M113.452516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 168.Cummings JH. Short chain fatty acids in the human colon. Gut. 1981;22:763–79. doi: 10.1136/gut.22.9.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 169.Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nature communications. 2013;4:1829. doi: 10.1038/ncomms2852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 170.De Vadder F, Kovatcheva-Datchary P, Goncalves D, et al. Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits. Cell. 2014;156:84–96. doi: 10.1016/j.cell.2013.12.016. [DOI] [PubMed] [Google Scholar]
  • 171.Chambers ES, Viardot A, Psichas A, et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015;64:1744–54. doi: 10.1136/gutjnl-2014-307913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 172.Canfora EE, van der Beek CM, Jocken JWE, et al. Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial. Scientific Reports. 2017;7:2360. doi: 10.1038/s41598-017-02546-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 173.Boets E, Gomand SV, Deroover L, et al. Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. The Journal of Physiology. 2017;595:541–55. doi: 10.1113/JP272613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 174.den Besten G, Lange K, Havinga R, et al. Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids. American journal of physiology Gastrointestinal and liver physiology. 2013;305:G900–10. doi: 10.1152/ajpgi.00265.2013. [DOI] [PubMed] [Google Scholar]
  • 175.Patrone V, Vajana E, Minuti A, et al. Postoperative Changes in Fecal Bacterial Communities and Fermentation Products in Obese Patients Undergoing Bilio-Intestinal Bypass. Frontiers in Microbiology. 2016;7 doi: 10.3389/fmicb.2016.00200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 176.Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS microbiology reviews. 2005;29:625–51. doi: 10.1016/j.femsre.2004.09.003. [DOI] [PubMed] [Google Scholar]
  • 177.Ridlon JM, Kang D-J, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. Journal of lipid research. 2006;47:241–59. doi: 10.1194/jlr.R500013-JLR200. [DOI] [PubMed] [Google Scholar]
  • 178.Sayin SI, Wahlstrom A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225–35. doi: 10.1016/j.cmet.2013.01.003. [DOI] [PubMed] [Google Scholar]
  • 179.Swann JR, Want EJ, Geier FM, et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proceedings of the National Academy of Sciences. 2011;108:4523–30. doi: 10.1073/pnas.1006734107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 180.Hofmann AF, Eckmann L. How bile acids confer gut mucosal protection against bacteria. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:4333–4. doi: 10.1073/pnas.0600780103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 181.Islam KB, Fukiya S, Hagio M, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141:1773–81. doi: 10.1053/j.gastro.2011.07.046. [DOI] [PubMed] [Google Scholar]
  • 182.Bindels LB, Porporato P, Dewulf EM, et al. Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br J Cancer. 2012;107:1337–44. doi: 10.1038/bjc.2012.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 183.Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as carcinogens in human gastrointestinal cancers. Mutation research. 2005;589:47–65. doi: 10.1016/j.mrrev.2004.08.001. [DOI] [PubMed] [Google Scholar]
  • 184.Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101. doi: 10.1038/nature12347. [DOI] [PubMed] [Google Scholar]
  • 185.Reddy BS, Mastromarino A, Wynder EL. Further leads on metabolic epidemiology of large bowel cancer. Cancer Res. 1975;35:3403–6. [PubMed] [Google Scholar]
  • 186.Porez G, Prawitt J, Gross B, Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. Journal of lipid research. 2012;53:1723–37. doi: 10.1194/jlr.R024794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 187.Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiological reviews. 2009;89:147–91. doi: 10.1152/physrev.00010.2008. [DOI] [PubMed] [Google Scholar]
  • 188.Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nature reviews Drug discovery. 2008;7:678–93. doi: 10.1038/nrd2619. [DOI] [PubMed] [Google Scholar]
  • 189.Kuo S-M, Merhige PM, Hagey LR. The Effect of Dietary Prebiotics and Probiotics on Body Weight, Large Intestine Indices, and Fecal Bile Acid Profile in Wild Type and IL10−/− Mice. PloS one. 2013;8:e60270. doi: 10.1371/journal.pone.0060270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 190.Pournaras DJ, Glicksman C, Vincent RP, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology. 2012;153:3613–9. doi: 10.1210/en.2011-2145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 191.Dutia R, Embrey M, O’Brien S, et al. Temporal changes in bile acid levels and 12alpha-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes. International journal of obesity (2005) 2015;39:806–13. doi: 10.1038/ijo.2015.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 192.Bone E, Tamm A, Hill M. The production of urinary phenols by gut bacteria and their possible role in the causation of large bowel cancer. The American journal of clinical nutrition. 1976;29:1448–54. doi: 10.1093/ajcn/29.12.1448. [DOI] [PubMed] [Google Scholar]
  • 193.Felig P, Marliss E, Cahill GF., Jr Plasma amino acid levels and insulin secretion in obesity. N Engl J Med. 1969;281:811–6. doi: 10.1056/NEJM196910092811503. [DOI] [PubMed] [Google Scholar]
  • 194.Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism: clinical and experimental. 1988;37:287–301. doi: 10.1016/0026-0495(88)90110-2. [DOI] [PubMed] [Google Scholar]
  • 195.Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell metabolism. 2009;9:311–26. doi: 10.1016/j.cmet.2009.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 196.Huffman KM, Shah SH, Stevens RD, et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes care. 2009;32:1678–83. doi: 10.2337/dc08-2075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 197.Tai ES, Tan ML, Stevens RD, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia. 2010;53:757–67. doi: 10.1007/s00125-009-1637-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 198.Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes. Nature medicine. 2011;17:448–53. doi: 10.1038/nm.2307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 199.Laferrere B, Reilly D, Arias S, et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Science translational medicine. 2011;3:80r.e2. doi: 10.1126/scitranslmed.3002043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 200.Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem. 2010;285:11348–56. doi: 10.1074/jbc.M109.075184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 201.Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016;535:376–81. doi: 10.1038/nature18646. [DOI] [PubMed] [Google Scholar]
  • 202.Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio. 2015;6:e02481. doi: 10.1128/mBio.02481-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 203.Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature medicine. 2013;19:576–85. doi: 10.1038/nm.3145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 204.Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Vol. 2016. Toxins; Basel: p. 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 205.Tang WHW, Wang Z, Levison BS, et al. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. New England Journal of Medicine. 2013;368:1575–84. doi: 10.1056/NEJMoa1109400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 206.Wang Z, Tang WH, Buffa JA, et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. European heart journal. 2014;35:904–10. doi: 10.1093/eurheartj/ehu002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 207.Trøseid M, Hov JR, Nestvold TK, et al. Major Increase in Microbiota-Dependent Proatherogenic Metabolite TMAO One Year After Bariatric Surgery. Metabolic Syndrome and Related Disorders. 2016;14:197–201. doi: 10.1089/met.2015.0120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 208.Kellermayer R. Epigenetics and the developmental origins of inflammatory bowel diseases. Can J Gastroenterol. 2012;26:909–15. doi: 10.1155/2012/526408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 209.Fofanova TY, Petrosino JF, Kellermayer R. Microbiome-Epigenome Interactions and the Environmental Origins of Inflammatory Bowel Diseases. J Pediatr Gastroenterol Nutr. 2016;62:208–19. doi: 10.1097/MPG.0000000000000950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 210.Kuhnen P, Handke D, Waterland RA, et al. Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity. Cell Metab. 2016;24:502–9. doi: 10.1016/j.cmet.2016.08.001. [DOI] [PubMed] [Google Scholar]
  • 211.Eclarinal JD, Zhu S, Baker MS, et al. Maternal exercise during pregnancy promotes physical activity in adult offspring. FASEB J. 2016;30:2541–8. doi: 10.1096/fj.201500018R. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 212.Keating ST, El-Osta A. Epigenetics and metabolism. Circ Res. 2015;116:715–36. doi: 10.1161/CIRCRESAHA.116.303936. [DOI] [PubMed] [Google Scholar]
  • 213.Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158:705–21. doi: 10.1016/j.cell.2014.05.052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 214.Saari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics. 2015;135:617–26. doi: 10.1542/peds.2014-3407. [DOI] [PubMed] [Google Scholar]
  • 215.Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143:913–6.e7. doi: 10.1053/j.gastro.2012.06.031. [DOI] [PubMed] [Google Scholar]
  • 216.Marotz CA, Zarrinpar A. Treating Obesity and Metabolic Syndrome with Fecal Microbiota Transplantation. Yale J Biol Med. 2016;89:383–8. [PMC free article] [PubMed] [Google Scholar]
  • 217.Kootte RS, Levin E, Salojarvi J, et al. Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. Cell metabolism. 2017;26:611–9.e6. doi: 10.1016/j.cmet.2017.09.008. [DOI] [PubMed] [Google Scholar]
  • 218.Thaiss CA, Itav S, Rothschild D, et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature. 2016 doi: 10.1038/nature20796. [DOI] [PubMed] [Google Scholar]
  • 219.Murphy R, Tsai P, Jullig M, Liu A, Plank L, Booth M. Differential Changes in Gut Microbiota After Gastric Bypass and Sleeve Gastrectomy Bariatric Surgery Vary According to Diabetes Remission. Obesity surgery. 2017;27:917–25. doi: 10.1007/s11695-016-2399-2. [DOI] [PubMed] [Google Scholar]
  • 220.Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009;294:1–8. doi: 10.1111/j.1574-6968.2009.01514.x. [DOI] [PubMed] [Google Scholar]
  • 221.Berni Canani R, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics. 2012;4:4. doi: 10.1186/1868-7083-4-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 222.DiBaise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE. Gut microbiota and its possible relationship with obesity. Mayo Clinic proceedings. 2008;83:460–9. doi: 10.4065/83.4.460. [DOI] [PubMed] [Google Scholar]
  • 223.Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;59:3049–57. doi: 10.2337/db10-0253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 224.Kong LC, Tap J, Aron-Wisnewsky J, et al. Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes. The American journal of clinical nutrition. 2013;98:16–24. doi: 10.3945/ajcn.113.058743. [DOI] [PubMed] [Google Scholar]
  • 225.Li JV, Reshat R, Wu Q, et al. Experimental bariatric surgery in rats generates a cytotoxic chemical environment in the gut contents. Front Microbiol. 2011;2:183. doi: 10.3389/fmicb.2011.00183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 226.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;119:92–6. doi: 10.1016/j.physbeh.2013.06.008. [DOI] [PubMed] [Google Scholar]
  • 227.Damms-Machado A, Mitra S, Schollenberger AE, et al. Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption. Biomed Res Int. 2015;2015:806248. doi: 10.1155/2015/806248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 228.Tremaroli V, Karlsson F, Werling M, et al. Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation. Cell metabolism. 2015;22:228–38. doi: 10.1016/j.cmet.2015.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 229.Ilhan ZE, DiBaise JK, Isern NG, et al. Distinctive microbiomes and metabolites linked with weight loss after gastric bypass, but not gastric banding. The ISME journal. 2017 doi: 10.1038/ismej.2017.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 230.Su X, Magkos F, Zhou D, et al. Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss. Obesity. 2015;23:329–34. doi: 10.1002/oby.20923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 231.Kim SH, Chun HJ, Choi HS, Kim ES, Keum B, Jeen YT. Current status of intragastric balloon for obesity treatment. World journal of gastroenterology: WJG. 2016;22:5495–504. doi: 10.3748/wjg.v22.i24.5495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 232.Sherwood NE, Butryn ML, Forman EM, et al. The BestFIT trial: A SMART approach to developing individualized weight loss treatments. Contemp Clin Trials. 2016;47:209–16. doi: 10.1016/j.cct.2016.01.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 233.Puzziferri N, Roshek TB, 3rd, Mayo HG, Gallagher R, Belle SH, Livingston EH. Long-term follow-up after bariatric surgery: a systematic review. Jama. 2014;312:934–42. doi: 10.1001/jama.2014.10706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 234.Arapis K, Chosidow D, Lehmann M, et al. Long-term results of adjustable gastric banding in a cohort of 186 super-obese patients with a BMI>/= 50 kg/m2. J Visc Surg. 2012;149:e143–52. doi: 10.1016/j.jviscsurg.2012.01.007. [DOI] [PubMed] [Google Scholar]
  • 235.Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Obesity. 2013;21(Suppl 1):S1–27. doi: 10.1002/oby.20461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 236.Horner K, Lee S. Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1. Appl Physiol Nutr Metab. 2015;40:1089–99. doi: 10.1139/apnm-2015-0050. [DOI] [PubMed] [Google Scholar]
  • 237.Schubert MM, Sabapathy S, Leveritt M, Desbrow B. Acute exercise and hormones related to appetite regulation: a meta-analysis. Sports Med. 2014;44:387–403. doi: 10.1007/s40279-013-0120-3. [DOI] [PubMed] [Google Scholar]
  • 238.Kohli R, Setchell KD, Kirby M, et al. A surgical model in male obese rats uncovers protective effects of bile acids post-bariatric surgery. Endocrinology. 2013;154:2341–51. doi: 10.1210/en.2012-2069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 239.Caligiuri SPB, Kenny PJ. Gastric bypass surgery stimulates the dormant gut-brain axis in obesity. Kidney Int. 2017;92:6–8. doi: 10.1016/j.kint.2017.05.001. [DOI] [PubMed] [Google Scholar]

RESOURCES