Metabolic surgery: Action via hormonal milieu changes,changes in bile acids or gut microbiota? A summary of the literature

Obesity and type 2 diabetes remain epidemic problems. Different bariatric surgical techniques causes weight loss and diabetes remission to varying degrees. The underlying mechanisms of the beneficial effects of bariatric surgery are complex, and include changes in diet and behaviour, as well as changes in hormones, bile acid flow, and gut bacteria. We summarized the effects of multiple different bariatric procedures, and their resulting effects on several hormones (leptin, ghrelin, adiponectin, glucagon-like peptide 1 (GLP-1), peptide YY, and glucagon), bile acid changes in the gut and the serum, and resulting changes to the gut microbiome. As much as possible, we have tried to incorporate multiple studies to try to explain underlying mechanistic changes. What emerges from the data is a picture of clear differences between restrictive and metabolic procedures. The latter, in particular the roux-en-Y gastric bypass, induces large and distinctive changes in most measured fat and gut hormones, including early and sustained increase in GLP-1, possible through intestinal bile acid signalling. The changes in bile flow and the gut microbiome are causally inseparable so far, but new studies show that each contributes to the effects of weight loss and diabetes resolution.     

Gastrointestinal Surgery for Obesity and Diabetes: Weight Loss and Control of Hyperglycemia

Obesity is associated with a variety of weight-related metabolic comorbidities. Bariatric surgery (metabolic/gastrointestinal surgery) not only achieves significant and sustainable weight loss, but also induces extraordinary effects on nearly all obesity-related comorbidities, particularly remission of type 2 diabetes mellitus (T2DM). The mechanisms underlying such effects are slowly being elucidated, and it appears that the metabolic benefits of bariatric surgery are not only attributable to weight loss, but there are also weight independent mechanisms at play. This article outlines the metabolic effects of the most commonly performed bariatric procedures, with a particular emphasis on how they affect glucose metabolism and T2DM.     

The gut microbiota and metabolic disease: current understanding and future perspectives

The human gut microbiota has been studied for more than a century. However, of nonculture‐based techniques exploiting next‐generation sequencing for analysing the microbiota, development has renewed research within the field during the past decade. The observation that the gut microbiota, as an environmental factor, contributes to adiposity has further increased interest in the field. The human microbiota is affected by the diet, and macronutrients serve as substrates for many microbially produced metabolites, such as short‐chain fatty acids and bile acids, that may modulate host metabolism. Obesity predisposes towards type 2 diabetes and cardiovascular disease. Recently, it has been established that levels of butyrate‐producing bacteria are reduced in patients with type 2 diabetes, whereas levels of Lactobacillus sp. are increased. Recent data suggest that the reduced levels of butyrate‐producing bacteria might be causally linked to type 2 diabetes. Bariatric surgery, which promotes long‐term weight loss and diabetes remission, alters the gut microbiota in both mice and humans. Furthermore, by transferring the microbiota from postbariatric surgery patients to mice, it has been demonstrated that an altered microbiota may contribute to the improved metabolic phenotype following this intervention. Thus, greater understanding of alterations of the gut microbiota, in combination with dietary patterns, may provide insights into how the gut microbiota contributes to disease progression and whether it can be exploited as a novel diagnostic, prognostic and therapeutic target.     

Gut Microbiota in Metabolic-associated Fatty Liver Disease and in Other Chronic Metabolic Diseases

The gut microbiome plays a key role in the health-disease balance in the human body. Although its composition is unique for each person and tends to remain stable throughout lifetime, it has been shown that certain bacterial patterns may be determining factors in the onset of certain chronic metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic-associated fatty liver disease (MAFLD), and metabolic syndrome. The gut-liver axis embodies the close relationship between the gut and the liver; disturbance of the normal gut microbiota, also known as dysbiosis, may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation. Regulation of gut microbiota is fundamental to maintaining gut integrity, as well as the bile acids composition. In the present review, we summarize the current knowledge regarding the microbiota, bile acids composition and their association with MAFLD, obesity, T2DM and metabolic syndrome.     

Diabetes resolution and hyperinsulinaemia after metabolic Roux‐en‐Y gastric bypass

The global prevalence of type 2 diabetes mellitus and impaired glucose metabolism continues to rise in conjunction with the pandemic of obesity. The metabolic Roux‐en‐Y gastric bypass operation offers the successful resolution of diabetes in addition to sustained weight loss and excellent long‐term outcomes in morbidly obese individuals. The procedure consists of the physiological BRAVE effects: (i) Bile flow alteration; (ii) Reduction of gastric size; (iii) Anatomical gut rearrangement and altered flow of nutrients; (iv) Vagal manipulation and (v) Enteric gut hormone modulation. This operation provides anti‐diabetic effects through decreasing insulin resistance and increasing the efficiency of insulin secretion. These metabolic outcomes are achieved through weight‐independent and weight‐dependent mechanisms. These include the foregut, midgut and hindgut mechanisms, decreased inflammation, fat, adipokine and bile metabolism, metabolic modulation, shifts in gut microbial composition and intestinal gluconeogenesis. In a small minority of patients, gastric bypass results in hyperinsulinaemic hypoglycaemia that may lead to nesidioblastosis (pancreatic beta‐cell hypertrophy with islet hyperplasia). Elucidating the precise metabolic mechanisms of diabetes resolution and hyperinsulinaemia after surgery can lead to improved operations and disease‐specific procedures including ‘diabetes surgery’. It can also improve our understanding of diabetes pathogenesis that may provide novel strategies for the management of metabolic syndrome and impaired glucose metabolism.     

Roles of the gut in the metabolic syndrome: an overview

The metabolic syndrome is a cluster of risk factors (central obesity, hyperglycaemia, dyslipidaemia and arterial hypertension), indicating an increased risk of diabetes, cardiovascular disease and premature mortality. The gastrointestinal tract is seldom discussed as an organ system of principal importance for metabolic diseases. The present overview connects various metabolic research lines into an integrative physiological context in which the gastrointestinal tract is included. Strong evidence for the involvement of the gut in the metabolic syndrome derives from the powerful effects of weight‐reducing (bariatric) gastrointestinal surgery. In fact, gastrointestinal surgery is now recommended as a standard treatment option for type 2 diabetes in obesity. Several gut‐related mechanisms that potentially contribute to the metabolic syndrome will be presented. Obesity can be caused by hampered release of satiety‐signalling gut hormones, reduced meal‐associated energy expenditure and microbiota‐assisted harvest of energy from nondigestible food ingredients. Adiposity per se is a well‐established risk factor for hyperglycaemia. In addition, a leaky gut mucosa can trigger systemic inflammation mediating peripheral insulin resistance that together with a blunted incretin response aggravates the hyperglycaemic state. The intestinal microbiota is strongly associated with obesity and the related metabolic disease states, although the mechanisms involved remain unclear. Enterorenal signalling has been suggested to be involved in the pathophysiology of hypertension and postprandial triglyceride‐rich chylomicrons; in addition, intestinal cholesterol metabolism probably contributes to atherosclerosis. It is likely that in the future, the metabolic syndrome will be treated according to novel pharmacological principles interfering with gastrointestinal functionality.     

Gut microbiota after Roux‐en‐Y gastric bypass and sleeve gastrectomy in a diabetic rat model: Increased diversity and associations of discriminant genera with metabolic changes

Recent work with gut microbiota after bariatric surgery is limited, and the results have not been in agreement. Given the role of the gut microbiota in regulating host metabolism, we explored the effect of Roux‐en‐Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on the modifications of gut microbiota with regard to the potential influence of food intake and/or weight loss and examined their links with host metabolism. Zucker diabetic fatty rats were divided into the following groups: RYGB; sham‐operated with pair‐fed as RYGB; sham‐operated fed ad libitum ; and SG. The metabolic effects and gut microbiota profile were analyzed 10 weeks postoperatively. Associations between discriminating genera and metabolic markers after RYGB were explored. The 2 procedures induced similar glucose improvement and increased flora diversity after 10 weeks compared with sham‐operated groups. RYGB induced a marked higher relative abundance of Proteobacteria/Gammaproteobacteria and Betaproteobacteria and increased emergence of Fusobacteria and Clostridium, whereas SG resulted in more abundant Actinobacteria compared with other groups. Most of the 12 discriminant genera correlated with changes in metabolic phenotype, but only 28.6% of these correlations were independent of weight, and 4 discriminant genera still negatively correlated with serum insulin level independent of food intake and weight loss after RYGB. These data demonstrate that RYGB and SG surgery produced similar diversity but different microbiota compositions changes in Zucker diabetic fatty rats. These findings stimulate deeper explorations of functions of the discriminate microbiota and the mechanisms linking postsurgical modulation of gut microbiota and improvements in insulin resistance.     

Intestinal microbiota and type 2 diabetes: From mechanism insights to therapeutic perspective

The incidence of type 2 diabetes (T2DM) is rapidly increasing worldwide. However, the pathogenesis of T2DM has not yet been well explained. Recent evidence suggests that the intestinal microbiota composition is associated with obesity and T2DM. In this review, we provide an overview about the mechanisms underlying the role of intestinal microbiota in the pathogenesis of T2DM. There is clear evidence that the intestinal microbiota influences the host through its effect on body weight, bile acid metabolism, proinflammatory activity and insulin resistance, and modulation of gut hormones. Modulating gut microbiota with the use of probiotics, prebiotics, antibiotics, and fecal microbiota transplantation may have benefits for improvement in glucose metabolism and insulin resistance in the host. Further studies are required to increase our understanding of the complex interplay between intestinal microbiota and the host with T2DM. Further studies may be able to boost the development of new effective therapeutic approaches for T2DM.     

The impact of bariatric surgery in patients with type-2 diabetes mellitus

Over 220 million individuals have type-2 diabetes mellitus (T2DM) worldwide. Obesity has been identified as a significant risk factor for the development of T2DM. Overweight or obese individuals develop insulin resistance with resultant hyperinsulinemia. This process may progress to impaired glucose intolerance and eventual T2DM. There is strong evidence indicating that bariatric surgery may produce sustainable long-term weight loss in obese individuals. Bariatric surgery consists of surgical operations classified as either primarily restrictive or malabsorptive. Restrictive bariatric procedures include gastric banding or sleeve gastrectomy, while malabsorptive procedures included gastric bypass and biliopancreatic diversion. Malabsorptive procedures have been shown to be superior in producing dramatic weight loss along with resolution or improvement of T2DM. Interestingly, improvement of diabetes has been shown to occur shortly following malabsorptive bariatric surgery, prior to significant weight loss, suggesting that hormone-mediated mechanisms may be involved. As the prevalence of obesity and T2DM continues to rise, so may the role of bariatric surgery to combat this growing epidemic.     

Gastrointestinal changes after bariatric surgery

Severe obesity is a preeminent health care problem that impacts overall health and survival. The most effective treatment for severe obesity is bariatric surgery, an intervention that not only maintains long-term weight loss but also is associated with improvement or remission of several comorbidies including type 2 diabetes mellitus. Some weight loss surgeries modify the gastrointestinal anatomy and physiology, including the secretions and actions of gut peptides. This review describes how bariatric surgery alters the patterns of gastrointestinal motility, nutrient digestion and absorption, gut peptide release, bile acids and the gut microflora, and how these changes alter energy homeostasis and glucose metabolism.     

Bariatric surgeries: beyond restriction and malabsorption

Behavioral and pharmaceutical intervention to treat obesity and its comorbidities typically results in only a 5-10% weight loss. Thus, bariatric surgery is the most effective obesity treatment with some surgeries resulting in 30% sustained weight loss. Although this degree of weight loss has profound metabolic impact, these surgeries seem to have metabolic effects that are independent of weight loss. In support of this is the clinical literature showing rapid resolution of Type 2 diabetes mellitus (T2DM) that occurs before significant weight loss. To gain a complete understanding of the weight loss-independent effects of bariatric surgery, animal models have been developed. These are becoming more widely implemented and allow the use of pair-fed or weight-matched sham-operated controls in order to gain mechanistic insights into the mode of action of bariatric surgery. Increases in anorectic gut hormones, such as glucagon-like peptide-1 and peptide YY, or decreases in the orexigenic hormone ghrelin have been seen and are implicated as mediators of weight loss-independent actions of bariatric surgery. Changes in nutrient processing and sensing may also have a mechanistic role that is independent of, or that regulates, gut hormone responses to these surgeries. Ultimately, the hope is that understanding the mechanisms of bariatric surgeries will aid in the development of less invasive surgeries or pharmacological therapies that are more specifically, and perhaps individually, targeted at weight loss and/or resolution of T2DM.     

Gut microbiome: Linking together obesity,bariatric surgery and associated clinical outcomes under a single focus

Obesity is increasingly prevalent in the post-industrial era, with increased mortality rates. The gut microbiota has a central role in immunological, nutritional and metabolism mediated functions, and due to its multiplexity, it is considered an independent organ. Modern high-throughput sequencing techniques have allowed phylogenetic exploration and quantitative analyses of gut microbiome and improved our current understanding of the gut microbiota in health and disease. Its role in obesity and its changes following bariatric surgery have been highlighted in several studies. According to current literature, obesity is linked to a particular microbiota profile that grants the host an augmented potential for calorie release, while limited diversity of gut microbiome has also been observed. Moreover, bariatric surgery procedures represent effective interventions for sustained weight loss and restore a healthier microbiota, contributing to the observed fat mass reduction and lean mass increase. However, newer evidence has shown that gut microbiota is only partially recovered following bariatric surgery. Moreover, several targets including FGF15/19 (a gut-derived peptide), could be responsible for the favorable metabolic changes of bariatric surgery. More randomized controlled trials and larger prospective studies that include well-defined cohorts are required to better identify associations between gut microbiota, obesity, and bariatric surgery.     

Bariatric Surgery to Prevent and Treat Diabetes

The obesity epidemic has become a significant issue worldwide. Type 2 diabetes mellitus (T2DM) is related and its prevalence is also on the rise. Bariatric surgery as part of a comprehensive weight management strategy is highly efficacious in treating obese individuals and promoting weight loss. The resultant loss of excess body weight is frequently associated with improvement of comorbid factors such T2DM. This review focuses on both restrictive and malabsorptive bariatric surgical procedures and explores their roles in preventing and treating T2DM. Currently, the use of bariatric surgery as a prevention strategy for T2DM in obese individuals is understudied; however, there is early evidence to suggest a protective effect. In addition, this review summarizes emerging evidence linking bariatric surgery and improvement of T2DM in diabetic obese patients.     

Bariatric surgery and type 2 diabetes: are there weight loss‐independent therapeutic effects of upper gastrointestinal bypass?

Type 2 diabetes (T2D) is a major worldwide public health concern. Despite a large armamentarium of T2D medications, a large proportion of patients fail to achieve recommended treatment goals for glycemic control. Weight loss has profound beneficial effects on the metabolic abnormalities involved in the pathogenesis of T2D. Accordingly, bariatric surgery, which is the most effective available weight loss therapy, is also the most effective therapy for treating patients with T2D. Surgical procedures that bypass the upper gastrointestinal (UGI) tract are particularly effective in achieving partial and even complete remission of T2D, suggesting that UGI bypass has weight loss‐independent effects on glycemic control. Although a number of hypotheses (e.g. a role for multiorgan insulin sensitivity, β‐cell function, incretin response, the gut microbiome, bile acid metabolism, intestinal glucose metabolism and browning of adipose tissue) have been proposed to explain the potential unique effects of UGI tract bypass surgery, none has yet been adequately evaluated to determine therapeutic importance in patients with T2D. Here, we review the efficacy of UGI bypass surgery in treating T2D and the mechanisms that have been proposed to explain its potential weight loss‐independent therapeutic effects.     

Neurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions?

Neurodegenerative diseases are amongst the leading causes of worldwide disability, morbidity and decreased quality of life. They are increasingly associated with the concomitant worldwide epidemic of obesity. Although the prevalence of both AD and PD continue to rise, the available treatment strategies to combat these conditions remain ineffective against an increase in global neurodegenerative risk factors. There is now epidemiological and mechanistic evidence associating obesity and its related disorders of impaired glucose homeostasis, type 2 diabetes mellitus and metabolic syndrome with both AD and PD. Here we describe the clinical and molecular relationship between obesity and neurodegenerative disease. Secondly we outline the protective role of weight loss, metabolic and caloric modifying interventions in the context of AD and PD. We conclude that the application of caloric restriction through dietary changes, bariatric (metabolic) surgery and gut hormone therapy may offer novel therapeutic strategies against neurodegenerative disorders. Investigating the protective mechanisms of weight loss, metabolic and caloric modifying interventions can increase our understanding of these major public health diseases and their management.     

Mechanisms of bariatric surgery for weight loss and diabetes remission

Obesity and type 2 diabetes(T2D) lead to defects in intestinal hormones secretion, abnormalities in the composition of bile acids (BAs), increased systemic and adipose tissue inflammation, defects of branched-chain amino acids (BCAAs) catabolism, and dysbiosis of gut microbiota. Bariatric surgery (BS) has been shown to be highly effective in the treatment of obesity and T2D, which allows us to view BS not simply as weight-loss surgery but as a means of alleviating obesity and its comorbidities, especially T2D. In recent years, accumulating studies have focused on the mechanisms of BS to find out which metabolic parameters are affected by BS through which pathways, such as which hormones and inflammatory processes are altered. The literatures are saturated with the role of intestinal hormones and the gut-brain axis formed by their interaction with neural networks in the remission of obesity and T2D following BS. In addition, BAs, gut microbiota and other factors are also involved in these benefits after BS. The interaction of these factors makes the mechanisms of metabolic improvement induced by BS more complicated. To date, we do not fully understand the exact mechanisms of the metabolic alterations induced by BS and its impact on the disease process of T2D itself. This review summarizes the changes of intestinal hormones, BAs, BCAAs, gut microbiota, signaling proteins, growth differentiation factor 15, exosomes, adipose tissue, brain function, and food preferences after BS, so as to fully understand the actual working mechanisms of BS and provide nonsurgical therapeutic strategies for obesity and T2D.     

Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome

Clinical studies have indicated that circulating bile acid(BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses(RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagonlike peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery- independently of calorie restriction and body-weight loss- could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes(T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gutmicrobiome may influence circulating BA concentrations and could subsequently contribute to T2 DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor(FXR) and membrane G-protein-receptor(TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2 DM remission.     

Cardiovascular benefits of bariatric surgery in morbidly obese patients

Morbid obesity is associated with increased morbidity and represents a major healthcare problem with increasing incidence worldwide. Bariatric surgery is considered an effective option for the management of morbid obesity. We searched MEDLINE, Current Contents and the Cochrane Library for papers published on bariatric surgery in English from 1 January 1990 to 20 July 2010. We also manually checked the references of retrieved articles for any pertinent material. Bariatric surgery results in resolution of major comorbidities including type 2 diabetes mellitus, hypertension, dyslipidemia, metabolic syndrome, non‐alcoholic fatty liver disease, nephropathy, left ventricular hypertrophy and obstructive sleep apnea in the majority of morbidly obese patients. Through these effects and possibly other independent mechanisms bariatric surgery appears to reduce cardiovascular morbidity and mortality. Laparoscopic Roux‐en‐Y gastric bypass (LRYGB) appears to be more effective than laparoscopic adjustable gastric banding (LAGB) in terms of weight loss and resolution of comorbidities. Operation‐associated mortality rates after bariatric surgery are low and LAGB is safer than LRYGB. In morbidly obese patients bariatric surgery is safe and appears to reduce cardiovascular morbidity and mortality.     

A role for exercise after bariatric surgery?

Obesity predisposes an individual to develop numerous comorbidities, including type 2 diabetes, and represents a major healthcare issue in many countries worldwide. Bariatric surgery can be an effective treatment option, resulting in profound weight loss and improvements in metabolic health; however, not all patients achieve similar weight loss or metabolic improvements. Exercise is an excellent way to improve health, with well‐characterized physiological and psychological benefits. In the present paper we review the evidence to determine whether there may be a role for exercise as a complementary adjunct therapy to bariatric surgery. Objectively measured physical activity data indicate that most patients who undergo bariatric surgery do not exercise enough to reap the health benefits of exercise. While there is a dearth of data on the effects of exercise on weight loss and weight loss maintenance after surgery, evidence from studies of caloric restriction and exercise suggest that similar adjunctive benefits may be extended to patients who perform exercise after bariatric surgery. Recent evidence from exercise interventions after bariatric surgery suggests that exercise may provide further improvements in metabolic health compared with surgery‐induced weight loss alone. Additional randomized controlled exercise trials are now needed as the next step to more clearly define the potential for exercise to provide additional health benefits after bariatric surgery. This valuable evidence will inform clinical practice regarding much‐needed guidelines for exercise after bariatric surgery.