Marco Bueter

Metabolic surgery profoundly influences gut microbial–host metabolic cross-talk

Background and aims Bariatric surgery is increasingly performed worldwide to treat morbid obesity and is also known as metabolic surgery to reflect its beneficial metabolic effects especially with respect to improvement in type 2 diabetes. Understanding surgical weight loss mechanisms and metabolic modulation is required to enhance patient benefits and operative outcomes. Methods The authors applied a parallel and statistically integrated bacterial profiling and metabonomic approach to characterise Roux-en-Y gastric bypass (RYGB) effects in a non-obese rat model. Results Substantial shifts of the main gut phyla towards higher concentrations of Proteobacteria (52-fold), specifically Enterobacter hormaechei, are shown. Low concentrations of Firmicutes (4.5-fold) and Bacteroidetes (twofold) in comparison with sham-operated rats were also found. Faecal extraction studies revealed a decrease in faecal bile acids and a shift from protein degradation to putrefaction through decreased faecal tyrosine with concomitant increases in faecal putrescine and diaminoethane. Decreased urinary amines and cresols were found and indices of modulated energy metabolism were demonstrated after RYGB, including decreased urinary succinate, 2-oxoglutarate, citrate and fumarate. These changes could also indicate renal tubular acidosis, which is associated with increased flux of mitochondrial tricarboxylic acid cycle intermediates. A surgically induced effect on the gut–brain–liver metabolic axis is inferred from modulated faecal γ-aminobutyric acid and glutamate. Conclusion This profound co-dependence of mammalian and microbial metabolism, which is systematically altered after RYGB surgery, suggests that RYGB exerts local and global metabolic effects. The effect of RYGB surgery on the host metabolic–microbial cross-talk augments our understanding of the metabolic phenotype of bariatric procedures and can facilitate enhanced treatments for obesity-related diseases.

Increased Postprandial Energy Expenditure May Explain Superior Long Term Weight Loss after Roux-en-Y Gastric Bypass Compared to Vertical Banded Gastroplasty

Background and Aims Gastric bypass results in greater weight loss than Vertical banded gastroplasty (VBG), but the underlying mechanisms remain unclear. In addition to effects on energy intake the two bariatric techniques may differentially influence energy expenditure (EE). Gastric bypass in rats increases postprandial EE enough to result in elevated EE over 24 hours. This study aimed to investigate alterations in postprandial EE after gastric bypass and VBG in humans. Methods Fourteen women from a randomized clinical trial between gastric bypass (nu200a=u200a7) and VBG (nu200a=u200a7) were included. Nine years postoperatively and at weight stability patients were assessed for body composition and calorie intake. EE was measured using indirect calorimetry in a respiratory chamber over 24 hours and focused on the periods surrounding meals and sleep. Blood samples were analysed for postprandial gut hormone responses. Results Groups did not differ regarding body composition or food intake either preoperatively or at study visit. Gastric bypass patients had higher EE postprandially (pu200a=u200a0.018) and over 24 hours (pu200a=u200a0.048) compared to VBG patients. Postprandial peptide YY (PYY) and glucagon like peptide 1 (GLP-1) levels were higher after gastric bypass (both p<0.001). Conclusions Gastric bypass patients have greater meal induced EE and total 24 hours EE compared to VBG patients when assessed 9 years postoperatively. Postprandial satiety gut hormone responses were exaggerated after gastric bypass compared to VBG. Long-term weight loss maintenance may require significant changes in several physiological mechanisms which will be important to understand if non-surgical approaches are to mimic the effects of bariatric surgery.

Roux-en-Y gastric bypass surgery in rats alters gut microbiota profile along the intestine

Roux-en-Y gastric bypass (RYGB) surgery might modify the gut microbiota composition differently in the three distinct anatomical sections of the small intestine compared to sham surgery. We showed that RYGB induced changes in the microbiota of the alimentary limb and the common channel resembling those seen after prebiotic treatment or weight loss by dieting. These changes may be associated with altered production of intestinal hormones known to control energy balance. Postsurgical modulation of gut microbiota may significantly contribute to the beneficial metabolic effects of RYGB surgery.

Hypertrophy Dependent Doubling of L-Cells in Roux-en-Y Gastric Bypass Operated Rats

Background and Aims Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes mellitus (T2DM), but the underlying mode of action remains incompletely understood. L-cell derived gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are thought to play a central role in the anti-diabetic effects of RYGB; therefore, an improved understanding of intestinal endocrine L-cell adaptability is considered pivotal. Methods The full rostrocaudal extension of the gut was analyzed in rats after RYGB and in sham-operated controls ad libitum fed or food restricted to match the body weight of RYGB rats. Total number of L-cells, as well as regional numbers, densities and mucosa volumes were quantified using stereological methods. Preproglucagon and PYY mRNA transcripts were quantified by qPCR to reflect the total and relative hormone production capacity of the L-cells. Results RYGB surgery induced hypertrophy of the gut mucosa in the food exposed regions of the small intestine coupled with a doubling in the total number of L-cells. No changes in L-cell density were observed in any region regardless of surgery or food restriction. The total gene expression capacity of the entire gut revealed a near 200% increase in both PYY and preproglucagon mRNA levels in RYGB rats associated with both increased L-cell number as well as region-specific increased transcription per cell. Conclusions Collectively, these findings indicate that RYGB in rats is associated with gut hypertrophy, an increase in L-cell number, but not density, and increased PYY and preproglucagon gene expression. This could explain the enhanced gut hormone dynamics seen after RYGB.

Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss in Patients With Morbid Obesity: The SM-BOSS Randomized Clinical Trial

Importance Sleeve gastrectomy is increasingly used in the treatment of morbid obesity, but its long-term outcome vs the standard Roux-en-Y gastric bypass procedure is unknown. Objective To determine whether there are differences between sleeve gastrectomy and Roux-en-Y gastric bypass in terms of weight loss, changes in comorbidities, increase in quality of life, and adverse events. Design, Setting, and Participants The Swiss Multicenter Bypass or Sleeve Study (SM-BOSS), a 2-group randomized trial, was conducted from January 2007 until November 2011 (last follow-up in March 2017). Of 3971 morbidly obese patients evaluated for bariatric surgery at 4 Swiss bariatric centers, 217 patients were enrolled and randomly assigned to sleeve gastrectomy or Roux-en-Y gastric bypass with a 5-year follow-up period. Interventions Patients were randomly assigned to undergo laparoscopic sleeve gastrectomy (n = 107) or laparoscopic Roux-en-Y gastric bypass (n = 110). Main Outcomes and Measures The primary end point was weight loss, expressed as percentage excess body mass index (BMI) loss. Exploratory end points were changes in comorbidities and adverse events. Results Among the 217 patients (mean age, 45.5 years; 72% women; mean BMI, 43.9) 205 (94.5%) completed the trial. Excess BMI loss was not significantly different at 5 years: for sleeve gastrectomy, 61.1%, vs Roux-en-Y gastric bypass, 68.3% (absolute difference, −7.18%; 95% CI, −14.30% to −0.06%; Pu2009=u2009.22 after adjustment for multiple comparisons). Gastric reflux remission was observed more frequently after Roux-en-Y gastric bypass (60.4%) than after sleeve gastrectomy (25.0%). Gastric reflux worsened (more symptoms or increase in therapy) more often after sleeve gastrectomy (31.8%) than after Roux-en-Y gastric bypass (6.3%). The number of patients with reoperations or interventions was 16/101 (15.8%) after sleeve gastrectomy and 23/104 (22.1%) after Roux-en-Y gastric bypass. Conclusions and Relevance Among patients with morbid obesity, there was no significant difference in excess BMI loss between laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass at 5 years of follow-up after surgery. Trial Registration clinicaltrials.gov Identifier: NCT00356213

Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation

Roux-en-Y gastric bypass (RYGB) surgery has been shown to decrease consummatory responsiveness of rats to high sucrose concentrations, and genetic deletion of glucagon-like peptide-1 receptors (GLP-1R) has been shown to decrease consummatory responsiveness of mice to low-sucrose concentrations. Here we assessed the effects of RYGB and pharmacological GLP-1R modulation on sucrose licking by chow-fed rats in a brief-access test that assessed consummatory and appetitive behaviors. Rats were tested while fasted presurgically and postsurgically and while nondeprived postsurgically and 5 h after intraperitoneal injections with the GLP-1R antagonist exendin-3(9-39) (30 μg/kg), agonist exendin-4 (1 μg/kg), and vehicle in 30-min sessions during which a sucrose concentration series (0.01-1.0 M) was presented in 10-s trials. Other rats were tested postsurgically or 15 min after peptide or vehicle injection while fasted and while nondeprived. Independent of food-deprivation state, sucrose experience, or GLP-1R modulation, RYGB rats took 1.5-3× as many trials as sham-operated rats, indicating increased appetitive behavior. Under nondeprived conditions, RYGB rats with presurgical sucrose experience licked more to sucrose relative to water compared with sham-operated rats. Exendin-4 and exendin-3(9-39) impacted 0.3 M sucrose intake in a one-bottle test, but never interacted with surgical group to affect brief-access responding. Unlike prior reports in both clearly obese and relatively leaner rats given RYGB and in GLP-1R knockout mice, we found that neither RYGB nor GLP-1R blockade decreased consummatory responsiveness to sucrose in our less obese chow-fed rats. Collectively, these results highlight the fact that changes in taste-driven motivated behavior to sucrose after RYGB and/or GLP-1R modulation are very model and measure dependent.

The physiology underlying Roux-en-Y gastric bypass: a status report

Obesity and its related comorbidities can be detrimental for the affected individual and challenge public health systems worldwide. Currently, the only available treatment options leading to clinically significant and maintained body weight loss and reduction in obesity-related morbidity and mortality are based on surgical interventions. This review will focus on two main clinical effects of Roux-en-Y gastric bypass (RYGB), namely body weight loss and change in eating behavior. Animal experiments designed to understand the underlying physiological mechanisms of these post-gastric bypass effects will be discussed. Where appropriate, reference will also be made to vertical sleeve gastrectomy. While caloric malabsorption and mechanical restriction seem not to be major factors in this respect, alterations in gut hormone levels are invariably found after RYGB. However, their causal role in RYGB effects on eating and body weight has recently been challenged. Other potential factors contributing to the RYGB effects include increased bile acid concentrations and an altered composition of gut microbiota. RYGB is further associated with remarkable changes in preference for different dietary components, such as a decrease in the preference for high fat or sugar. It needs to be noted, however, that in many cases, the question about the necessity of these alterations for the success of bariatric surgery procedures remains unanswered.

Roux-en-Y gastric bypass surgery reduces bone mineral density and induces metabolic acidosis in rats

Roux-en-Y gastric bypass (RYGB) surgery leads to bone loss in humans, which may be caused by vitamin D and calcium malabsorption and subsequent secondary hyperparathyroidism. However, because these conditions occur frequently in obese people, it is unclear whether they are the primary causes of bone loss after RYGB. To determine the contribution of calcium and vitamin D malabsorption to bone loss in a rat RYGB model, adult male Wistar rats were randomized for RYGB surgery, sham-operation-ad libitum fed, or sham-operation-body weight-matched. Bone mineral density, calcium and phosphorus balance, acid-base status, and markers of bone turnover were assessed at different time points for 14 wk after surgery. Bone mineral density decreased for several weeks after RYGB. Intestinal calcium absorption was reduced early after surgery, but plasma calcium and parathyroid hormone levels were normal. 25-hydroxyvitamin D levels decreased, while levels of active 1,25-dihydroxyvitamin D increased after surgery. RYGB rats displayed metabolic acidosis due to increased plasma lactate levels and increased urinary calcium loss throughout the study. These results suggest that initial calcium malabsorption may play a key role in bone loss early after RYGB in rats, but other factors, including chronic metabolic acidosis, contribute to insufficient bone restoration after normalization of intestinal calcium absorption. Secondary hyperparathyroidism is not involved in postoperative bone loss. Upregulated vitamin D activation may compensate for any vitamin D malabsorption.

Estradiol Increases Body Weight Loss and Gut-Peptide Satiation After Roux-en-Y Gastric Bypass in Ovariectomized Rats

Despite the fact that ∼85% of bariatric operations are performed in women, the effects of the reproductive axis function on outcome of bariatric surgery remain to be determined. Here we developed the first published model of Roux-en-Y gastric bypass (RYGB) in female rats. We show in ovariectomized rats receiving estradiol or control treatment that (1) RYGB-induced body weight loss and (2) the satiating efficacy of endogenous glucagon-like peptide-1 and cholecystokinin satiation were significantly increased in estradiol-treated rats. These data are relevant to the care of obese women, in particular perimenopausal women, undergoing bariatric surgery.

The gut–brain axis in obesity

Currently the only effective treatment for morbid obesity with a proven mortality benefit is surgical intervention. The underlying mechanisms of these surgical techniques are unclear, but alterations in circulating gut hormone levels have been demonstrated to be at least one contributing factor. Gut hormones seem to communicate information from the gastrointestinal tract to the regulatory appetite centres within the central nervous system (CNS) via the so-called Gut-Brain-Axis. Such information may be transferred to the CNS either via vagal or non-vagal afferent nerve signalling or directly via blood circulation. Complex neural networks, distributed throughout the forebrain and brainstem, are in control of feeding and energy homoeostasis. This article aims to review how appetite is potentially regulated by these gastrointestinal hormones. Identification of the underlying mechanisms of appetite and weight control may pave the way to develop better surgical techniques and new therapies in the future.