Tobias Meile

Effects of Surgical and Dietary Weight Loss Therapy for Obesity on Gut Microbiota Composition and Nutrient Absorption

Evidence suggests a correlation between the gut microbiota composition and weight loss caused by caloric restriction. Laparoscopic sleeve gastrectomy (LSG), a surgical intervention for obesity, is classified as predominantly restrictive procedure. In this study we investigated functional weight loss mechanisms with regard to gut microbial changes and energy harvest induced by LSG and a very low calorie diet in ten obese subjects (n = 5 per group) demonstrating identical weight loss during a follow-up period of six months. For gut microbiome analysis next generation sequencing was performed and faeces were analyzed for targeted metabolomics. The energy-reabsorbing potential of the gut microbiota decreased following LSG, indicated by the Bacteroidetes/Firmicutes ratio, but increased during diet. Changes in butyrate-producing bacterial species were responsible for the Firmicutes changes in both groups. No alteration of faecal butyrate was observed, but the microbial capacity for butyrate fermentation decreased following LSG and increased following dietetic intervention. LSG resulted in enhanced faecal excretion of nonesterified fatty acids and bile acids. LSG, but not dietetic restriction, improved the obesity-associated gut microbiota composition towards a lean microbiome phenotype. Moreover, LSG increased malabsorption due to loss in energy-rich faecal substrates and impairment of bile acid circulation. This trial is registered with ClinicalTrials.gov NCT01344525.

Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes

Objective Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type-2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO), opening the possibility that FGF21 is a cross-talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion. Methods In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole-body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro. Results Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, −15% and −40%, respectively; p < 0.01 both), reduced adiponectin expression (−20%; p < 0.05), markedly reduced adiponectin release (−60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release. Conclusions The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes.

Metabolic Signatures of Cultured Human Adipocytes from Metabolically Healthy versus Unhealthy Obese Individuals

Background and Aims Among obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO) can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO. Methods 10 insulin-resistant (IR) vs. 10 insulin-sensitive (IS) non-diabetic morbidly obese (BMI >40 kg/m2) Caucasians were matched for gender, age, BMI, and percentage of body fat. From subcutaneous fat biopsies, primary preadipocytes were isolated and differentiated to adipocytes in vitro. About 280 metabolites were investigated by a targeted metabolomic approach intracellularly, extracellularly, and in plasma. Results/Interpretation Among others, aspartate was reduced intracellularly to one third (p = 0.0039) in IR adipocytes, pointing to a relative depletion of citric acid cycle metabolites or reduced aspartate uptake in MUHO. Other amino acids, already known to correlate with diabetes and/or obesity, were identified to differ between MUHOs and MHOs adipocytes, namely glutamine, histidine, and spermidine. Most species of phosphatidylcholines (PCs) were lower in MUHOs extracellular milieu, though simultaneously elevated intracellularly, e.g., PC aa C32∶3, pointing to increased PC synthesis and/or reduced PC release. Furthermore, altered arachidonic acid (AA) metabolism was found: 15(S)-HETE (15-hydroxy-eicosatetraenoic acid; 0 vs. 120pM; p = 0.0014), AA (1.5-fold; p = 0.0055) and docosahexaenoic acid (DHA, C22∶6; 2-fold; p = 0.0033) were higher in MUHO. This emphasizes a direct contribution of adipocytes to local adipose tissue inflammation. Elevated DHA, as an inhibitor of prostaglandin synthesis, might be a hint for counter-regulatory mechanisms in MUHO. Conclusion/Interpretation We identified adipocyte-inherent metabolic alterations discriminating between MHO and MUHO.

Impact of risk factors for prolonged operative time in laparoscopic cholecystectomy.

Objective Laparoscopic cholecystectomy (LC) remains one of the most frequent surgical therapies for symptomatic gallstone disorders. Prolonged operative time is frequently associated with increased complication rates. The aim of this study was to identify the risk factors for prolonged operative times to minimize perioperative morbidity and optimize clinical management. Methods A total of 677 consecutive patients underwent LC. The exclusion criteria were conversion to an open procedure, intraoperative cholangiography, and liver cirrhosis (n=81). Data were analyzed retrospectively with respect to age, sex, BMI, ASA score, previous abdominal surgery, preoperative endoscopic retrograde cholangiopancreatography, acute cholecystitis, and surgeon’s experience. Univariate and multivariate analyses were performed. Results A total of 596 patients, mean (±SD) age of 52.2±16.7 years, were analyzed. In all, 29% of the patients were obese (BMI≥30 kg/m2); 11% had ASA III. Five percent of patients had undergone previous upper abdominal surgery. Overall, 105/596 patients had an acute cholecystitis. Residents of general surgery performed 58% of all operations. The median operative time was 80 min (range, 15–281 min). No statistical significance was found between intraoperative and postoperative complications by surgeon’s experience. Statistically, independent preoperative predictors for prolonged operative time as identified through multivariate analysis were acute cholecystitis, obesity, previous upper abdominal surgery, male sex, and low degree of surgical expertise. Conclusion The risk for prolonged operative times in LC can be assessed on the basis of patients’ characteristics. Assessment of these factors not only helps to optimize the individual outcome for each patient but also improves the decision process toward operative training for junior surgeons.

Impact of protein supplementation after bariatric surgery: A randomized controlled double-blind pilot study

OBJECTIVES Bariatric patients are at risk of protein deficiency. The aim of this study was to determine possible benefits of postoperative protein supplementation weight reduction, body composition, and protein status. METHODS Twenty obese patients who underwent bariatric surgery were randomized either to the protein (PRO) group, which received a daily protein supplement over 6 months postoperatively, or to the control (CON) group, which received an isocaloric placebo in a double-blind fashion. Data on protein and energy intake, body weight, body composition, blood proteins, and grip force was collected preinterventionally and at 1, 3, and 6 months postoperatively. RESULTS In both groups body weight was significantly reduced to a similar extent (after 6 months: PRO group 25.4 ± 7.2%, CON group 20.9 ± 3.9%; intergroup comparison P > 0.05). Protein intake was steadily increased in the PRO group, but not in the CON group, and reached maximum at month 6 (25.4 ± 3.7% of energy intake versus 15.8 ± 4.4%; P < 0.001). In the PRO group, body fat mass loss was higher than that in the CON group (79% of absolute weight loss versus 73%; P = 0.02) while lean body mass loss was less pronounced (21% versus 27%, P = 0.05). Blood proteins and grip force did not differ at any time point between the two groups. CONCLUSIONS The present study suggests that protein supplementation after bariatric surgery improves body composition by enhancing loss of body fat mass and reducing loss of lean body mass within the 6 months follow up.

Psychological dimensions after laparoscopic sleeve gastrectomy: reduced mental burden, improved eating behavior, and ongoing need for cognitive eating control

BACKGROUND Obesity as a chronic disease has spread worldwide. Conservative treatment, especially with severe obesity, often fails. Obesity surgery has been shown to be an effective treatment. Laparoscopic sleeve gastrectomy (LSG), as a restrictive procedure, has low risks and results in good weight loss outcomes. However, to date, no studies have investigated the changes in psychological dimensions-especially concerning eating behavior and cognitive restraint-after LSG. The present study investigated, for the first time, eating behavior (cognitive restraint, disinhibition, hunger), depression, and perceived stress before and 1 year after LSG. The setting was a university hospital, comprehensive obesity center. METHODS Of 59 patients who had undergone LSG from 2008 to 2010, 40 patients were evaluated using questionnaires on eating behavior, depression, and stress, with measurements made before and 1 year after surgery. RESULTS The body mass index had decreased, on average, by 15.5 kg/m(2) 1 year after LSG (62.7% excess weight loss). The eating behaviors had changed, with patients experiencing less hunger, fewer food cravings, and decreased disinhibition. Depressive symptoms and perceived stress improved. However, the results showed high levels in the dimension of cognitive restraint of eating 1 year after LSG. CONCLUSIONS Most psychological dimensions improved as expected. The patients were less distracted by food, experienced less hunger, and were less disturbed by emotional distress. However, we found persistent cognitive restraint, reflecting an ongoing need for central eating control. Additional investigations are needed to describe the communication between the gut and brain after surgery.

A 1-year videoconferencing-based psychoeducational group intervention following bariatric surgery: results of a randomized controlled study.

BACKGROUND For severely obese patients, bariatric surgery has been recommended as an effective therapy. OBJECTIVES The Bariataric Surgery and Education (BaSE) study aimed to assess the efficacy of a videoconferencing-based psychoeducational group intervention in patients after bariatric surgery. SETTING The BaSE study is a randomized, controlled multicenter clinical trial involving 117 patients undergoing bariatric surgery (mean preoperative body mass index [BMI] 49.9 kg/m(2), SD 6.4). Patients were enrolled between May 2009 and November 2012 and were randomly assigned to receive either conventional postsurgical visits or, in addition, a videoconferencing-based 1-year group program. METHODS Primary outcome measures were weight in kilograms, health-related quality of life (HRQOL), and general self-efficacy (GSE). Secondary outcome measures were depression symptoms and eating behavior. RESULTS 94% of the patients completed the study. Mean weight loss for all patients was 45.9 kg (SD 16.4) 1 year after surgery (mean excess weight loss [EWL] 63%). Intention-to-treat analyses revealed no differences in weight loss, EWL, HRQOL, or self-efficacy between study groups at 1 year after surgery. However, patients with clinically significant depression symptoms (CSD) at baseline assigned to the intervention group (n = 29) had a significantly better HRQOL (P = .03), lower depression scores (P = .02), and a trend for a better EWL (.06) 1 year after surgery compared with the control group (n = 20). CONCLUSION We could not prove the efficacy of the group program for the whole study sample. However, results indicate that the intervention is effective for the important subgroup of patients with CSD.

The Gut is not only the Target but a Source of Inflammatory Mediators Inhibiting Gastrointestinal Motility During Sepsis

Background: Sepsis is a common problem in intensive care patients leading to multi-organ failure and gastrointestinal paralysis. Aim: The aim of the study was to investigate whether the gastrointestinal tract is not only the target but also the source of inflammatory mediators inhibiting gastrointestinal motility. Methods: Mesenteric lymph was obtained from rats in which a sepsis was induced by lipopolysaccharide (LPS) intraperitoneally. Gastrointestinal motility was recorded following mesenteric lymph- or TNFα infusion into the jugular vein of separate healthy recipient rats using the strain gauge transducer technique. Results: Infusion of sepsis lymph significantly impairs gastric and colonic motility, decreasing the motility-index in the stomach and colon by about 57% and 21% respectively in comparison to baseline motility. Among other inflammatory mediators, TNFα plays an important role in mediating the inhibitory effect of mesenteric lymph on gastrointestinal motility during sepsis. Conclusions: The gastrointestinal tract is the source and the target of inflammatory mediators released during sepsis causing paralytic ileus.

Effects of laparoscopic sleeve gastrectomy on attentional processing of food-related information: Evidence from eye-tracking

BACKGROUND Weight loss after laparoscopic sleeve gastrectomy (LSG) might be associated partially with changes in reward system functioning and altered appetitive responses to food cues. Food cue processing refers to motivational, affective, and cognitive responses to stimuli that are associated with food. We investigated if food cue processing is altered 6 months after weight loss that is induced by LSG. We expected patients after LSG to show reduced appetitive responses to food cues. METHODS In an experimental longitudinal exploratory study, 17 severely obese patients (body mass index [BMI]: 48.3 ± 6.5 kg/m²) were investigated presurgery and 6 months postsurgery. We used eye-tracking to assess attentional biases during free viewing of food versus nonfood cues, assessed pleasantness ratings of food cues, and self-reported food craving. RESULTS After LSG, the mean BMI of patients was 36.4 ± 6.0 kg/m², and the percentage of excess weight loss (%EWL) was 46.6% ± 14.0%. Six months after LSG, patients showed an attentional bias toward nonfood cues compared with presurgery, reported lower food craving, and rated presented food stimuli as less pleasant. CONCLUSION Evidence of altered food cue processing was found in patients after LSG, which may be interpreted as reduced food reward associated with increased cognitive control. Surgery-induced physiologic, cognitive-motivational, and behavioral changes may lead to a desensitization of the reward system and enhanced cognitive control.

Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity

Gastrointestinal hormone release and the regulation of appetite and body weight are thought to be dysbalanced in obesity. However, human data investigating the expression of gastrointestinal hormones in the obese are rare. We studied the expression of ghrelin, leptin, and the serotonergic system in stomach tissue and serum of obese and non‐obese individuals.