Disruption of lateral hypothalamic calorie detection by a free choice high fat diet.

During the last few decades, the consumption of low-calorie sweeteners, as a substitute for caloric sweeteners, has sharply increased. Although research shows that caloric versus low-calorie sweeteners can have differential effects on the brain, it is unknown which neuronal populations are responsible for detecting the difference between the two types of sweeteners. Using in vivo two-photon calcium imaging, we investigated how drinking sucrose or sucralose (a low-calorie sweetener) affects the activity of glutamatergic neurons in the lateral hypothalamus. Furthermore, we explored the consequences of consuming a free-choice high fat diet on the calorie detection abilities of these glutamatergic neurons. We found that glutamatergic neurons indeed can discriminate sucrose from water and sucralose, and that consumption of a free-choice high fat diet shifts the glutamatergic neuronal response from sucrose-specific to sucralose-specific, thereby disrupting calorie detection. These results highlight the disruptive effects of a diet high in saturated fat on calorie detection in the lateral hypothalamus.

The Clash of Two Epidemics: the Relationship Between Opioids and Glucose Metabolism.

PURPOSE OF REVIEW: We are currently in the midst of a global opioid epidemic. Opioids affect many physiological processes, but one side effect that is not often taken into consideration is the opioid-induced alteration in blood glucose levels. RECENT FINDINGS: This review shows that the vast majority of studies report that opioid stimulation increases blood glucose levels. In addition, plasma levels of the endogenous opioid ß-endorphin rise in response to low blood glucose. In contrast, in hyperglycaemic baseline conditions such as in patients with type 2 diabetes mellitus (T2DM), opioid stimulation lowers blood glucose levels. Furthermore, obesity itself alters sensitivity to opioids, changes opioid receptor expression and increases plasma ß-endorphin levels. Thus, opioid stimulation can have various side effects on glycaemia that should be taken into consideration upon prescribing opioid-based medication, and more research is needed to unravel the interaction between obesity, glycaemia and opioid use.

Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake.

Objective: To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)-mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage. Approach and Results: Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI- mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI-mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI-mediated HDL-C uptake is unknown. Differentiated cells from Ldlr-/-/Pcpe2-/- (Pcpe2-/-) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake compared to Ldlr-/- (control) adipose tissue. SR-BI-mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans. Conclusions: Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women.

Retinol-binding protein-4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity-induced insulin resistance and correlates inversely with insulin-stimulated glucose disposal. But its role in insulin-mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux-en-Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin-mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4-activated macrophages markedly increased basal lipolysis and impaired insulin-mediated lipolysis suppression. RBP4 treatment of macrophages increased TNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro-inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed to determine whether this mechanism explains RBP4-induced insulin resistance in humans.

Effects of a Hypercaloric and Hypocaloric Diet on Insulin-Induced Microvascular Recruitment, Glucose Uptake, and Lipolysis in Healthy Lean Men.

OBJECTIVE: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis. Approach and Results: Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after the hypercaloric diet in study participants and controls (n=5). The hypercaloric diet increased body weight (3.5 kg; P<0.001) and fat percentage (3.5%; P<0.001) but did not affect glucose uptake nor lipolysis. The hypercaloric diet increased adipose tissue microvascular recruitment (P=0.041) and decreased the ratio between skeletal muscle and adipose tissue microvascular blood volume during hyperinsulinemia (P=0.019). Insulin-induced vasodilation of isolated skeletal muscle arterioles was significantly lower in participants compared with controls (P<0.001). The hypocaloric diet reversed all of these changes, except the increase in adipose tissue microvascular recruitment. CONCLUSIONS: In lean men, short-term overfeeding reduces insulin-induced vasodilation of skeletal muscle resistance arteries and shifts the distribution of tissue perfusion during hyperinsulinemia from skeletal muscle to adipose tissue without affecting glucose uptake and lipolysis. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02628301.

The Role of the Gut Microbiota in the Gut-Brain Axis in Obesity: Mechanisms and Future Implications.

Interaction between the gut and the brain is essential for energy homeostasis. In obesity, this homeostasis is disrupted, leading to a positive energy balance and weight gain. Obesity is a global epidemic that affects individual health and strains the socioeconomic system. Microbial dysbiosis has long been reported in obesity and obesity-related disorders. More recent literature has focused on the interaction of the gut microbiota and its metabolites on human brain and behavior. Developing strategies that target the gut microbiota could be a future approach for the treatment of obesity. Here, we review the microbiota-gut-brain axis and possible therapeutic options.

Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time.

OBJECTIVE: Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects. DESIGN: Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks. RESULTS: We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa. CONCLUSION: Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects. TRIAL REGISTRATION NUMBER: NTR4327.

Intravenous supplementation type and volume are associated with 1-year outcome and major complications in patients with chronic intestinal failure.

BACKGROUND AND AIM: No marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity. METHODS: At baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as <1, 1-2, 2-3 and >3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI). RESULTS: Fifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN <1 L/day than for FE and all PN >1 L/day), patients' death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2-3 and PN >3 L/day). CONCLUSIONS: The type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.

Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders.

PURPOSE OF REVIEW: The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. RECENT FINDINGS: In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients.

The effect of dapagliflozin on apolipoprotein B and glucose fluxes in patients with type 2 diabetes and well-controlled plasma LDL cholesterol.

AIM: To dissect the effects of the sodium-glucose linked transporter 2 inhibitor dapagliflozin on lipid metabolism and assess whether these effects could potentially offset cardiovascular benefit with this drug-class. MATERIALS AND METHODS: We assessed the effect of dapagliflozin on lipid metabolism in 11 adults with uncomplicated type 2 diabetes. After 4 weeks of statin wash-out and 4 weeks of rosuvastatin 10 mg treatment, participants were treated with dapagliflozin 10 mg once-daily for 5 weeks. Before and after dapagliflozin, plasma lipids were measured and very low-density lipoprotein (VLDL)-1 and VLDL-2 apolipoprotein (Apo)B fluxes were assessed using (5.5.5-2 H3 )-leucine tracer infusion. In addition, hepatic and peripheral insulin sensitivity as well as insulin-mediated inhibition of peripheral lipolysis were measured during a two-step hyperinsulinemic-euglycaemic clamp using (6,6-2 H2 )-glucose and (1,1,2,3,3-2 H5 )-glycerol tracers. RESULTS: Rosuvastatin decreased all plasma lipids significantly: total cholesterol from 4.5 (3.2-6.2) to 3.1 (2.5-3.8) mmol/L, LDL cholesterol from 2.6 (1.7-3.4) to 1.5 (1.1-2.2) mmol/L, HDL cholesterol from 1.34 (0.80-2.02) to 1.19 (0.74-1.89) mmol/L and triglycerides from 0.92 (0.31-3.91) to 0.79 (0.32-2.10) mmol/L. The addition of dapaglifozin to rosuvastatin did not raise either LDL cholesterol or total cholesterol, and only increased HDL cholesterol by 0.08 (-0.03-0.13) mmol/L (P = 0.03). In line with this, dapagliflozin did not affect VLDL-1 or VLDL-2 ApoB fluxes. Fasting endogenous glucose production tended to increase by 0.9 (-3.4-3.1) µmol kg-1 min-1 (P = 0.06), but no effect on hepatic and peripheral insulin sensitivity or on peripheral lipolysis was observed. CONCLUSIONS: Dapagliflozin has no effect on plasma LDL-cholesterol levels or VLDL-apoB fluxes in the context of optimal lipid-lowering treatment, which will thus not limit cardiovascular benefit when lipids are adequately controlled.

Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD.

To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding.

Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these neurotransmitter systems. We studied the effect of a 4 wk hypocaloric diet with either 50% of daily calories consumed at breakfast (BF group) or at dinner (D group) on hypothalamic and thalamic serotonin transporter (SERT) binding and on striatal dopamine transporter (DAT) binding. The BF and D groups lost a similar amount of weight. Striatal DAT and thalamic SERT binding increased in the BF group, while decreasing in the D group after the diet (ΔDAT 0.37 ± 0.63 vs. -0.53 ± 0.77, respectively; P = 0.005; ΔSERT 0.12 ± 0.25 vs. -0.13 ± 0.26 respectively, P = 0.032). Additional voxel-based analysis showed an increase in DAT binding in the ventral striatum in the BF group and a decrease in the dorsal striatum in the D group. During weight loss, striatal DAT and thalamic SERT binding increased weight independently when 50% of daily calories were consumed at breakfast, whereas it decreased when caloric intake was highest at dinner. These findings may contribute to the earlier reported favorable effect of meal timing on weight maintenance after hypocaloric diets.-Versteeg, R. I., Schrantee, A., Adriaanse, S. M., Unmehopa, U. A., Booij, J., Reneman, L., Fliers, E., la Fleur, S. E., Serlie, M. J. Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding.

Iloprost infusion prevents the insulin-induced reduction in skeletal muscle microvascular blood volume but does not enhance peripheral glucose uptake in type 2 diabetic patients.

AIMS: In type 2 diabetes impaired insulin-induced muscle perfusion is thought to contribute to reduced whole-body glucose uptake. In this study, we examined the effects of iloprost, a stable prostacyclin analogue, on insulin-induced muscle capillary recruitment and whole-body glucose uptake. MATERIALS AND METHODS: In a randomized cross-over design, 12 type 2 diabetes patients (age, 55 [46-69] years; BMI, 33.1 [31.0-39] kg/m2 ) underwent two hyperinsulinaemic-euglycaemic clamps, one with and one without simultaneous low-dose iloprost infusion. Contrast-enhanced ultrasonography of the vastus lateralis muscle was performed before and during the clamp. Muscle capillary recruitment was calculated as percentage change in microvascular blood volume (MBV) before and during the clamp. RESULTS: Insulin infusion reduced skeletal muscle MBV by ~50% compared to the fasting state (fasting, 1.77·10-4 [1.54·10-5 -2.44·10-3 ] arbitrary units (AU); hyperinsulinaemia, 6.69·10-5 [2.68·10-6 -5.72·10-4 ] AU; P = 0.050). Infusion of iloprost prevented this insulin-induced skeletal muscle capillary derecruitment, from (-49.5 [-89.5 to 55.3] %) to (8.0 [-68.8 to 306.6] %), for conditions without and with iloprost, respectively. The rate of glucose disappearance (Rd ) did not change significantly during iloprost infusion (17.3 [10.0-40.8] µmol/kg/min) compared with insulin infusion alone (17.6 [9.9-68.7] µmol/kg/min). CONCLUSIONS: Our data suggest that acute improvement in insulin-stimulated muscle perfusion is not an attractive therapeutic approach to bypass cellular resistance to glucose uptake in type 2 diabetes. Whether long-term improvements in insulin-induced muscle perfusion may prove beneficial for glucose disposal remains to be determined.

A Systematic Review and Meta-analysis of Timing and Outcome of Intestinal Failure Surgery in Patients with Enteric Fistula.

BACKGROUND: The timing of intestinal failure (IF) surgery has changed. Most specialized centers now recommend postponing reconstructive surgery for enteric fistula and emphasize that abdominal sepsis has to be resolved and the patient's condition improved. Our aim was to study the outcome of postponed surgery, to identify risk factors for recurrence and mortality, and to define more precisely the optimal timing of reconstructive surgery. METHODS: PubMed, Embase, and the Cochrane Library were systematically reviewed on the outcomes of reconstructive IF surgery (fistula recurrence, mortality, morbidity, hernia recurrence, total closure, enteral autonomy). If appropriate, meta-analyses were performed. Optimal timing was explored, and risk factors for recurrence and mortality were identified. RESULTS: Fifteen studies were included. The weighted pooled fistula recurrence rate was 19% (95% CI 15-24). Lower recurrence rates were found in studies with a longer median time and/or, at the minimum of the range, a longer time interval to surgery. Overall mortality was 3% (95% CI 2-5). Total fistula closure rates ranged from 80 to 97%. Enteral autonomy after reconstructive surgery, mentioned in four studies, varied between 79 and 100%. CONCLUSIONS: Postponed IF surgery for enteric fistula is associated with lower recurrence. Due to the wide range of time to definitive surgery within each study, optimal timing of surgery could not be defined from published data.

Serotonin Transporter Binding in the Diencephalon Is Reduced in Insulin-Resistant Obese Humans.

BACKGROUND: Altered brain dopaminergic and serotonergic pathways have been shown in obese rodents and humans, but it is unknown whether this is related to obesity per se or to the metabolic derangements associated with obesity. METHODS: We performed a case-control study in insulin-sensitive obese (ISO) and insulin-resistant obese (IRO) subjects (n = 12) and age-matched lean controls (n = 8) and measured serotonin transporter (SERT) binding in the whole diencephalon and specifically in the hypothalamus, as well as dopamine transporter (DAT) binding in the striatum using 123I- FP-CIT single-photon emission computed tomography. We assessed insulin sensitivity using the homeostatic model assessment of insulin resistance. RESULTS: BMI did not differ between the IRO and ISO subjects. SERT binding in the diencephalon was significantly lower in IRO than in ISO subjects, but was not different between lean and obese subjects. SERT binding in the hypothalamus tended to be reduced in obese versus lean subjects, but was not different between IRO and ISO subjects. Striatal DAT binding was similar between lean and obese subjects as well as between ISO and IRO subjects. CONCLUSIONS: We conclude that SERT binding in the diencephalon is reduced in insulin-resistant subjects independently of body weight, while hypothalamic SERT binding tends to be lower in obesity, with no difference between insulin-resistant and insulin-sensitive subjects. This suggests that the metabolic perturbations associated with obesity independently affect SERT binding within the diencephalon.

Hypercaloric diets with increased meal frequency, but not meal size, increase intrahepatic triglycerides: a randomized controlled trial.

UNLABELLED: American children consume up to 27% of calories from high-fat and high-sugar snacks. Both sugar and fat consumption have been implicated as a cause of hepatic steatosis and obesity but the effect of meal pattern is largely understudied. We hypothesized that a high meal frequency, compared to consuming large meals, is detrimental in the accumulation of intrahepatic and abdominal fat. To test this hypothesis, we randomized 36 lean, healthy men to a 40% hypercaloric diet for 6 weeks or a eucaloric control diet and measured intrahepatic triglyceride content (IHTG) using proton magnetic resonance spectroscopy ((1) H-MRS), abdominal fat using magnetic resonance imaging (MRI), and insulin sensitivity using a hyperinsulinemic euglycemic clamp with a glucose isotope tracer before and after the diet intervention. The caloric surplus consisted of fat and sugar (high-fat-high-sugar; HFHS) or sugar only (high-sugar; HS) and was consumed together with, or between, the three main meals, thereby increasing meal size or meal frequency. All hypercaloric diets similarly increased body mass index (BMI). Increasing meal frequency significantly increased IHTG (HFHS mean relative increase of 45%; P = 0.016 and HS mean relative increase of 110%; P = 0.047), whereas increasing meal size did not (2-way analysis of variance [ANOVA] size versus frequency P = 0.03). Abdominal fat increased in the HFHS-frequency group (+63.3 ± 42.8 mL; P = 0.004) and tended to increase in the HS-frequency group (+46.5 ± 50.7 mL; P = 0.08). Hepatic insulin sensitivity tended to decrease in the HFHS-frequency group while peripheral insulin sensitivity was not affected. CONCLUSION: A hypercaloric diet with high meal frequency increased IHTG and abdominal fat independent of caloric content and body weight gain, whereas increasing meal size did not. This study suggests that snacking, a common feature in the Western diet, independently contributes to hepatic steatosis and obesity. ( TRIAL REGISTRATION: www.clinicaltrials.gov; nr.NCT01297738.)

Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity.

BACKGROUND & AIMS: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS: Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters. CONCLUSIONS: Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566).

Challenges in Providing an Overview of Results of Intermittent Fasting Interventions on Diabetes Parameters. Comment on Silva et al. Effects of Intermittent Fasting on Regulation of Metabolic Homeostasis: A Systematic Review and Meta-Analysis in Health and Metabolic-Related Disorders. J. Clin. Med. 2023, 12, 3699.

We hereby comment on the systematic review "Effects of Intermittent Fasting on Regulation of Metabolic Homeostasis: A Systematic Review and Meta-Analysis in Health and Metabolic-Related Disorders" by Silva et al [...].

Clinical trial: The effectiveness of long-acting somatostatin analogue for output reduction of high-output intestinal fistula or small bowel enterostomy. A randomised controlled trial.

BACKGROUND: High-output intestinal fistulas and small bowel enterostomies are associated with morbidity and mortality. Current standard treatment for output reduction consists of fluid and dietary restrictions and medical therapy. There is conflicting evidence regarding the use of somatostatin analogues for output reduction. AIM: The aim of this study is to investigate whether lanreotide, added to current standard treatment, further reduces intestinal output in patients with high-output fistulas and enterostomies. METHODS: This was an open-label, multicentre, randomised controlled trial. Adult patients with a high-output intestinal fistula (>500 mL/24 h) or small bowel enterostomy (>1500 mL/24 h) more than 4 weeks post-surgery and receiving standard medical treatment (dietary- and fluid restriction, PPI, loperamide and codeine) for at least 2 weeks were eligible for inclusion. We randomised patients 1:1 between continuing standard treatment (control), and subcutaneous lanreotide 120 mg every 4 weeks with standard treatment. The primary outcome was the number of responders, with response defined as an output reduction of ≥25%, 8 weeks after randomisation. We also investigated the proportional change in output. RESULTS: We randomised 40 patients; 17 had a fistula and 23 a small bowel enterostomy. There were 9/20 responders in the intervention group and 2/20 in the control group (p = 0.013). The proportional output reduction was -26% (IQR -4 to -38) in the intervention group, compared to an increase of 4% (IQR 20 to -13) in the control group (p = 0.004). CONCLUSIONS: In patients with a high-output fistula or small bowel enterostomy, addition of lanreotide to current standard treatment can provide a clinically relevant output reduction. TRIAL REGISTRATION: EudraCT: 2013-003998-10.

The effect of active vitamin D supplementation on body weight and composition: A meta-analysis of individual participant data.

BACKGROUND & AIMS: Obesity is associated with vitamin D (VitD) deficiency. However, previous studies showed mixed effects of VitD (25-hydroxyVitD/calcidiol) supplementation on body weight. The biological actions of VitD require the hydroxylation of inactive VitD into active VitD (1.25-dihydroxyVitD/calcitriol). This step is highly regulated; therefore, supplementing with inactive VitD might not be sufficient to overcome the potential adverse health effects of VitD deficiency. The objective of this study was to conduct a systematic review and individual participant data (IPD) meta-analysis of data acquired from randomised placebo-controlled calcitriol trials (RCTs) to determine the effects of calcitriol on body weight and weight-related parameters. METHODS: Studies were identified from MEDLINE, EMBASE, and CENTRAL databases up to January 27, 2024, and excluded those involving dialysis or cancer patients. We obtained IPD from eligible trials and assessed bias using the Cochrane Collaboration risk-of-bias tool and methodological quality using the Heyland Methodological Quality Score. The study was prospectively registered with PROSPERO (CRD42017076202). RESULTS: Although none of the studies reported information regarding our primary objective, we obtained IPD for 411 patients, with 206 randomised to receive calcitriol and 205 to placebo. This dataset enabled us to conduct an IPD meta-analysis with 17,084 person-months of follow-up (median: 11 months). Meta-analysis showed that calcitriol does not alter body weight, BMI, waist circumference, fat mass or lean body mass compared to placebo. Adjusting for age and sex did not alter the outcomes. CONCLUSIONS: In conclusion, this systematic review and IPD meta-analysis indicate that calcitriol does not affect body weight in normal-weight postmenopausal women and lean patients with type 1 diabetes nor in people suffering from obesity, type 2 diabetes and chronic kidney disease. Whether calcitriol lowers body weight in VitD-sufficient people with obesity remains to be elucidated.