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.

18F-FDG uptake in the colon is modulated by metformin but not associated with core body temperature and energy expenditure.

PURPOSE: Physiological colonic 18F-fluorodeoxyglucose (18F-FDG) uptake is a frequent finding on 18F-FDG positron emission tomography computed tomography (PET-CT). Interestingly, metformin, a glucose lowering drug associated with moderate weight loss, is also associated with an increased colonic 18F-FDG uptake. Consequently, increased colonic glucose use might partly explain the weight losing effect of metformin when this results in an increased energy expenditure and/or core body temperature. Therefore, we aimed to determine whether metformin modifies the metabolic activity of the colon by increasing glucose uptake. METHODS: In this open label, non-randomized, prospective mechanistic study, we included eight lean and eight overweight males. We measured colonic 18F-FDG uptake on PET-CT, energy expenditure and core body temperature before and after the use of metformin. The maximal colonic 18F-FDG uptake was measured in 5 separate segments (caecum, colon ascendens,-transversum,-descendens and sigmoid). RESULTS: The maximal colonic 18F-FDG uptake increased significantly in all separate segments after the use of metformin. There was no significant difference in energy expenditure or core body temperature after the use of metformin. There was no correlation between maximal colonic 18F-FDG uptake and energy expenditure or core body temperature. CONCLUSION: Metformin significantly increases colonic 18F-FDG uptake, but this increased uptake is not associated with an increase in energy expenditure or core body temperature. Although the colon might be an important site of the glucose plasma lowering actions of metformin, this mechanism of action does not explain directly any associated weight loss.

Epidemiology, recognition and documentation of sepsis in the pre-hospital setting and associated clinical outcomes: a prospective multicenter study.

INTRODUCTION: General practitioners (GPs) and the emergency medical services (EMS) personnel have a pivotal role as points of entry into the acute care chain. This study was conducted to investigate the recognition of sepsis by GPs and EMS personnel and to evaluate the associations between recognition of sepsis in the pre-hospital setting and patient outcomes. Methods Design: prospective, observational study during a 12 week period in the emergency department (ED) of two academic hospitals. STUDY POPULATION: Patients >18 years presenting with sepsis at the ED. The information available in the ED discharge letter and the ED charts was used to make a definite diagnosis of sepsis, severe sepsis and septic shock Outcome measures: primary: recognition/documentation of sepsis. Secondary: ED arrival time to antibiotic administration, in-hospital mortality, hospital length of stay (LOS) and intensive care unit (ICU) admission. RESULTS: A total of 301 patients were included in the study. GPs and EMS personnel correctly identified and documented 31.6% (n=114) and 41.4% of all sepsis patients (n=140) respectively. Recognition and documentation of sepsis improved with increasing severity. The mean time to administration of antibiotics (TTA) was nearly halved for the group of patients where sepsis was documented (GP: 66,4 minutes, EMS: 65,6 minutes) compared to the group in which sepsis was not documented (GP: 123,9 minutes, EMS: 101,5 minutes; p: 0.365 and p: 0.024 respectively). Conclusions There is room for improvement in the recognition of sepsis, severe sepsis and septic shock by practitioners working in the pre-hospital setting. Documentation of sepsis prior to arrival in hospital led to a reduced time delay in administration of antibiotics.

Interobserver and intraobserver variability for the assessment of brown adipose tissue activity on 18F-FDG PET-CT.

OBJECTIVE: Measurement of brown adipose tissue (BAT) activity is the focus of intensive research, among others as a potential target for weight-lowering strategies. In this, BAT activity is visualized and quantified using F-fluorodeoxyglucose (F-FDG) PET-CT. The aim of this study was to determine the interobserver and intraobserver variability for detecting and quantifying BAT on F-FDG PET-CTs. METHODS: Three observers retrospectively independently assessed 55 F-FDG PET-CTs (performed between April 2013 and January 2014) for BAT activity parameters: BAT volume, the maximal and mean standardized uptake value (SUVmax and SUVmean) obtained in healthy male controls. One observer reassessed the scans after 2 months for the intraobserver variability. Interobserver and intraobserver variability were expressed using Lin's concordance coefficient (LCC) and Bland-Altman plots. Correlations between the three parameters were assessed using Spearman's correlation. RESULTS: The LCCs for the interobserver and intraobserver concordance for SUVmax were the highest (LCC SUVmax varied between 0.998 and 0.999, for SUVmean between 0.989 and 0.991 and for volume between 0.947 and 0.972). The Bland-Altman analysis showed a small absolute mean difference between all observers for both SUVmax and SUVmean, but the differences for volume were markedly higher. All parameters correlated statistically strongly and positively. CONCLUSION: The SUVmax showed the lowest interobserver and intraobserver variation. Although SUVmean and BAT volume had a higher interobserver and intraobserver variation, the variation is still within acceptable limits. Therefore, all parameters can be used to describe BAT activity. However, for an adequate comparison between studies, we recommend the use of SUVmax.

Effects of T3 treatment on brown adipose tissue and energy expenditure in a patient with craniopharyngioma and hypothalamic obesity.

OBJECTIVE: Patients treated for childhood craniopharyngioma often develop hypothalamic obesity (HO), which has a huge impact on the physical condition and quality of life of these patients. Treatment for HO thus far has been disappointing, and although several different strategies have been attempted, all interventions had only transient effects. Since thyroid hormones increase energy expenditure metabolism (thyroid hormone induced thermogenesis), it was speculated that treatment with tri-iodothyronine (T3) may be beneficial. In 2002, a case report was published on reduction of body weight after T3 treatment for HO. No studies have been reported since. Recent experimental studies in rodents showed that T3 increases brown adipose tissue (BAT) activity via (pre)sympathetic pathways between the hypothalamus and BAT. Our aim was to investigate whether T3 treatment increases BAT activity in a patient with HO resulting from (treatment of) childhood craniopharyngioma. METHODS: Thyroxine treatment for central hypothyroidism was switched to T3 monotherapy. Serum T3 and free thyroxine (FT4) concentrations were measured twice weekly for 2 months. ¹²³I-MIBG and ¹8F-FDG-PET after induction of non-shivering thermogenesis for the assessment of sympathetic and metabolic activity of BAT as well as indirect calorimetry for assessment of resting energy expenditure were performed before and during T3 treatment. RESULTS: No change in sympathetic and metabolic BAT activity, energy expenditure, or BMI was seen during T3 treatment despite the expected changes in thyroid hormone plasma concentrations. CONCLUSION: We conclude that T3 monotherapy does not seem to be effective in decreasing HO in childhood craniopharyngioma.

Combining 123I-metaiodobenzylguanidine SPECT/CT and 18F-FDG PET/CT for the assessment of brown adipose tissue activity in humans during cold exposure.

UNLABELLED: Brown adipose tissue (BAT) has become a focus of research in the hope of finding a new target to fight obesity. Metabolic BAT activity can be visualized with (18)F-FDG PET/CT. Furthermore, the sympathetic innervation of BAT can be visualized with the radiolabeled norepinephrine analog (123)I-metaiodobenzylguanidine ((123)I-MIBG). We aimed to determine whether (123)I-MIBG SPECT/CT and (18)F-FDG PET/CT identify the same anatomic regions as active BAT in adult humans. Furthermore, we investigated whether the magnitude of BAT activity measured by these techniques correlated. Finally, we tried to establish the optimal time interval between (123)I-MIBG administration and subsequent SPECT/CT acquisition to visualize sympathetic stimulation of BAT. METHODS: Ten lean (body mass index, 19-25 kg/m(2)), healthy Caucasian men (age, 18-32 y) underwent one (18)F-FDG PET/CT and two (123)I-MIBG-SPECT/CT scans within a 2-wk interval. On 2 separate occasions, the subjects were exposed to mild cold (17°C) for 2 h after an overnight fast. After 1 h of cold exposure, (18)F-FDG (one occasion) or (123)I-MIBG (other occasion) was administered. (18)F-FDG PET/CT was performed at 1 h after (18)F-FDG administration, and (123)I-MIBG-SPECT/CT was performed at 4 and 24 h after (123)I-MIBG injection. RESULTS: (18)F-FDG uptake in BAT was observed in 8 of 10 subjects, whereas (123)I-MIBG uptake was observed in 7 of 10 subjects in both the SPECT/CT scans acquired at 4 h after (123)I-MIBG administration and the SPECT/CT scans acquired at 24 h after (123)I-MIBG administration. All subjects who showed (123)I-MIBG uptake in BAT also showed (18)F-FDG uptake in BAT. There was no statistically significant correlation between maximal standardized uptake value of (18)F-FDG and semiquantitative uptake of (123)I-MIBG at 4 h after administration. However, a positive correlation was found between the maximal standardized uptake value of (18)F-FDG and semiquantitative uptake of (123)I-MIBG at 24 h after administration (r = 0.64, P = 0.04). CONCLUSION: (123)I-MIBG SPECT/CT, as a marker of sympathetic activity, and (18)F-FDG PET/CT, as a marker of metabolic activity, identified the same anatomic regions as active BAT. Moreover, when (123)I-MIBG SPECT/CT was performed at 24 h after (123)I-MIBG administration, the magnitude of BAT activity measured with these techniques correlated strongly. This finding not only supports that BAT activity in humans is sympathetically influenced but also identifies (123)I-MIBG SPECT/CT, when performed 24 h after (123)I-MIBG injection, as a method to visualize and quantify sympathetic stimulation of BAT.