Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy improves lipid and glucose homeostasis in ob/ob mice.

OBJECTIVE: The objective of this study was to compare the general and metabolic impact of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) with Roux-en-Y gastric bypass (RYGB) in an obese (ob/ob) mouse model. METHODS: 10-week-old male ob/ob mice underwent either SADI-S, RYGB, or laparotomy surgery (Sham group). General and metabolic parameters were assessed during a 5-week period thereafter. RESULTS: SADI-S induced a deeper weight loss ([mean ± SEM] -41.2% ± 3.3%) than RYGB (-5.6% ± 3.5%, p < 0.001) compared with the Sham group (+6.3% ± 1.0%, p < 0.05). A significant food restriction was observed after SADI-S only (-31%, 117.4 ± 10.3 g vs. 170.2 ± 5.2 g of food at day 35 in Sham group mice, p < 0.001). Random-fed glycemia and glucose tolerance were more improved after SADI-S than RYGB. SADI-S decreased plasma cholesterol concentration by 60% (0.49 ± 0.04 g/L vs. 1.40 ± 0.10 g/L in the Sham group at day 35, p < 0.01), significantly more than RYGB (1.04 ± 0.14 g/L, p = 0.018). Plasma sitosterol/cholesterol and campesterol/cholesterol ratios were decreased after SADI-S, suggesting a reduced intestinal cholesterol absorption. SADI-S increased exogenous plasma cholesterol-D7 clearance and fecal elimination, also indicating an increased plasma cholesterol excretion. Studying a pair-fed group demonstrated that calorie restriction alone did not explain the beneficial impact of SADI-S. CONCLUSIONS: SADI-S is associated with a greater improvement in lipid and glucose homeostasis than RYGB in ob/ob mice.

Late-Stage Glioma Is Associated with Deleterious Alteration of Gut Bacterial Metabolites in Mice.

Brain-gut axis refers to the bidirectional functional connection between the brain and the gut, which sustains vital functions for vertebrates. This connection also underlies the gastrointestinal (GI) comorbidities associated with brain disorders. Using a mouse model of glioma, based on the orthotopic injection of GL261 cell line in syngeneic C57BL6 mice, we show that late-stage glioma is associated with GI functional alteration and with a shift in the level of some bacterial metabolites in the cecum. By performing cecal content transfer experiments, we further show that cancer-associated alteration in cecal metabolites is involved in end-stage disease progression. Antibiotic treatment results in a slight but significant delay in mice death and a shift in the proportion of myeloid cells in the brain tumor environment. This work rationally considers microbiota modulating strategies in the clinical management of patients with late-stage glioma.

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly.

OBJECTIVE: To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations. Approach and Results: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [LDLR] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9-gain-of-function and familial hypercholesterolemia-LDLR groups compared with controls and PCSK9-loss-of-function groups (14±12 versus 5±4 mg/dL; P=0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9-loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated (r=0.50; P<0.05). ApoE-to-apolipoprotein (a) molar ratios in Lp(a) increased with plasma Lp(a) (r=0.96; P<0.001) but not with PCSK9 levels. Extended-release niacin-induced reductions in Lp(a) and VLDL-apoE absolute production rate were correlated (r=0.83; P=0.015). In contrast, PCSK9 reduction (-35%; P=0.008) was only correlated with that of VLDL-apoE absolute production rate (r=0.79; P=0.028). CONCLUSIONS: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate.

Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.

Comparison of gas chromatography-mass spectrometry and gas chromatography-combustion-isotope ratio mass spectrometry analysis for in vivo estimates of metabolic fluxes.

Gas chromatography-mass spectrometry (GC-MS) was compared with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) for measurements of cholesterol (13)C enrichment after infusion of labeled precursor ([(13)C1,2]acetate). Paired results were significantly correlated, although GC-MS was less accurate than GC-C-IRMS for higher enrichments. Nevertheless, only GC-MS was able to provide information on isotopologue distribution, bringing new insights to lipid metabolism. Therefore, we assessed the isotopologue distribution of cholesterol in humans and dogs known to present contrasted cholesterol metabolic pathways. The labeled tracer incorporation was different in both species, highlighting the subsidiarity of GC-MS and GC-C-IRMS to analyze in vivo stable isotope studies.