RISE IN PLASMA BILE ACIDS FOLLOWING HYPOABSORPTIVE BARIATRIC SURGERIES PREDICT BENEFICIAL METABOLIC AND HOMEOSTATIC OUTCOMES IN MALE RATS.

The effects of three hypoabsorptive bariatric surgeries, Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S), on bile acids (BAs) were assessed including the changes in BA plasma levels associated with the metabolic and homeostatic effects of the surgeries. Male Wistar rats, etheir fed high- (HF) or a low-fat (LF) diets, were divided into seven groups: RYGB HF, BPD-DS HF, SADI-S HF, sleeve-gastrectomy (SG) HF, sham-operation (SHAM) HF, SHAM LF and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). The rats were treated 56 days. The results demonstrate the ability of RYGB, BPD-DS and SADI-S to raise plasma levels of BAs, whose elevations, most notably those of the secondary BAs (deoxycholic acid, ursodooxycholic acid and lithocholic acid) associated negatively with body weight gain, fat gain and fasting insulin levels and positively with plasma peptide tyrosine-tyrosine (PYY). Plasma BAs also correlated positively with the fecal levels of Clostridium, Sutterella and Enterobacteriaceae and negatively with Clostridiales_f_g_2, Christensenellaceae, Ruminococcaceae_g_2, Oscillibacter and Oscillospira. Additionally, they associated positively with the short-chain fatty acid (SCFA) levels of propionate, butyrate, isobutyrate, valerate and isovalerate. Altogether, the present study emphasizes the ability of RYGB, BPD-DS and SADI-S to induce circulating BA elevations that predict the beneficial consequences of those hypoabsorptive bariatric surgeries on energy and glucose homeostasis and circulating levels of PYY. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are also linked to significant fat losses and metabolic health improvements.

Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects.

OBJECTIVE: To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. METHODS: Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. RESULTS: BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. CONCLUSIONS: BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.

Consistent gut bacterial and short-chain fatty acid signatures in hypoabsorptive bariatric surgeries correlate with metabolic benefits in rats.

OBJECTIVE: The study aimed at comparing how changes in the gut microbiota are associated to the beneficial effects of the most clinically efficient hypoabsorptive bariatric procedures, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). METHODS: Diet-induced obese (DIO) male Wistar rats were divided into seven groups. In addition to the groups subjected to RYGB, BPD-DS and SADI-S, the following four control groups were included: SHAM-operated rats fed a high-fat diet (SHAM HF), SHAM fed a low-fat diet (SHAM LF), SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW) and sleeve-gastrectomy (SG) rats. Body weight, food intake, glucose tolerance, insulin sensitivity/resistance, and L-cell secretion were assessed. The gut microbiota (16 S ribosomal RNA gene sequencing) as well as the fecal and cæcal contents of short-chain fatty acids (SCFAs) were also analyzed prior to, and after the surgeries. RESULTS: The present study demonstrates the beneficial effect of RYGB, BPD-DS and SADI-S on fat mass gain and glucose metabolism in DIO rats. These benefits were proportional to the effect of the surgeries on food digestibility (BPD-DS > SADI-S > RYGB). Notably, hypoabsorptive surgeries led to consonant microbial signatures characterized by decreased abundance of the Ruminococcaceae (Oscillospira and Ruminococcus), Oscillospiraceae (Oscillibacter) and Christensenellaceae, and increased abundance of the Clostridiaceae (Clostridium), Sutterellaceae (Sutterella) and Enterobacteriaceae. The gut bacteria following hypoabsorptive surgeries were associated with higher fecal levels of propionate, butyrate, isobutyrate and isovalerate. Increases in the fecal SCFAs were in turn positively and strongly correlated with the levels of peptide tyrosine-tyrosine (PYY) and with the beneficial effects of the surgery. CONCLUSION: The present study emphasizes the consistency with which the three major hypoabsorptive bariatric procedures RYGB, BPD-DS and SADI-S create a gut microbial environment capable of producing a SCFA profile favorable to the secretion of PYY and to beneficial metabolic effects.

Alterations of Gut Microbiota After Biliopancreatic Diversion with Duodenal Switch in Wistar Rats.

BACKGROUND: The biliopancreatic diversion with duodenal switch (BPD/DS) represents the most effective surgical procedure for the treatment of severe obesity and associated type 2 diabetes. The mechanisms whereby BPD/DS exerts its positive metabolic effects have however yet to be fully delineated. The objective of this study was to distinguish the effects of the two components of BPD/DS, namely the sleeve gastrectomy (SG) and the DS derivation, on gut microbiota, and to appraise whether changes in microbial composition are linked with surgery-induced metabolic benefits. METHODS: BPD/DS, DS, and SG were performed in Wistar rats fed a standard chow diet. Body weight and energy intake were measured daily during 8 weeks post-surgery, at which time glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY), insulin, and glucose were measured. Fecal samples were collected prior to surgery and at 2 and 8 weeks post-surgery. Intraluminal contents of the alimentary, biliopancreatic, and common limbs (resulting from BPD/DS) were taken from the proximal portion of each limb. Fecal and small intestinal limb samples were analyzed by 16S ribosomal RNA gene sequencing. RESULTS: BPD/DS and DS led to lower digestible energy intake (P = 0.0007 and P = 0.0002, respectively), reduced weight gain (P < 0.0001) and body fat mass (P < 0.0001), improved glucose metabolism, and increased GLP-1 (P = 0.0437, SHAM versus DS) and PYY levels (P < 0.0001). These effects were associated with major alterations of both the fecal and small intestinal microbiota, as revealed by significant decrease in bacterial richness and diversity at 2 (P < 0.0001, Chao1 index; P < 0.0001, Shannon index) and 8 weeks (P = 0.0159, SHAM versus DS, Chao1 index; P = 0.0219, SHAM versus DS, P = 0.0472, SHAM versus BPD/DS, Shannon index) post-surgery in BPD/DS and DS, and increased proportions of Bifidobacteriales (a 60% increase in both groups) but reduced Clostridiales (a 50% decrease and a 90% decrease respectively), which were mostly accounted at the genus level by higher relative abundance of Bifidobacterium in both the fecal and intestinal limb samples, as well as reduced abundance of Peptostreptococcaceae and Clostridiaceae in the small intestine. Those effects were not seen in SG rats. CONCLUSION: The metabolic benefits following BPD/DS are seemingly due to the DS component of the surgery. Furthermore, BPD/DS causes marked alterations in fecal and small intestinal microbiota resulting in reduced bacterial diversity and richness. Our data further suggest that increased abundance of Bifidobacterium and reduced level of two Clostridiales species in the gut microbiota might contribute to the positive metabolic outcomes of BPD/DS.

A new family of secreted toxins in pathogenic Neisseria species.

The genus Neisseria includes both commensal and pathogenic species which are genetically closely related. However, only meningococcus and gonococcus are important human pathogens. Very few toxins are known to be secreted by pathogenic Neisseria species. Recently, toxins secreted via type V secretion system and belonging to the widespread family of contact-dependent inhibition (CDI) toxins have been described in numerous species including meningococcus. In this study, we analyzed loci containing the maf genes in N. meningitidis and N. gonorrhoeae and proposed a novel uniform nomenclature for maf genomic islands (MGIs). We demonstrated that mafB genes encode secreted polymorphic toxins and that genes immediately downstream of mafB encode a specific immunity protein (MafI). We focused on a MafB toxin found in meningococcal strain NEM8013 and characterized its EndoU ribonuclease activity. maf genes represent 2% of the genome of pathogenic Neisseria, and are virtually absent from non-pathogenic species, thus arguing for an important biological role. Indeed, we showed that overexpression of one of the four MafB toxins of strain NEM8013 provides an advantage in competition assays, suggesting a role of maf loci in niche adaptation.