Efficacy of butyrate-producing therapies for use in pediatric intestinal failure

intestinal failure;butyrate;intestinal adaptation;prebiotics;probiotics

Barnes, Jennifer

关键词: intestinal failure;    butyrate;    intestinal adaptation;    prebiotics;    probiotics;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/44789/Jennifer_Barnes.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

In 2011, preterm births accounted for approximately 12% of all births in the United States (1).Preterm infants have an immature gastrointestinal tract and are at increased risk of developing necrotizing enterocolitis, which may result in intestinal resection, intestinal failure (IF) and dependence on parenteral nutrition (PN).Exclusive PN therapy results in intestinal atrophy (2, 3) and long-term use increases risk for serious complications.PN supplemented with butyrate, a 4-carbon short chain fatty acid (SCFA) produced in vivo by bacterial fermentation, stimulates structural and functional adaptation of the residual gastrointestinal tract following small bowel resection (4).Intestinal adaptation is critical for successful PN weaning; however, butyrate is not currently added to PN formulations due to its undesirable chemical properties. The central hypothesis of this research is that strategic pre- and probiotic supplementation can be a clinically feasible means of delivering butyrate and stimulating intestinal adaptations in a pediatric IF model.Our first experiment aimed to determine whether prebiotic and/or probiotic supplementation could serve as a clinically feasible means of providing butyrate to the residual intestine and assess structural and functional adaptations.Neonatal piglets (48 hours old, n=87) underwent placement of a jugular catheter, an 80% jejunoileal resection and were randomized to one of the following treatment groups: 1) control (20% standard enteral nutrition (EN)/80% standard PN); 2) control plus prebiotic (10 g short chain fructooligosaccharides (scFOS)/L EN); 3) control plus probiotic (1 x 109 CFU Lactobacillus rhamnosus GG (LGG)), or; 4) control plus synbiotic (scFOS + LGG) (5).Animals received infusions for 24 hours to assess acute adaptations and 3 or 7 days to assess chronic adaptations.Dependent variables of intestinal adaptation including gross morphology, cellular composition, mucosal architecture, epithelial cellular kinetics, disaccharidase activity, nutrient transport, and glucagon-like peptide-2 (GLP-2) were assessed.Prebiotic treatment increased ileal mucosa weight compared to all other treatments (P= 0.017) and ileal protein compared to control (P= 0.049), regardless of day. Ileal villus length increased in the prebiotic and synbiotic groups (P= 0.011), regardless of day, specifically due to an increase in epithelial proliferation (P= 0.003).Epithelial proliferation was also increased with prebiotic and synbiotic treatments in the duodenum (P= 0004), residual jejunum (P< 0.0001), and colon (P= 0.0007).Apoptosis was decreased with prebiotic and synbiotic treatments in the jejunum (P= 0.030) and ileum (P= 0.004). Cdx-2 mRNA expression, a marker of differentiation, was unchanged in the jejunum but increased with scFOS in the ileum (P= 0.033).In the 7 day prebiotic group, peptide transport was up-regulated in the jejunum (P= 0.026) whereas glutamine transport was increased in both the jejunum and colon (P= 0.001 and 0.003, respectively).Disaccharidase activity was not affected by treatment in any intestinal segment.Glucagon-like peptide-2, a hormonal mediator of intestinal adaptation (6), was not impacted by treatment.We concluded that prebiotic and/or synbiotic supplementation resulted in enhanced structure and function throughout the residual intestine but that LGG was ineffective.In addition, the signaling mechanism mediating these adaptations was not identified.Our next experiment aimed to investigate possible signaling mechanisms through the intestinal epithelium resulting in intestinal adaptations.We hypothesized that prebiotic supplementation would increase colon luminal butyrate concentration, SCFA transporters MCT1 and SMCT1 and G-protein SCFA receptors FFAR2 and FFAR3 mRNA expression in the ileum and colon of IF piglets.Prebiotic supplementation was associated with increased butyrate concentrations compared to control, independent of time (P= 0.050), while other SCFA or lactate did not differ.Total acetate, propionate, and butyrate concentration tended to increase after 3 days of synbiotic treatment (P= 0.078).Ileal MCT1 and SMCT1 mRNA increased in prebiotic, probiotic, and synbiotic groups compared to control after 24 hours of treatment (P= 0.012 and 0.014).Ileal FFAR2 and FFAR3 mRNA were greatest in the prebiotic and probiotic group compared to control after 24 hours of treatment (P= 0.013 and 0.008).After 3 days of treatment, synbiotic-supplemented animals had greater mRNA expression of MCT1, FFAR2, and FFAR3 in the ileum (P= 0.004, 0.017, and 0.039).On day 7, ileal MCT1 mRNA was greater in control, pre-, and probiotic treatments compared to synbiotic treatment (P= 0.004). Seven days of treatment was also associated with greater expression of ileal FFAR2 and FFAR3 with probiotic treatment compared to prebiotic and synbiotic but similar to control (P= 0.025 and 0.004).Colon mRNA levels were not as significantly impacted by treatment.This investigation suggests that treatment may acutely influence expression of SCFA transporters and receptors and is a potential regulatory mechanism for butyrate-associated intestinal adaptation.Butyrate-stimulated intestinal adaptation is also associated with an increase in expression of the facilitative glucose transporter 2, GLUT2 (7-9).We hypothesized that scFOS administration would be associated with an increased mRNA expression of GLUT2 and the sweet taste receptor T1R3.Jejunal GLUT2 mRNA expression was greater after control and probiotic treatments compared to prebiotic treatment on day 3 (P= 0.034), while ileal GLUT2 mRNA was not different at any individual time point.On day 3, jejunal T1R3 mRNA was increased (P= 0.049) in control animals compared to prebiotic and synbiotic treatments but was similar to probiotic.The 24 hour and 7 day time points were not statistically different in the jejunum.In the ileum, 24 hours of prebiotic or probiotic treatment tended to result in greater T1R3 mRNA compared to control (P= 0.054).On day 3 in the ileum, control piglets expressed greater T1R3 mRNA compared to probiotic treatment (P= 0.056).By day 7, probiotic piglets had greater ileal T1R3 expression compared to prebiotic and synbiotic groups while control was greater than synbiotic (P< 0.001).Jejunal T1R3 mRNA expression did not differ after 24 hours or 7 days of treatment.After 3 days of treatment, control piglets expressed a significantly greater amount of T1R3 mRNA in the jejunum compared to synbiotic piglets (P= 0.049).Main treatment effects for T1R3 did not differ in the jejunum (P= 0.239) or the ileum (P= 0.120).Jejunal and ileal GLUT2 mRNA was not statistically different when time points were pooled within treatment (P= 0.166 and 0.446, respectively).Overall, GLUT2 mRNA expression was not impacted by treatment while T1R3 expression was associated with treatment but this was not reflected in GLUT2 mRNA expression.This suggests that T1R3 expression was not regulating GLUT2 expression in this model.In summary, scFOS but not LGG, administration is associated with increased butyrate concentrations and intestinal adaptation in a neonatal piglet model of IF. SCFA receptor and transporter gene expression may an important acute signaling mechanism for these adaptations.Identification of a synergistic prebiotic and probiotic combination may enhance the promising results obtained with prebiotic treatment alone.