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Title:Pre-, pro-, and synbiotic modulation of the intestinal microbiota stimulates enteroendocrine mediated intestinal adaptation in piglets with short-bowel syndrome
Author(s):Loman, Brett Richard
Director of Research:Tappenden, Kelly
Doctoral Committee Chair(s):Swanson, Kelly
Doctoral Committee Member(s):Donovan, Sharon; Miller, Michael
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):short-bowel syndrome
intestinal failure
probiotic
prebiotic
synbiotic
short-chain fatty acid
butyrate
lactate
glucagon-like peptide 2
dipeptidyl-peptidase 4
microbiota
Abstract:Short-bowel syndrome (SBS) is a costly condition primarily affecting very low birth weight, premature infants with long-term detriment to nutritional adequacy and quality of life. Necrotizing enterocolitis (NEC) -the primary cause of surgical resection leading to pediatric SBS- has an ill-defined etiology that is associated with intestinal microbial dysbiosis, defined by altered intestinal microbiota, decreased bacterial diversity, and antibiotic use. SBS is associated with an enteroendocrine cascade beginning with intestinal secretion of glucagon-like peptide-2 (GLP-2), an intestinotrophic hormone, stimulating innate intestinal adaptation. Treatments such as prebiotics and probiotics that increase luminal production of short-chain fatty acids (SCFA), especially butyrate, could further enhance this process through stimulating higher secretion of GLP-2 from enteroendocrine L-cells. Hence, manipulation of the intestinal microbiota is a logical target for the treatment of NEC and SBS, given its ability to produce butyrate and other SCFA through microbial syntrophy. In this series of studies, we: 1) Identified key existing information related to the etiology, treatment, and physiology related to SBS and the intestinal microbiota (literature review) 2) Investigated potential interactions between abundances of ileal and colonic butyrate and lactate-producing bacterial populations and their modulation of intestinal nutrient transport 3) Determined the associations between changes in the intestinal microbiota, intestinal epithelium, and enteroendocrine system related to intestinal adaptation in the distal ileum and proximal colon 4) Identified key traits that differentiated our four treatment groups utilizing linear discriminant analysis, and developed statistical models that could identify which variables accounted for changes in specific structural and functional adaptations using multiple linear regression. Studies 2-4 were conducted within the same group of piglets receiving an 80% ileojejunal resection, receiving 80% of their nutritional needs via parenteral nutrition and 20% of their needs via enteral nutrition, supplemented with: [1] nothing, control (CON); [2] 10g/L short-chain fructooligosaccharide (scFOS), prebiotic (PRE); [3] 109 colony forming units Lactobacillus rhamnosus GG (LGG), probiotic (PRO); OR [4] scFOS + LGG. Treatments with scFOS were associated with increased chao1 alpha diversity (P = 0.0427) and increased butyrate-producing bacteria in the ileal digesta (P = 0.04) (as measured by 16s, V3-V5 DNA sequencing), which was associated with increased electrogenic glucose absorption as measured ex vivo in modified Ussing chambers (R2 = 0.477, P = 0.0529). The probiotic, LGG, primarily colonized the ileal digesta where it increased total Lactobacillus (all P = 0.04). Specifically, PRO increased D-lactate producing Lactobacillus (P = 0.0712) with negative effects on ileal peptide absorption (R2 = -0.485, P = 0.0567). L-cell density, as assessed by immunofluorescence, did not differ between treatments in the ileum (P = 0.602) or the colon (P = 0.4319), but L-cell density was higher in the ileum vs the colon (P = 0.0003). mRNA expression of primary GLP-2 signaling elements was enhanced by PRE in the ileum. Most notably, PRE decreased expression of Dipeptidyl-peptidase 4 (P = 0.0027). mRNA expression of secondary GLP-2 signaling elements was diminished by PRO in the colon. Treatments with scFOS (PRE and SYN) decreased abundance of bacterial species detrimental to GLP-2 signaling, including Enterococcus faecalis (P = 0.04) and Escherichia coli E851/71 (P = 0.01). Three linear models were generated to predict ileal villus height (R2 adjusted = 0.890, 0.793, and 0.753; all P < 0.001) two linear models were generated to predict colonic electrogenic glutamine transport (R2 adjusted = 0.815 and 0.655; both P < 0.001), and one LDA was conducted to differentiate between treatment groups for each the ileum and the colon (all groups completely differentiated with 100% confidence and P < 0.0001). Overall, this data demonstrates that overabundance of Lactobacillus, especially those that produce D-lactate, contraindicates the use of LGG with scFOS as a synbiotic combination. The increase in total butyrate-producers and glucose absorption associated with scFOS reinforces its potential usefulness in the treatment of SBS. Furthermore, the associated increase in butyrate may enhance primary GLP-2 signaling through altered gene expression and decreasing abundance of detrimental bacterial species, highly contributing to predictions of enhanced structural and functional adaptation in the ileum and colon.
Issue Date:2017-04-21
Type:Thesis
URI:http://hdl.handle.net/2142/97617
Rights Information:Copyright 2017 Brett R Loman
Date Available in IDEALS:2017-08-10
Date Deposited:2017-05


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