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Characterization of the Role of Host and Dietary Factors in the Establishment of Bacteria in the Gastrointestinal Tract Janina A

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Characterization of the Role of Host and Dietary Factors in the Establishment of Bacteria in the Gastrointestinal Tract Janina A University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Dissertations and Theses in Biological Sciences Biological Sciences, School of Summer 8-2016 Characterization of the Role of Host and Dietary Factors in the Establishment of Bacteria in the Gastrointestinal Tract Janina A. Krumbeck University of Nebraska - Lincoln, [email protected] Follow this and additional works at: http://digitalcommons.unl.edu/bioscidiss Part of the Biology Commons, Dietetics and Clinical Nutrition Commons, and the Microbiology Commons Krumbeck, Janina A., "Characterization of the Role of Host and Dietary Factors in the Establishment of Bacteria in the Gastrointestinal Tract" (2016). Dissertations and Theses in Biological Sciences. 87. http://digitalcommons.unl.edu/bioscidiss/87 This Article is brought to you for free and open access by the Biological Sciences, School of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Dissertations and Theses in Biological Sciences by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Characterization of the Role of Host and Dietary Factors in the Establishment of Bacteria in the Gastrointestinal Tract by Janina A. Krumbeck A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy Major: Biological Sciences (Genetics Cell & Molecular Biology) Under the Supervision of Professors Robert W. Hutkins and Jens Walter Lincoln, Nebraska August, 2016 Characterization of the Role of Host and Dietary Factors in the Establishment of Bacteria in the Gastrointestinal Tract Janina A. Krumbeck, Ph.D. University of Nebraska, 2016 Advisors: Robert W. Hutkins and Jens Walter Probiotic bacteria and synbiotics are used as therapeutic and prophylactic agents. The majority of probiotic and synbiotic applications contain bacterial strains that are allochthonous to the human gastrointestinal (GI) tract. Accordingly, many bacterial strains do not survive digestion, or are not capable of persisting and competing the resident gut microbiota, and are therefore washed out of the GI tract shortly after the treatment is discontinued. This might reduce the health effects of these treatments. Therefore, research is needed to address the ecological challenges that probiotic strains encounter in the GI tract in order to develop probiotic regimens. Determining which ecological factors are limiting the colonization of bacteria remains a challenge. To gain insight into the complex interplay between host and microbe, we chose Lactobacillus reuteri and its rodent host as a model to investigate which genes of L. reuteri contribute to tolerance towards host gastric acid secretion. We established the urease cluster as the predominant factor in mediating resistance to gastric acid, and a mutation of this cluster resulted in substantially decreased population levels of L. reuteri in mice. Secondly, we established a method to select for synergistic synbiotic combinations. Based on in vivo selection (IVS), autochthonous putative probiotic strains are enriched in the GI tract of subjects by the continued consumption of a prebiotic. We used IVS to select a strain of Bifidobacterium adolescentis that became enriched in a human feeding trail with galactooligosaccharides (GOS). Here we have shown that the synbiotic combination of Bifidobacterium adolescentis IVS-1 and GOS significantly enriched for the putative probiotic component in rats. IVS-1 became the most dominant operational taxonomic unit in the GI tract, outcompeting the resident Bifidobacterium species. Similarly, we tested this synbiotic in a human trial with obese adults. In this random, placebo-controlled parallel arm study, the synbiotic combination of IVS-1 and GOS led to establishment of IVS-1 in significantly higher numbers in the GI tract than a commercial synbiotic. Together, the studies presented in this dissertation allowed new insights into the colonization factors of a true GI symbiont, which could contribute to the development of improved probiotics, and provided novel insight into a rational selection of probiotics and synbiotics. iv ACKNOWLEDGEMENTS I would like to send my greatest appreciation to my two advisors Dr. Hutkins and Dr. Walter. Your guidance, patience, support, and advice were invaluable to me throughout these years at the University of Nebraska, Lincoln. You both have been indispensable in your contribution to these projects and my professional and personal development. Thank you. I would like to thank Dr. Harris for all his help and advice during the rat study. I would also like to thank the other members of my committee, Drs. Brown and Moriyama, for their valuable advice throughout my pursuit of this degree. Your input has helped me to develop as a scientist and improved my work. Thanks to Dr. Peterson, Dr. Ramer-Tait, Robert Schmaltz, and Brandon White for their help in the mouse facility. Thank you Dr. Marsteller for spending countless hours gavaging mice for me and all your help during the mouse experiments, and thank you Dr. Frese for training me in the lab and all your substantial contributions to the mouse study. Without all of you the mouse study would not have been possible. Special thanks to Dr. Keshavarzian and Dr. Rasmussen at the Rush University Medical Center in Chicago and all the people in their team for their efforts conducting the human study and their support. Without their engagement it would have not been possible to conduct this trial. Special thanks to my friends and laboratory colleagues of the Walter and Hutkins Labs, who shared their knowledge with me. It has been great sharing all these years with you. Thank you Dr. Martinez for training me in bioinformatics, and to Dr. Maldonado- Gomez for her development of strain specific primers and help in statistical analyses. To all my friends in Germany, thank you for always making me feel like I have never left, you all are so special to me. Thank you to my friends in Lincoln, and especially Nathan, you have made these four years so special to me. I would have not accomplished any of this without the love and endless support of my family. You are so dear to my heart, thank you for always supporting me no matter what. v PREFACE This dissertation is comprised of five chapters. Chapter 1 focuses on the current literature on synbiotic applications, with an emphasis on clinical studies. In particular, the claimed health benefits of synbiotic applications and the implications of recent studies on future design of synbiotics to promote gastrointestinal health are addressed. Chapter 2 describes our published research on the ecological role of genes that mediate acid resistance in Lactobacillus reuteri during colonization of the rodent gastrointestinal tract (Krumbeck et al. 2015). In Chapter 3 our published work on the novel concept of in vivo selection is introduced, which can be applied to identify bacterial strains that possess enhanced ecological performance in synbiotic applications (Krumbeck et al. 2015). Chapter 4 describes the results of a human clinical trial that applied a synbiotic combination that has been selected by in vivo selection. Finally, Chapter 5 provides a conclusion that summarizes the findings provided in this thesis. vi Table of Contents List of Figures . xii List of Tables. xv Chapter 1 Recent developments on formulating synbiotics to improve gastrointestinal health . 1 1.1 Purpose of review . 1 1.2 Introduction . 1 1.3 Functional importance of the colonic microbiota . 2 1.4 Addressing intestinal health with pro-, pre- and synbiotics . 5 1.5 Synbiotic concepts . 7 1.6 Synbiotics and their outcome on human health in clinical studies . 12 1.7 Commercial synbiotics: recent developments and future prospects . 38 1.8 Remaining questions and specific aims . 40 1.9 References . 43 Chapter 2 Characterization of the ecological role of genes mediating acid resistance in Lactobacillus reuteri during colonization of the gastrointestinal tract . 71 2.1 Summary . 71 2.2 Introduction . 72 vii 2.3 Results . 74 2.3.1 Selection of genes of L. reuteri 100-23 predicted to be involved in acid resistance . 74 2.3.2 In vitro characterization of putative acid resistance genes . 77 2.3.3 Importance of acid resistance genes during colonization of the mouse GI tract . 80 2.3.4 Urease activity is regulated by pH . 83 2.4 Discussion . 86 2.5 Experimental procedures ethics statement . 93 2.5.1 Bacterial strains and media used in the study . 93 2.5.2 Determination of genes predicted to be involved in acid resistance of L. reuteri 100-23 . 94 2.5.3 Derivation of mutants. 94 2.5.4 In vitro acid survival assay . 95 2.5.5 Determination of genes’ role in in vivo acid resistance. 95 2.5.6 Determination of pH regulation of urease activity . 97 2.5.7 Measurement of urease activity . 97 2.5.8 RNA extraction from L. reuteri cell cultures . 98 viii 2.5.9 Determination of gene expression by quantitative reverse transcription PCR (qRT-PCR) . 99 2.5.10 Statistical analysis . 100 2.6 Acknowledgements . 100 2.7 References . 101 Chapter 3 In vivo selection to identify bacterial strains with enhanced ecological performance in synbiotic applications . 110 3.1 Abstract . 111 3.2 Introduction . 112 3.3 Materials and methods . 114 3.3.1 Isolation of in vivo-enriched bifidobacteria from humans . 114 3.3.2 In vitro growth on GOS . 115 3.3.3. Strain-specific primer design and validation . 115 3.3.4 Quantitative real-time PCR . 117 3.3.5 Administration of the probiotic, prebiotic, and synbiotic to rats 117 3.3.6 Rat study design . 118 3.3.7 Evaluation of host physiological parameters in rats . 119 ix 3.3.8 Illumina 16S RNA sequencing and sequence analysis . 120 3.3.9 Microbial community analysis . 121 3.3.10 Statistical analysis . 122 3.3.11 Nucleotide sequence accession number . 123 3.4 Results . 123 3.4.1 In vivo selection of B.
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