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Propositions 1. the Gut Commensal Akkermansia Muciniphila Expands Its Glycolytic Repertoire to Human Milk Oligosaccharides Util

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Propositions 1. the Gut Commensal Akkermansia Muciniphila Expands Its Glycolytic Repertoire to Human Milk Oligosaccharides Util Propositions 1. The gut commensal Akkermansia muciniphila expands its glycolytic repertoire to human milk oligosaccharides utilization. (this thesis) 2. Mucolytic activity is essential for A. muciniphila to survive in the complex gut ecosystem. (this thesis) 3. Human gut microbiome is considered as “the invisible organ” (Li, et al. 2020), however its contribution to human’s health is not acknowledged the same as the visible ones. 4. Science is always playing with your sanity. 5. As a PhD student multi-tasking can be your best friend but also your worst enemy. 6. Humans should use learnings from bacterial collaborations in complex ecosystems to make this planet a better place. Belonging to the thesis entitled: “Mucin and Human milk oligosaccharides utilization: a strategy of Akkermansia muciniphila to ensure survival in the human gut” Ioannis Kostopoulos Wageningen, January 8th 2020 a strategy of of a strategy utilization: Milk Oligosaccharides Human Mucin and Mucin and Human Milk Oligosaccharides INVITATION utilization: a strategy of Akkermansia Akkermansia muciniphila Akkermansia muciniphila to ensure survival in the human gut You are kindly invited to attend the public defense of my PhD thesis Ioannis Kostopoulos Mucin and Human Milk Oligosaccharides utilization: a strategy of to ensure survival in the human gut human in the survival ensure to Akkermansia muciniphila to ensure survival in the human gut Friday, 8th January 2020 at 16:00 Aula of Wageningen University & Research General Foulkesweg 1A Wageningen Ioannis Kostopoulos [email protected] Paranymphs Prokopis Konstanti [email protected] Steven Aalvink [email protected] Ioannis Kostopoulos Ioannis Mucin and Human Milk Oligosaccharides utilization: a strategy of Akkermansia muciniphila to ensure survival in the human gut Ioannis Kostopoulos Thesis committee Promotor Prof. dr Jan Knol Special Chair Intestinal Microbiology of Early Life Laboratory of Microbiology Wageningen University & Research Co-Promotor Dr Clara Belzer Associate Professor, Microbiology Laboratory of Microbiology Wageningen University & Research Other members Prof. dr T. Abee, Wageningen University & Research Prof. dr D. van Sinderen, University College Cork, Ireland Dr W.T. Steegenga, Wageningen University & Research Dr K. Strijbis, Utrecht University This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences) Mucin and Human Milk Oligosaccharides utilization: a strategy of Akkermansia muciniphila to ensure survival in the human gut Ioannis Kostopoulos Thesis submitted in fulfillment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. dr A. P. J. Mol, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 8 January 2021 at 4 p.m. in the Aula Ioannis Kostopoulos Mucin and Human Milk Oligosaccharides utilization: a strategy of Akkermansia muciniphila to ensure survival in the human gut. 302 pages PhD thesis, Wageningen University, Wageningen, the Netherlands (2021) With references, with summaries in English and Dutch ISBN: 978-94-6395-552-2 DOI: https://doi.org/10.18174/531651 Table of contents Chapter 1 General introduction and Thesis outline 7 Chapter 2 Akkermansia muciniphila in the Human Gastrointestinal Tract: 31 When, Where and How? Chapter 3 Akkermansia muciniphila used Human Milk Oligosaccharides to 63 thrive in the early life conditions in vitro Chapter 4 A continuous battle for host-derived glycans in the gut between 101 a mucus specialist and a glycan generalist in vitro and in vivo Chapter 5 Minimalist Approach for Deciphering the Ecophysiology of 131 Human Gut Microbes Chapter 6 The main functions of key species Akkermansia muciniphila 177 remain stable across different microbial ecosystems Chapter 7 General discussion 199 Thesis Summary 213 Nederlandse Samenvatting 219 References 225 Appendices 287 Co-author affiliations 288 Acknowledgments 289 About the author 299 List of Publications 300 Overview of completed training activities 301 5 Chapter 1 General introduction and Thesis outline Chapter 1 General Introduction and Thesis Outline General Introduction This thesis describes the ability of Akkermansia muciniphila to survive in competitive ecological environments through its capacity to utilize and degrade host-derived glycans, such as mucins and Human Milk Oligosaccharides (HMOs). Furthermore, this thesis examines A. muciniphila’s capacity to survive in competitive environments by degrading mucin glycans. In this thesis, the microbe-to-microbe interaction between A. muciniphila and other glycan-degrading bacteria is also discussed. This bacterium is the focus of this thesis. A. muciniphila is a mucin-degrading colonizer of the gastrointestinal (GI) tract and was first isolated at the Laboratory of Microbiology at Wageningen University (Derrien et al. 2004). Akkermansia’s name is named after Dr. Antoon Akkermans, who led the Microbial Ecology group of the Laboratory of Microbiology at Wageningen University at the time that A. muciniphila was isolated (Derrien et al. 2004). The establishment of the gut microbiota The human gut harbours a complex and diverse bacterial community known as the gut microbiota (Dethlefsen, McFall-Ngai, and Relman 2007), which plays an important role in the balance between health and disease. The intestinal microbiota consists of approximately 500 to 1000 species that belong to only few of the known bacteria phyla. The most abundant phyla in the human gut are Firmicutes and Bacteroidetes, but also include members of the phyla Proteobacteria, Verrucomicrobia, Actinobacteria, Fusobacteria, and Cyanobacteria (Huttenhower et al. 2012; Qin et al. 2010). The establishment of the human gut microbiota starts at birth, when microbes rapidly colonize the infant gut, although the composition and diversity only stabilize after seven years in humans (Bäckhed et al. 2015; Yatsunenko et al. 2012). The microbiota composition is influenced by numerous factors such as delivery mode, administration of antibiotics to the infant or the mother, mode of feeding (breastfeeding and/or formula) and the intake of dietary fibre (Bergström et al. 2014). The development of the microbiota in early life is important, as this period is critical in shaping the host’s long-term metabolic, immunological and neurological development (Kundu et al. 2017; Thompson 2012). The mode of delivery has a significant effect on the development of the microbial ecosystem in neonates (Van den Abbeele et al. 2019). Initial microbial exposure during vaginal delivery predominately originates from the maternal 8 Chapter 1 General Introduction and Thesis Outline microbiota, while exposure upon caesarean delivery is related to the environment (Lennox-King et al. 1976a, 1976b). The desirable transmission of vaginal and gut microbiota from mother to infant is observed in vaginally delivered infants during birth, but this is not the case in caesarean-delivered infants (Dominguez-Bello et al. 2016). In general, Escherichia coli and Streptococcus spp. are the first bacterial species to colonize the gastrointestinal tract of neonates. These facultative anaerobes create an optimal environment for the subsequent colonization by obligate anaerobes such as Bacteroides spp., Bifidobacterium spp., and Clostridium spp. Apart from the delivery mode, another factor that contributes significantly to the development of the gut microflora is the intake of dietary fibre (glycans) into the intestine, mostly from diet and host mucosal secretions (Koropatkin, Cameron, and Martens 2012). The dietary fibre passes undigested to the human intestine because of the lack of hydrolytic enzymes in the human genome (Koropatkin, Cameron, and Martens 2012). Gut bacteria utilise and transform these indigestible glycans into short- chain fatty acids (SCFAs), which serve as nutrients for colonocytes and other gut epithelial cells (Koropatkin, Cameron, and Martens 2012). Human intestinal microbiota, therefore, plays a significant symbiotic role in helping humans access and utilise the indigestible dietary fibre. Glycan-degrading bacteria in the intestine have various glycan preferences. Therefore, selective consumption of these nutrients can influence the composition and balance of the gut microbiota (Koropatkin, Cameron, and Martens 2012). Switching from HMOs to mucin glycans The acquisition of a stable intestinal microbial community during the first months of life constitutes a critical developmental window (L. M. Cox et al. 2014). Distinct faecal microbial compositions differ between infants fed with human milk and those fed with formula. The microbiota of breastfed infants, for example, is characterised by high levels of Actinobacteria (mainly bifidobacteria) and low microbial diversity (Koropatkin, Cameron, and Martens 2012). Mother’s milk is the only source of nutrients and dietary glycans for breastfed infants, and it is considered the best nourishment for the development of the new-born (Neville et al. 2012). The glycans in human milk are known as HMOs, and they have proven to influence infant intestinal microbiota composition (Koropatkin, Cameron, and Martens 2012). Human milk contains 5-15 g/L HMOs, with more than 200 different HMO structures reported, of 9 Chapter 1 General Introduction and Thesis Outline which 100 have been successfully described (Ninonuevo et al. 2006; Ruiz-Palacios et al. 2003; Stahl
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