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Non-Digestible Polysaccharides to Support the Intestinal Immune Barrier: in Vitro Models to Unravel Molecular Mechanisms

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Non-Digestible Polysaccharides to Support the Intestinal Immune Barrier: in Vitro Models to Unravel Molecular Mechanisms Non - digestible polysaccharides to support the intestinal immune barrier: Non-digestible polysaccharides to support the intestinal immune barrier: in vitro models to unravel molecular mechanisms Yongfu Tang in in vitro models to unravel molecular M cell mechanisms Yongfu 2017 Tang Macrophage Propositions: 1. To support the immune system by dietary fibers, one should eat whole grain food. (this thesis) 2. Fibers steer macrophages. (this thesis) 3. Artificial intelligence is smarter than humans. 4. Plants have an adaptive immune system. (Spoel et al., Nature Reviews Immunology. 2012. 12(2): 89-100) 5. Amyloid-ß peptide protects the brain. (Kumar et al., Science Translational Medicine. 2016. 8(340): 340ra72) 6. To be yourself, select food smartly, otherwise you will be controlled by microbiota. 7. A guaranteed result of research is that it leads to new scientific questions. Propositions belonging to the thesis, entitled: Non-digestible polysaccharides to support the intestinal immune barrier: in vitro models to unravel molecular mechanisms Yongfu Tang Wageningen, 18 December 2017 Non-digestible polysaccharides to support the intestinal immune barrier: in vitro models to unravel molecular mechanisms Yongfu Tang Thesis committee Promotors Prof. Dr H.J. Wichers Special Professor Immune modulation by food Wageningen University & Research Co-promotors Dr J.J. Mes Senior Scientist, Fresh Food & Chains Wageningen University & Research Dr C.C.F.M. Govers Scientist, Fresh Food & Chains Wageningen University & Research Other members Prof. Dr R. F. Witkamp, Wageningen University & Research Dr F. Liu, The University of Texas Health Science Center at Houston, USA Dr W. Chanput, Kasetsart University, Thailand Dr C. Soler Rivas, Universidad Autonoma de Madrid, Spain This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Non-digestible polysaccharides to support the intestinal immune barrier: in vitro models to unravel molecular mechanisms Yongfu Tang Thesis submitted in fulfilment 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 Monday 18 December 2017 at 11 a.m. in the Aula. Yongfu Tang Non-digestible polysaccharides to support the intestinal immune barrier: in vitro models to unravel molecular mechanisms 168 pages. PhD thesis, Wageningen University, Wageningen, the Netherlands (2017) With references, with summary in English ISBN: 978-94-6343-713-4 DOI: 10.18174/425674 For my family Table of contents Chapter 1 General introduction 9 Chapter 2 Microarray analysis of Caco-2 exposed to non-digestible 27 polysaccharides reveals differential regulation of immune and cholesterol-related genes Chapter 3 Non-digestible polysaccharide treated macrophages 57 demonstrate a transcriptionally unique subtype Chapter 4 Human macrophages stimulated with non-digestible 85 polysaccharides are in function and chemokine production different from inflammatory and tolerant macrophages Chapter 5 Macrophage plasticity is modulated by non-digestible 109 polysaccharides Chapter 6 General discussion 137 Summary 155 Acknowledgements 159 About the author 163 Chapter 1 General introduction Chapter 1 Intestinal immune barrier The intestine has an intestinal immune barrier which is composed of, firstly, the epithelial barrier that is formed by a single layer of intestinal epithelial cells (IECs) composed of various cell lineages, such as enterocytes, enteroendocrine cells, Paneth cells, goblet cells, and Microfold cells (M cells), all differentiated from a common intestinal epithelial stem cells [1]. IECs provide a physical protective barrier for luminal factors harmful/undesired for the body and are involved in regulation of inflammatory processes [2]. IECs can regulate inflammation in response to antigens by secreting cytokines that attract and/or activate immune cells. IECs not only function as barrier but also absorb nutrients and other compounds from the intestinal lumen. This leads to the passage of an enormous number of antigens into the body. These antigens can be derived from commensal microbiota, pathogens, or ingested foods. To respond to these antigens, there is a large body of immune cells present in the intestines that have a gatekeeper function and form a second part of the intestinal immune barrier (Figure 1). These can be found in the lamina propria of the intestine, but also in Peyers paches (PPs), mesenteric lymph nodes (MLNs), colon patches, and appendix. The intestinal immune system includes B cells, T cells, monocytes, macrophages, dendritic cells, and recently discovered innate lymphoid cells (ILCs) [3]. The intestinal homeostatic balance between tolerance and inflammation, requires complex interactions between intestinal microbiota, IECs, and intestinal immune cells. Intestinal homeostasis is jeopardized upon imbalance of tolerance and inflammation, and can lead to intestinal dysfunction. As IECs and macrophages are in the first line of immune defense, their response towards food components is pivotal to analyze the immunomodulatory effects of foods. Intestinal epithelial cells The intestinal epithelium is the largest surface of the human body. Often, its surface is described as approximately 300 m2, but recent estimates are more in the order of 30 m2 [4]. The principal function of IECs is that of absorptive enterocytes, to process and absorb nutrients to serve metabolic and digestive functions. Besides that, it also serves as a physical barrier that aids in maintaining intestinal homeostasis. IECs form an essential part of immunity, by maintaining the integrity, and through secretion of mucins by goblet cells, antimicrobial proteins by Paneth cells, and transcytosis of IgA after secretion by plasma cells [5]. IECs also express Toll-like receptors (TLRs) that respond to LPS, LPA, or flagellin which are pathogen-associated molecular patterns (PAMPs) from 10 General introduction microorganisms [6]. TLR2 and TLR4 are reported to be limitedly expressed by IECs. However, when intestinal damage induces inflammatory stress, TLR2 stimulation effectively preserves tight junction integrity and controls intestinal inflammation [7]. Mucosal inflammation and apoptosis in colitis were suppressed by oral TLR2 ligand treatment which resulted in restoring tight junction-associated barrier [7]. In addition, it was shown that TLR2 could be activated by a dietary fibre (Inulin β 2→1-fructans) [8]. Small intestine Villus Commensal Lumen bacteria Goblet cell Enterocyte M cell Dendritic cell M1 T cell B cell Crypt IgA Lamina propria Innate lymphoid cell Epithelial stem cell Enteroendocrine cell Paneth cell Antimicrobial proteins Muscularis propria M2 Figure 1. The intestinal immune barrier is composed of an epithelial barrier formed by various cell types with immune cells residing in the lamina propria, Peyer’s path, mesenteric lymph nodes, colon patches, and appendix (Adapted and modified from [9]). M cells as specialized IECs, sample antigens and interact with microbiota to communicate with immune cells. These immune cells are concentrated in Peyer’s patches. In addition, IECs recognize and integrate signals from the luminal side to intestinal immune cells [10] by secreting cytokines and chemokines that in turn modulate cytokine production by immune cells [11, 12]. Cytokines produced by the IECs in a steady-status function as anti- inflammatory and include TSLP, TGFβ, IL8, CCL20, CXCL10, IL18, IL33, and IL37. Those anti- 11 Chapter 1 inflammatory cytokines are important to maintain immune tolerance, wound healing and also to recruit monocytes, neutrophils, eosinophils, lymphocytes, T cells, B cells, macrophages, and dendritic cells [11, 13, 14]. Specifically the role of TSLP in maintaining immune homeostasis by IEC that attenuate inflammation status and promote anti- inflammation is important, since TSLP secretion could inhibit IL12 production by DCs and activates Th2 polarizing cells [15]. Intestinal macrophages Macrophages are described as one of the largest populations of cells which function in maintaining intestinal immune barrier [16]. Macrophages can be differentiated from monocytes in response to antigens presented by IECs or other immune cells [17]. In the steady state, these signals will be anti-inflammatory, produced by the IECs that are in close contact with the macrophages and resident Treg cells. This will lead to tolerant macrophages. In inflammatory status, those anti-inflammatory signals are reduced and inflammatory signals are produced which lead to inflammatory macrophages. Macrophages work as effector cells of the intestinal innate immune system. The contact between macrophages and IECs includes numerous immunoregulatory signals. This contact is in part mediated by the interaction of IECs and microbiota [18]. Through those interactions, macrophages direct the appropriate innate and adaptive immune cell responses and limited intestinal inflammation [19]. Two extreme phenotypes have been described for macrophages, and termed as classical macrophages (inflammatory macrophages or M1) [20] or alternative macrophages (tolerant macrophages or M2) [21]. Based on the most recent insights, an even larger variation of macrophage phenotypes has been described with an almost infinite continuum between the two most extremes. Therefore, it was suggested to indicate specific
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