University of Groningen Modulating the immune system and intestinal barrier integrity with functional oligosaccharides Figueroa Lozano, Susana

(1)

University of Groningen

Modulating the immune system and intestinal barrier integrity with functional oligosaccharides

Figueroa Lozano, Susana

DOI:

10.33612/diss.151659844

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date:

2021

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Figueroa Lozano, S. (2021). Modulating the immune system and intestinal barrier integrity with functional

oligosaccharides. University of Groningen. https://doi.org/10.33612/diss.151659844

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

(2)

(3)

Abbreviations

Author affiliations

List of publications

About the author

Acknowledgements

(4)

Abbreviations

2’-FL 2’-fucosyllactose

5-HT Serotonin

bLF Bovine lactoferrin

BMOs Bovine milk oligosaccharides

CHST5 Carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 5 CLCA1 Chloride channel accessory 1

CNS Central nervous system EECs Enteroendocrine cells ENS Enteric nervous system FOS Fructo-oligosaccharides Fuc Fucose FUT2 α1,2 fucosyltransferase FUT3/4 α1,3/1,4 fucosyltransferase Gal Galactose GAL3ST2 Galactose-3-O-sulfotransferase 2 GalNAc N-acetyl-D-galactosamine Glc Glucose GlcNAc N-acetylglucosamine GOS Galacto-oligosaccharides hBD-1,-2, -3 Human beta defensin 1, -2, -3 HD5 Human alpha defensin 5 HD6 Human alpha defensin 6 HEK293 cells Human embryonic kidney cells hLF Human lactoferrin

HMGLs Human milk glycolipids HMGPs Human milk glycoproteins HMOS Human milk oligosaccharides IBD Inflammatory bowel disease IECs intestinal epithelial cells IFNγ Interferon gamma

Lac Lactose

LacdiNAc N,N’-Diacetyllactosamine LAcNac L-Acetyl-D-lactosamine

LDO Lactose-derived oligosaccharides

Le Lewis phenotype

(5)

175

ABBREVIATIONS

8

LPS Lipopolysaccharide

MAGI3 Membrane Associated Guanylate Kinase MFGM Milk fat globule membrane

MLCK Myosin light chain kinase

Mo Monocytes

MoDCs Monocyte-derived dendritic cells

MUC2 Mucin2

MyD88 Myeloid differentiation primary response protein 88 NDCs Non-digestible carbohydrates

NEC Necrotizing enterocolitis Neu5A Sialic acid

Neu5Ac N-acetylneuraminic acid Neu5Gc N-glycolylneuraminic acid

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells NOD2 Nucleotide-binding oligomerization domain-containing protein 2 PBMCs Peripheral blood mononuclear cells

PRRs Pattern recognition receptors RELMβ Resistin-like molecule beta RETNLB Resistin-like molecule beta SCFAs Short-chain fatty acids Se Secretor phenotype

SEAP Secreted embryonic alkaline phosphatase TEER Transepithelial electrical resistance TFF3 Trefoil factor 3

THP1 cells Human acute monocytic leukemia cells TLR-8 Toll-like receptor 8

TLRs Toll-like receptors

TNFα Tumor necrosis factor alpha ZG16 Zymogen granule protein 16

(6)

Author affiliations

Lubbert Dijkhuizen

Chief Scientific Officer

CarbExplore Research BV Groningen, NL

Sander van Leeuwen

Scientist Glycobiology

Department of Laboratory Medicine Cluster Human Nutrition and Health

University Medical Center Groningen (UMCG) Groningen, NL

Wayel Abdulahad

Principal Investigator, Head of Flow Cytometry Unit,

Department of Pathology and Medical Biology Division of Medical Biology

Paul de Vos

Full Professor Immunoendocrinology

Rivca L. Valk-Weeber

Research Technician

Aldena Groningen, NL

(7)

177

AUTHOR AFFILIATIONS

8

Renate Akkerman

PhD student

University Medical Center Groningen (UMCG Groningen, NL

Chengcheng Ren

PhD student

University Medical Center Groningen (UMCG Groningen, NL Huifang Yin Scientist Dupont Shanghai, China Hien Pham R&D Researcher Curesupport Deventer, NL Martin Beukema PhD student

University Medical Center Groningen (UMCG Groningen, NL

(8)

List of publications

2020

Figueroa-Lozano, S., Valk-Weeber, R.L., Akkerman, R., Abdulahad, W., et al., Inhibitory

Effects of Dietary N-Glycans From Bovine Lactoferrin on Toll-Like Receptor 8; Comparing Efficacy With Chloroquine. Front. Immunol. 2020, 11, 1–12

Figueroa-Lozano, S., Ren, C., Yin, H., Pham, H., et al., The Impact of Oligosaccharide

Content, Glycosidic Linkages and Lactose Content of Galacto-Oligosaccharides (GOS) on the Expression of Mucus-Related Genes in Goblet Cells. Food Funct. 2020, 11, 3506-3515

2019

Ren, C., Dokter-Fokkens, J., Figueroa Lozano, S., Zhang, Q., et al.,. Fibroblasts Impact Goblet Cell Responses to Lactic Acid Bacteria After Exposure to Inflammatory Cytokines and Mucus Disruptors. Mol. Nutr. Food Res 2019, 63, 1–13.

Figueroa-Lozano, S., de Vos, P., Relationship Between Oligosaccharides and

Glycoconjugates Content in Human Milk and the Development of the Gut Barrier. Compr.

Rev. Food Sci. Food Saf. 2019, 18, 121-139.

2018

Ren, C., Dokter-Fokkens, J., Figueroa Lozano, S., Zhang, Q., et al., Lactic Acid Bacteria may Impact Intestinal Barrier Function by Modulating Goblet Cells. Mol. Genet. Metab. 2018, 62, 1–14.

Figueroa-Lozano, S., Valk-Weeber, R.L., van Leeuwen, S.S., Dijkhuizen, L., et al., Dietary

N-glycans from Bovine Lactoferrin and TLR Modulation. Mol. Nutr. Food Res. 2018, 62,

1700389.

In preparation

Figueroa-Lozano, S., Akkerman, R., Beukema, M., van Leeuwen, S., Dijkhuizen, L.,

de Vos, P. 2’-Fucosyllactose Impacts the Expression of Mucus-Related Genes in Goblet Cells and Maintains Barrier Function of Gut Epithelial Cells. Molecular Nutrition and Food

(9)

179

LIST OF PUBLICATIONS AND ABOUT THE AUTHOR

8 About the author

I was born in Santafé de Bogotá, Colombia on the 26th October 1978. In 2004 I completed my bachelor in Pharmacy in the Universidad Nacional de Colombia. After finishing my bachelor studies I really wanted to put into practice the knowledge gained during my university years. Therefore, in 2005 I started my professional career as clinical pharmacist in a high complexity hospital. After 3 years in this position I was promoted to manager of the pharmaceutical service. During this time, I started my Msc studies in Epidemiology in the Universidad de Rosario and received my diploma in 2009. Because my horizon expanded into the field of Clinical Research, in 2010, I started a new position as scientist lead in a multinational company that performed studies in clinical cosmetic efficacy. In 2012 I came to the Netherlands to pursue my dream of studying abroad. Two years later, I received my diploma in Master Pharmaceutical Sciences granted by the University of Groningen. In 2015, I started to work in the department of Pathology and Medical Biology as PhD under the supervision of Prof. Paul de Vos. At the moment I work as project manager in PRA, a clinical research organization that perform phase I studies in The Netherlands.

(10)

Acknowledgements

Which is more important? asked the panda, the journey or the destination? The company, said the little dragon.

James Norbury

These years of PhD have enriched my life in many different ways. It is thanks to the people I met during this time that I grew in many aspects of my life. Therefore, here I want to express how much I appreciate and treasure all the lessons I have learned from you. To begin with, I want to thank my promoter, Paul de Vos. Dear Paul, thanks for giving me the opportunity to do my PhD in your research group. I thank you for teaching me about focus, strategy, communication, and structure. Marijke Faas, thank you for the scientific input.

The scientific work presented in this thesis would not being possible without the collaboration with Prof. Lubbert Dijkhuizen and his team: Sander, Rivca, Hien, and Huifang. Dear

Lubbert, thank you for your positive and constructive feedback. Dear Sander, thank you

for the critical analysis you gave me in every meeting and review. Your knowledge about carbohydrates really enriched this project. Dear Rivca, it was really fun to work with you. You are a very kind and smart woman. Thank you all for this great collaboration. I really learned a lot from all of you. We faced many challenges but at the end we all worked it out. To my collaborator within the Pathology and Medical biology, Wayel Abdulahad, thank you for the very constructive, critical and encouraging discussions about TLRs and the dendritic cells experiments. Many things did not go as planned but your knowledge and passion for science motivated me to keep trying and it paid off.

I sincerely thank the members of the reading committee Prof. Henk Schols, Prof.

Lubbert Dijkhuizen, and Prof. Torsten Plosch for taking the time to read and assess

(11)

181

ACKNOWLEDGEMENTS

181

8

To everybody from the Immunoendocrinology group, a big thank you: Bart, Marlies,

Sandra, Gea, Luis, Rei, Chunli, Yu, Xhuxian, Lianghui, Anne, Tom, Neha, Chengcheng, Alexia, Tamara, Genaro, Martin, Yuanrui, and Renate. You all made

these years of work in the lab more fun and rewarding.

I want to specially thank Alexia, for being always a source of laugh and energy. Your humour, spontaneity, and cheerfulness always helped me to go through the tough moments. Chunli, thank you for teaching me how to make moon cakes. It was also super fun to team up as paranymphs. Your comments are so witty and funny, it is never boring when you are around. Yu, you are also such a kind person. I really respect your patience and commitment to science and I wish you lots of success in the future. Roderick, the long hours in the lab had more laughs because of you. Your interest in all kind of documentaries was a source of knowledge and entertainment.

My dear office mates: Yuanrui, Virinchi, Luis, Renate and Martin. I am very glad we shared so much time in the Z9 room. Dear Yuanrui, thank you for your great sense of humour. Although you were very busy, you were always kind and considerate. You are such a sweet, dedicated, and smart person. Dear Virinchi, thank you for bringing your fun sarcasm to the office. I really missed you when you moved out. Dear Luis, thank you for your analytical and constructive input. No matter what, you try to provide solutions to any situation. Dear Renate, I have never met a person with such a fast ability to make calculations and an incredible memory. Most importantly, thank you for being kind, honest, and persistent. Dear Martin, you are such a kind soul. No matter what, you always managed to remain rational and positive and that inspired me many times to keep going. You both know it well, I am so glad that we worked and shared so much time together!.

Ana Maria, thank you for being always kind. Your determination to achieve your goals

was inspiring. Nataly and Rebeca, my dear cangrechiks. It was so amazing to have our coffee breaks and lunch time together. Afterwards I was recharged to keep working. I feel very fortunate that we could laugh so much about our ‘desgracias’.

I met in the research group an incredible group of people that are not anymore in The Netherlands but stay close to my heart. Genaro, you can extract laughs from anyone and get away with your backhanded compliments. I wish I could do that. Thank you for your friendship despite the distance. Tamara-chan, you have the most otaku words of wisdom and solidarity. Thank you for holding my back. We have so many interests in common that we could never stop talking. I am glad we stay in touch. Estas en mi kokoro. Chengcheng, you are such a pure person, you made every day at work a sunny and positive experience. I am very thankful for all the support you gave me. I enjoyed every moment we worked together. We have such a powerful friendship. Thank you for helping me to complete my

(12)

collection of Changzhou combs and for sharing with me so much of your background, traditions, and culture. Byamba, you were always serene, even stressed you managed to stay centered. Talking with you brought me always great calm and positivity. Thank you

Monica, you are such a strong and sensitive person, thank you for sharing your journey

with me in all the different geographical locations you’ve been to. You always reminded me all those things that keep us connected to our roots and your Moninoticias are the best.

Daniela, you are also incredibly pragmatic. Thank you for all the nice talks.

I want to thank also to my Colombian friends David, Alejandro and Gabriela. The endless moments of laughter are memorable. Around you I had the feeling to be close again to all the things I love and miss from my country.

My dear friends of GRIN, it was so amazing to work and meet you all through this experience. All this started thanks to Andrea. Andrea, you are so talented at connecting people and so authentic. I am really happy we stay close. I am really glad we crossed roads here in Groningen. Vera, thank you for all the Italian lessons and for having always a creative solution for any challenge. That was always refreshing, whether it was a serious matter or just girly talk. Magda, you are also such an example of determination. It was great to organize activities with you. Floor, your were always kind and considerate. I really enjoyed our talks because you have a very sweet but firm approach to life. Isa, you are the queen of multitasking and networking. Thank you for being so inspiring.

During my PhD I also had to do a lot of paper work and it went better thanks to the help of

Annet, Caroline, and Hans. Hans, thank you for being always helpful. I also appreciate

all the moments in which I could practice speaking Dutch with you.

Also the work in the lab would have not been efficient or constructive without the input of the team of lab technicians. Thank you Timara, Henk, Theo, Henk, Peter, Josée,

Pytrick, Linda, Marja, Marnix, Johan, Geert, Ninke, Anita, and Jelleke. Dear Jelleke,

I worked the most with you and during the working hours you taught me so much. I really appreciate all your guidance and I will never forget that difficult does not mean impossible. My journey would not being complete without my dear friends Emma, Emilia, and

Manuel. Since the moment I arrived in the Netherlands, the three of you have been my

support. Dear Emma, your stress-away philosophy and your pragmatic approach to life has been inspiring. Since day one I admire your intelligence and confidence. Thank you for being my friend and my paranymph. Emilia, thank you for keeping me positive and motivated specially at the end of this PhD. This book would not been possible without your words of encouragement, design input and sweetness. You are not only smart, you heart

(13)

183

ACKNOWLEDGEMENTS

183

8

is pure gold. Dear Manu, your friendship is like food for the soul. I am lucky to have met you here. Thank you for being always critical and kind. And also always the sober person at any party.

Quiero agradecer a mi familia en Colombia. No fue fácil dejar mi vida allí, pero cuando partí, lo hice llena de entusiasmo y determinación. Muchas gracias por haberme dado siempre palabras de amor y confianza. Gracias mama y papa. Mama linda, siempre me inculcaste el amor por aprender, quizas nunca te imaginaste que llegaria literalmente tan lejos… hasta Holanda. Aunque estar separadas geograficamente ha sido mas que duro, nunca nos hemos separado de corazón. Gracias por ser una fuente de amor y de valentia. Se que no ha sido fácil para ti. Pero aqui estoy: aplicando todo lo que me enseñaste.

Diana, a ti te agradezco por siempre llenar mi vida de risas. Nadie puede como tu,

hacerme reir… o llorar. Eres la major hermana del mundo y estoy orgullosa de compartir contigo cada alegria, triunfo, o dia gris. No importa a donde vaya, siempre hay algo que contarte. Ademas siempre quiero comprarte todas las chucherias que veo. Alejo, gracias por tu humor y tu espiritu noble. Cada vez que hablo contigo, aprendo siempre algo y lo aprecio mucho. Giovanny y Juanita, gracias por enviarme su cariño. Marina y abuela, gracias por celebrar conmigo mis alegrias, las llevo en mi corazon. Miller y Yenny, no tengo palabras para definir nuestra connexion. Son mis hermanos (con menos peleas). Gracias por mantener nuestra conexion viva y latente. Celebro que sean parte de mi vida y me alegra que ustedes sean parte de mis logros.

Mijn lieve Nederlandse familie: Dirkje, Wim, Monique, Mark, Yinthe, Rense, Fieke,

Feikje, Marten en Sofie. Thank you for embracing me in the family. I have learned so

much from all of you and it is because of Edwin and because of you that now I feel at home here. Dirkje and Wim, there are not enough words to thank you for the support and love I have received from you. Every time I doubted myself or I felt I could not see a clear solution, you gave me a positive and accurate word of encouragement.

My dear Edwin, I am so lucky to have you in my life. You are my lifelong kindred spirit. Thank you for all your love and support. You are all I need and all I want is to keep enjoying life holding your hand and the hand of our little Aiden. Pequeño hijo mio, mi maestro, mi

Aiden, eres energia pura y me haces feliz. Contigo descubri una nueva forma de poder

que me hace imparable y me impulsa a ser mejor persona cada día.

Thank you all,