Erythritol and xylitol differentially impact brain networks involved in appetite regulation in healthy volunteers

ABSTRACT

Background

There is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown.

Aim

The study’s objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release.

Methods

The study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose.

Results

We found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin.

Conclusion

Xylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose.

KEYWORDS:

• Xylitol
• erythritol
• low-calorie sweetener
• fMRI
• resting cerebral blood flow
• resting-state functional connectivity
• peptide tyrosine tyrosine
• cholecystokinin

Acknowledgments

We would like to thank Damian Gschwend and Nico Streit (doctoral students), Philipp Madoerin (radiographer), Luisa Baselgia, Claudia Bläsi and Sylvia Ketterer (technical assistance), and Stefan Borgwardt (neuropsychologist).

Disclosure statement

No potential conflict of interest was reported by the author(s). ACMG, CB, and BKW designed the research; ACMG and BKW conducted research; ACMG, JW, JFR, CLR, PD, OOD, and LVO analyzed data and performed statistical analysis; ACMG, LVO, and BKW wrote the manuscript. ACMG and BKW have primary responsibility for the final content. All authors read and approved the final manuscript.

Ethics approval

The study was performed in accordance with the principles of the Helsinki Declaration of 1975 as revised in 2013. The protocol was approved by the State Ethical Committee of Basel (Ethikkommission Nordwest- und Zentralschweiz: EKNZ 2014-072; approval date: 02 April 2014) and registered at ClinicalTrials.gov (NCT02823249). Each subject gave written informed consent.

Additional information

Funding

This work was supported by the Swiss National Science Foundation (SNSF) under Grant 138 157 (CB), and PMPDP3-145486/1 (BKW); the foundation of the University of Basel (ACMG); and the foundation Förderung der gastroenterologischen Forschung (CB).

Notes on contributors

Anne Christin Meyer-Gerspach

Anne Christin Meyer-Gerspach graduated in nutritional science from the Technical University of Munich, Germany, in 2009. She obtained her Ph.D. from the University Basel, Switzerland, in 2012. A grant from the Swiss National Science Foundation enabled her to carry out a post-doctoral research project at the Catholic University of Leuven, Belgium (Translational Research Centre for Gastrointestinal Disorders, Prof. Jan Tack), in 2015 and 2016. In July 2016, She moved to St. Clara Research Ltd/St. Clara Hospital in Basel for a position as academic scientist where she later took up a group leader position in the Metabolic Research Group. Her main research interests are nutritional physiology, obesity, process of eating control, taste perception and gut-brain-axis. The research activities are supported by competitive third-party funding, and she publishes regularly in peer-reviewed journals of high repute.

Jed O. Wingrove

Jed O. Wingrove is a Research Fellow working in the Centre for Obesity Research at University College London (UCL). As an early career researcher his work uses functional neuroimaging techniques to look at brain function with applications in obesity and insulin resistance. His work holds an interest for understanding the neuronal changes that occur within the brain following bariatric surgery and how this impacts on gustatory processing as well as appetite control systems.

Christoph Beglinger

Christoph Beglinger graduated in medicine from the University of Berne, Switzerland, in 1977. Following graduation, he undertook a medical thesis at the same institution. After two years of clinical work, he received a post-doctoral fellowship at the Center for Ulcer Research and Education at the University of California, Los Angeles (UCLA), USA. In 1985, he became Board-Certified in Internal Medicine, and in 1987, Board-Certified in Gastroenterology. He was appointed Assistant Professor in the Faculty of Medicine at the University of Basel, Switzerland, in 1988 and became Associate Professor in 1994. In 1999, he was named full Professor for Gastroenterology and was elected as chairman of the Department of Gastroenterology and Hepatology at the University Hospital in Basel, Switzerland. He retired from the University Hospital in 2015 and became head of the department of clinical research of the St. Claraspital, a University-affiliated hospital, a position he held until the end of 2017. Since 2018 he is the Head of the Ethical Committee of Northwestern and Central Switzerland (EKNZ).

Jens F. Rehfeld

Jens F. Rehfeld Born 1941 Aarhus, Denmark. MD University of Aarhus 1967. Resident in Internal Medicine and Surgery (1967–1969), and then research fellow and resident in clinical biochemistry at Copenhagen hospitals (1969–1975). Professor in medical biochemistry, University of Aarhus (1975–1981), and clinical biochemistry at Rigshospitalet, University of Copenhagen (1981–) The main theme of research is biologically active peptides (primarily in the brain, pancreas, and gastrointestinal tract), their biogenesis, and methods for their measurement in biology, pathogenesis, and diagnosis. The results have been published in 636 original articles (11 in Nature and Science), discussed in 85 review articles and 55 book chapters, all in peer-reviewed periodicals. Still employed full-time as university professor.

Carel W. Le Roux

Carel W. Le Roux graduated from medical school in Pretoria South Africa, and completed his specialist training in metabolic medicine at St Bartholomew’s Hospitals and the Hammersmith Hospitals. He obtained his Ph.D. from Imperial College London where he later took up a faculty position. He moved to University College Dublin for the Chair in Experimental Pathology, and he is now a Director of the Metabolic Medicine Group. He also holds the position of Professor of Metabolic Medicine at Ulster University. He currently coordinates an Innovative Medicine Initiative project on obesity. He previously received a President of Ireland Young Researcher Award, Irish Research Council Laureate Award, Clinician Scientist Award from the National Institute Health Research in the UK, and a Wellcome Trust Clinical Research Fellowship for his work on how the gut talks to the brain.

Ralph Peterli

Ralph Peterli is head of bariatric reference center and head of visceral surgery research at Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital, and University Hospital Basel, Switzerland. He is an active visceral surgeon (>14,500 operations) and researcher (106 original articles, 6 book chapters, approximately 200 invited lectures, 5 national, 2 international prizes). He is an internationally known and respected expert in the field of bariatric and metabolic surgery as well as in metabolic research. As scientific chair and board member of the European Chapter of the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) and as president of the Swiss Society for the Study of Morbid Obesity and Metabolic disorders (SMOB) it is his goal to bring basic researchers in the field of obesity, nutrition, and diabetes together with clinicians (physicians and surgeons) in combined international and national congresses and meetings.

Patrick Dupont

Patrick Dupont is currently a full professor of brain imaging at the Laboratory for Cognitive Neurology and chair of the department of neurosciences at KU Leuven. He is also a board member of the Leuven Brain Institute and an extraordinary professor in nuclear medicine at the University of Stellenbosch, South Africa. His main research interest is related to image and data analysis in brain imaging and it is characterized by the use of advanced mathematical techniques and by a multimodal imaging approach including SPECT, PET, MRI and EEG. Since 2008 prof. He is the director of the Postgraduate Studies in Advanced Medical Imaging at KU Leuven and he teaches several courses related to medical imaging. He is a member of the Federation of European Neuroscience Societies, the society of neuroscience, the Organization of Human Brain Mapping and the International Society for Magnetic Resonance in Medicine.

Owen O’Daly

Owen O’Daly is a senior lecturer working in the Centre for Neuroimaging Sciences at King’s College London (KCL). His work focusses on using functional neuroimaging techniques to study the role of motivation and control in the context of eating disorders and obesity and the effects of pharmacological agents on brain function.

Lukas Van Oudenhove

Lukas Van Oudenhov graduated as a Medical Doctor at KU Leuven in 2001. During his specialist training in psychiatry at the Onze-Lieve-Vrouw Hospital Aalst and at the University Psychiatric Center KU Leuven, he was granted a PhD-fellowship of the Research Foundation – Flanders. This allowed him to perform doctoral research from October 2004 until the end of his psychiatry training in September 2008, resulting in the successful defense of his doctoral thesis at KU Leuven. After a sabbatical-cum-postdoc in his beloved Mexico, he worked as a post-doctoral fellow of the Research Foundation – Flanders at the Translational Research Center for Gastrointestinal Diseases (TARGID) of KU Leuven from 2009 until 2012. In October 2012, he was appointed assistant research professor funded by the KU Leuven Special Research Fund, which allowed him to establish his own group within TARGID, the Laboratory for Brain-Gut Axis Studies (LaBGAS). The highly collaborative research lines of his group cover various aspects of gut-brain interactions, including psychobiological mechanisms underlying gastrointestinal symptom perception as well as the control of appetite and food intake in health and disease and, most recently, the influence of nutrient- and microbiota-related gut-brain signals on psychological processes and their neural basis. His research has been internationally authoritative, as reflected by more than 200 peer-reviewed publications and numerous invited and abstract presentations at international scientific meetings. He also won several international research awards: a Young Scholar Award and MacLean Scholar Award from the American Psychosomatic Society in 2006 & 2010, respectively, a Young Investigator Award from the Functional Brain-Gut Research Group in 2008 and a Fellow Abstract Prize from the American Gastroenterological Association in 2009. In 2012, he was chosen as ‘Rising Star’ by United European Gastroenterology and in 2013, he won the Junior Clinical Researcher Award of the International Foundation for Functional Gastrointestinal Disorders. He also served as co-chair of the Rome IV committee on psychosocial aspects of functional gastrointestinal disorders. During his sabbatical in Tor Wager’s Cognitive and Affective Neuroscience Lab at Dartmouth College (Hanover, NH, USA) in 2020-2021, he gained expertize in advanced multivariate brain imaging analysis techniques. In the same year, Lukas got granted a prestigious Consolidator Award by the European Research Council. His MoodBugs project will focus on microbiota-gut-brain signaling mechanisms mediating the putative impact of the gut microbiota on stress and fear responses in humans, and will provide him with a unique opportunity to consolidate and expand LaBGAS.

Bettina K. Wölnerhanssen

Bettina K. Wölnerhanssen completed her medical studies at the University of Basel, Switzerland, in 2001, where she also wrote her medical doctoral thesis. After graduation, she spent six months as a research associate in Philadelphia at the Children's Hospital of Philadelphia. She thereafter focused on her specialization as a surgeon and received her board certification in 2010. From then on, she devoted herself exclusively to clinical research, especially in the field of metabolic surgery and nutritional research. Since 2018, she has headed St. Clara Research Ltd - the clinical research department of St. Claraspital in Basel, a hospital affiliated with the University of Basel. She is an active researcher; her research activities are generously supported by competitively acquired external funding, and she regularly publishes in renowned journals.