Gut Microbes (Dec 2022)
Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction
- Torsten P.M. Scheithauer,
- Hilde Herrema,
- Hongbing Yu,
- Guido J. Bakker,
- Maaike Winkelmeijer,
- Galina Soukhatcheva,
- Derek Dai,
- Caixia Ma,
- Stefan R. Havik,
- Manon Balvers,
- Mark Davids,
- Abraham S. Meijnikman,
- Ömrüm Aydin,
- Bert-Jan H. van den Born,
- Marc G. Besselink,
- Olivier R. Busch,
- Maurits de Brauw,
- Arnold van de Laar,
- Clara Belzer,
- Martin Stahl,
- Willem M. de Vos,
- Bruce A. Vallance,
- Max Nieuwdorp,
- C. Bruce Verchere,
- Daniël H. van Raalte
Affiliations
- Torsten P.M. Scheithauer
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Hilde Herrema
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Hongbing Yu
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, and BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Guido J. Bakker
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Maaike Winkelmeijer
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Galina Soukhatcheva
- Departments of Surgery and Pathology and Laboratory Medicine Pathology and Laboratory Medicine, BC Children’s Hospital Research Institute, Centre for Molecular Medicine & Therapeutics, Vancouver, British Columbia, Canada
- Derek Dai
- Departments of Surgery and Pathology and Laboratory Medicine Pathology and Laboratory Medicine, BC Children’s Hospital Research Institute, Centre for Molecular Medicine & Therapeutics, Vancouver, British Columbia, Canada
- Caixia Ma
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, and BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Stefan R. Havik
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Manon Balvers
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Mark Davids
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Abraham S. Meijnikman
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Ömrüm Aydin
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Bert-Jan H. van den Born
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Marc G. Besselink
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, the Netherlands
- Olivier R. Busch
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, the Netherlands
- Maurits de Brauw
- Department of Surgery, Spaarne Gasthuis, Hoofddorp, The Netherlands
- Arnold van de Laar
- Department of Surgery, Spaarne Gasthuis, Hoofddorp, The Netherlands
- Clara Belzer
- Laboratory of Microbiology, Wageningen University and Research, Wageningen, The Netherlands
- Martin Stahl
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, and BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Willem M. de Vos
- Laboratory of Microbiology, Wageningen University and Research, Wageningen, The Netherlands
- Bruce A. Vallance
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, and BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
- Max Nieuwdorp
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- C. Bruce Verchere
- Departments of Surgery and Pathology and Laboratory Medicine Pathology and Laboratory Medicine, BC Children’s Hospital Research Institute, Centre for Molecular Medicine & Therapeutics, Vancouver, British Columbia, Canada
- Daniël H. van Raalte
- Department of (Experimental) Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- DOI
- https://doi.org/10.1080/19490976.2022.2111951
- Journal volume & issue
-
Vol. 14,
no. 1
Abstract
Hyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied, but causal links remain enigmatic. Obese individuals with or without T2D were included from two independent Dutch cohorts. Human data were translated in vitro and in vivo by using pancreatic islets from C57BL6/J mice and by injecting flagellin into obese mice. Flagellin is part of the bacterial locomotor appendage flagellum, present in gut bacteria including Enterobacteriaceae, which we show to be more abundant in the gut of individuals with T2D. Subsequently, flagellin induces a pro-inflammatory response in pancreatic islets mediated by the Toll-like receptor (TLR)-5 expressed on resident islet macrophages. This inflammatory response is associated with beta-cell dysfunction, characterized by reduced insulin gene expression, impaired proinsulin processing and stress-induced insulin hypersecretion in vitro and in vivo in mice. We postulate that increased systemically disseminated flagellin in T2D is a contributing factor to beta-cell failure in time and represents a novel therapeutic target.
Keywords
