title: Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat.
abstract: OBJECTIVE
  Impaired intestinal barrier function is observed in type 1 diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type 1 diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model.
  
  
  METHODS
  DP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose-mannitol test and ex vivo by measuring transepithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. Ileal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction-related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf-ß (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR.
  
  
  RESULTS
  The HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered.
  
  
  CONCLUSIONS
  Improved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect.
authors.affiliation: Department of Cell Biology, Section Immunology, University Medical Center Groningen, University of Groningen, PO Box 196, 9700 AD Groningen, the Netherlands. j.t.j.visser@med.umcg.nl
authors.forename: J T J
authors.initials: JT
authors.lastname: Visser
authors.forename: K
authors.initials: K
authors.lastname: Lammers
authors.forename: A
authors.initials: A
authors.lastname: Hoogendijk
authors.forename: M W
authors.initials: MW
authors.lastname: Boer
authors.forename: S
authors.initials: S
authors.lastname: Brugman
authors.forename: S
authors.initials: S
authors.lastname: Beijer-Liefers
authors.forename: A
authors.initials: A
authors.lastname: Zandvoort
authors.forename: H
authors.initials: H
authors.lastname: Harmsen
authors.forename: G
authors.initials: G
authors.lastname: Welling
authors.forename: F
authors.initials: F
authors.lastname: Stellaard
authors.forename: N A
authors.initials: NA
authors.lastname: Bos
authors.forename: A
authors.initials: A
authors.lastname: Fasano
authors.forename: J
authors.initials: J
authors.lastname: Rozing
mesh_terms: D000818:Animals; D002364:Caseins / Q000493:pharmacokinetics / Q000627:therapeutic use; D002772:Cholera Toxin / Q000235:genetics / Q000378:metabolism; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004032:Diet; D004198:Disease Susceptibility / Q000178:diet therapy / Q000378:metabolism; D017097:Electric Impedance; D006242:Haptoglobins; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D011498:Protein Precursors; D051381:Rats; D011922:Rats, Mutant Strains
chemical_list: D002364:Caseins; D057167:Claudins; D016207:Cytokines; D006242:Haptoglobins; D011498:Protein Precursors; C113469:myosin IXB; C408043:zonulin; C475729:casein hydrolysate; D002772:Cholera Toxin; D009218:Myosins