title: Lactobacillus salivarius reverse diabetes-induced intestinal defense impairment in mice through non-defensin protein.
abstract: Altered intestinal microbiota and subsequent endotoxemia play pathogenic roles in diabetes. We aimed to study the mechanisms of intestinal defense impairment in type 1 diabetes and the effects of Lactobacillus salivarius as well as fructooligosaccharides (FOS) supplementation on diabetes-induced bacterial translocation. Alterations in the enteric microbiome, expression of mucosal antibacterial proteins and bacteria-killing activity of the intestinal mucosa in streptozotocin (STZ)-induced diabetic mice and Ins2(Akita) mice were investigated. The effects of dead L. salivarius (2×10(8)CFU/ml) and FOS (250 mg per day) supplementation for 1 week on endotoxin levels and Klebsiella pneumoniae translocation were also examined. Finally, germ-free mice were cohoused with wild-type or Ins2(Akita) mice for 2 weeks to examine the contribution of microbiota on the antibacterial protein expression. STZ-induced diabetic mice developed intestinal defense impairment as demonstrated by decreased mucosal bacteria-killing activity; reduction of non-defensin family proteins, such as Reg3β, Reg3γ, CRP-ductin and RELMβ, but not the defensin family proteins; and increased bacterial translocation. Intestinal bacteria overgrowth, enteric dysbiosis and increased intestinal bacterial translocation, particularly pathogenic K. pneumoniae in STZ-induced diabetic mice and Ins2(Akita) mice, were noted. Treating diabetic mice with dead L. salivarius or FOS reversed enteric dysbiosis, restored mucosal antibacterial protein and lessened endotoxin levels as well as K. pneumoniae translocation. Moreover, germ-free mice cohoused with wild-type mice demonstrated more intestinal Reg3β and RELMβ expression than those cohoused with Ins2(Akita) mice. These results indicate that hyperglycemia induces enteric dysbiosis, reduction of non-defensin proteins as well as bacteria-killing activity of the intestinal mucosa and intestinal defense impairment. Reversal of enteric dysbiosis with dead L. salivarius or FOS supplementation decreases diabetes-induced K. pneumoniae translocation and endotoxin levels through the induction of non-defensin proteins.
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, No. 386, Ta-chung 1st Road, Kaohsiung, 813, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, No. 70, Lien-Hai Road, Kaohsiung, 804, Taiwan.
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Chung
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, No. 386, Ta-chung 1st Road, Kaohsiung, 813, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, No. 386, Ta-chung 1st Road, Kaohsiung, 813, Taiwan.
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Institute of Emergency and Critical Care Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei, 112, Taiwan; Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei City, 112, Taiwan.
authors.forename: Chang-Phone
authors.initials: CP
authors.lastname: Fung
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, No. 70, Lien-Hai Road, Kaohsiung, 804, Taiwan.
authors.forename: Ching-Mei
authors.initials: CM
authors.lastname: Hsu
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, No. 386, Ta-chung 1st Road, Kaohsiung, 813, Taiwan; Institute of Emergency and Critical Care Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei, 112, Taiwan. Electronic address: lwchen@vghks.gov.tw.
authors.forename: Lee-Wei
authors.initials: LW
authors.lastname: Chen
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D003922:Diabetes Mellitus, Type 1 / Q000178:diet therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D019587:Dietary Supplements; D064806:Dysbiosis / Q000178:diet therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D005786:Gene Expression Regulation; D005856:Germ-Free Life; D006729:Hormones, Ectopic / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018928:Immunity, Mucosal; D036341:Intercellular Signaling Peptides and Proteins; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D000069996:Ligilactobacillus salivarius / Q000737:chemistry / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009844:Oligosaccharides / Q000627:therapeutic use; D000073718:Pancreatitis-Associated Proteins; D056692:Prebiotics; D011506:Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation
chemical_list: D004731:Endotoxins; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; D009844:Oligosaccharides; D000073718:Pancreatitis-Associated Proteins; D056692:Prebiotics; D011506:Proteins; C490253:Reg3b protein, mouse; C486522:Retnlb protein, mouse; C116580:fructooligosaccharide
keywords: Endotoxin; Enteric dysbiosis; Fructooligosaccharides; Hyperglycemia; K. pneumoniae; Reg3β