Duodenal Mucosa of Patients With Type 1 Diabetes Shows Distinctive Inflammatory Profile and Microbiota.
Increasing evidences suggest a correlation between gut and type 1 diabetes (T1D).



The objective of this study is to evaluate the gut inflammatory profile and microbiota in patients with T1D compared with healthy control (CTRL) subjects and patients with celiac disease (CD) as gut inflammatory disease controls.



The inflammatory status and microbiome composition were evaluated in biopsies of the duodenal mucosa of patients with T1D (n = 19), in patients with CD (n = 19), and CTRL subjects (n = 16) recruited at San Raffaele Scientific Institute, in Milan, Italy, between 2009 and 2015.



Inflammation was evaluated by gene expression study and immunohistochemistry. Microbiome composition was analyzed by 16S ribosomal RNA gene sequencing.



An increased expression of CCL13, CCL19, CCL22, CCR2, COX2, IL4R, CD68, PTX3, TNFα, and VEGFA was observed in patients with T1D compared with CTRL subjects and patients with CD. Immunohistochemical analysis confirmed T1D-specific inflammatory status compared with healthy and CD control tissues, mainly characterized by the increase of the monocyte/macrophage lineage infiltration. The T1D duodenal mucosal microbiome results were different from the other groups, with an increase in Firmicutes and Firmicutes/Bacteroidetes ratio and a reduction in Proteobacteria and Bacteroidetes. The expression of genes specific for T1D inflammation was associated with the abundance of specific bacteria in the duodenum.



This study shows that duodenal mucosa in T1D presents disease-specific abnormalities in the inflammatory profile and microbiota. Understanding the mechanisms underlying these features is critical to disentangle the complex pathogenesis of T1D and to gain new perspectives for future therapies targeting the intestine.
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Silvia
S
Pellegrini
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Valeria
V
Sordi
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Andrea Mario
AM
Bolla
Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Diego
D
Saita
Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Roberto
R
Ferrarese
Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|Department of Biotechnology and Life Sciences, University of Insubria, Varese 21100, Italy.
Filippo
F
Canducci
Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|University "Vita-Salute" San Raffaele, Milan 20132, Italy.
Massimo
M
Clementi
Pathology Department, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Francesca
F
Invernizzi
Gastroenterology and Digestive Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Alberto
A
Mariani
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|Pediatrics and Neonatal Disease Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Riccardo
R
Bonfanti
Pediatrics and Neonatal Disease Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Graziano
G
Barera
Gastroenterology and Digestive Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|University "Vita-Salute" San Raffaele, Milan 20132, Italy.
Pier Alberto
PA
Testoni
Pathology Department, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|University "Vita-Salute" San Raffaele, Milan 20132, Italy.
Claudio
C
Doglioni
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|University "Vita-Salute" San Raffaele, Milan 20132, Italy.
Emanuele
E
Bosi
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|University "Vita-Salute" San Raffaele, Milan 20132, Italy.
Lorenzo
L
Piemonti
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D002097:C-Reactive Protein / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002446:Celiac Disease / Q000276:immunology / Q000382:microbiology; D054415:Chemokine CCL19 / Q000235:genetics / Q000276:immunology; D054422:Chemokine CCL22 / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D004386:Duodenum / Q000276:immunology* / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D006801:Humans; D007223:Infant; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000276:immunology; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000276:immunology; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology; D055815:Young Adult; D000099153:Pentraxins; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002097:C-Reactive Protein; D054415:Chemokine CCL19; D054422:Chemokine CCL22; D051546:Cyclooxygenase 2; D053662:Interleukin-4 Receptor alpha Subunit; D018945:Monocyte Chemoattractant Proteins; D012336:RNA, Ribosomal, 16S; D054390:Receptors, CCR2; D000683:Serum Amyloid P-Component; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000099153:Pentraxins; C099677:CCL13 protein, human; C515460:CCL19 protein, human; C515482:CCL22 protein, human; C515334:CCR2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C504000:IL4R protein, human; C439524:TNF protein, human; C467484:VEGFA protein, human; C496540:PTGS2 protein, human