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Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency.

Authors
  • Duan, Yaqian1, 2
  • Prasad, Ram3
  • Feng, Dongni4
  • Beli, Eleni4
  • Li Calzi, Sergio3
  • Longhini, Ana Leda F3
  • Lamendella, Regina5
  • Floyd, Jason L3
  • Dupont, Mariana3
  • Noothi, Sunil K3
  • Sreejit, Gopalkrishna6
  • Athmanathan, Baskaran6
  • Wright, Justin5
  • Jensen, Amanda R7
  • Oudit, Gavin Y5
  • Markel, Troy A7
  • Nagareddy, Prabhakara R6
  • Obukhov, Alexander G1
  • Grant, Maria B3
  • 1 From the Department of Anatomy, Cell Biology and Physiology (Y.D., A.G.O.), Indiana University School of Medicine, Indianapolis. , (India)
  • 2 Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, China (Y.D.). , (China)
  • 3 Department of Ophthalmology and Visual Sciences (R.P., S.L.C., A.L.F.L., J.L.F., M.D., S.K.N., M.B.G.), University of Alabama at Birmingham.
  • 4 Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute (D.F., E.B.), Indiana University School of Medicine, Indianapolis. , (India)
  • 5 Ohio State University, Wright Labs, LLC, Huntingdon, PA (R.L., J.W.).
  • 6 Department of Surgery (G.K.S., B.A., P.R.N.).
  • 7 Riley Hospital for Children, Pediatric Surgery (A.R.J., T.A.M.), Indiana University School of Medicine, Indianapolis. , (India)
Type
Published Article
Journal
Circulation Research
Publisher
Ovid Technologies Wolters Kluwer -American Heart Association
Publication Date
Nov 08, 2019
Volume
125
Issue
11
Pages
969–988
Identifiers
DOI: 10.1161/CIRCRESAHA.119.315743
PMID: 31610731
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

There is incomplete knowledge of the impact of bone marrow cells on the gut microbiome and gut barrier function. We postulated that diabetes mellitus and systemic ACE2 (angiotensin-converting enzyme 2) deficiency would synergize to adversely impact both the microbiome and gut barrier function. Bacterial 16S rRNA sequencing and metatranscriptomic analysis were performed on fecal samples from wild-type, ACE2-/y, Akita (type 1 diabetes mellitus), and ACE2-/y-Akita mice. Gut barrier integrity was assessed by immunofluorescence, and bone marrow cell extravasation into the small intestine was evaluated by flow cytometry. In the ACE2-/y-Akita or Akita mice, the disrupted barrier was associated with reduced levels of myeloid angiogenic cells, but no increase in inflammatory monocytes was observed within the gut parenchyma. Genomic and metatranscriptomic analysis of the microbiome of ACE2-/y-Akita mice demonstrated a marked increase in peptidoglycan-producing bacteria. When compared with control cohorts treated with saline, intraperitoneal administration of myeloid angiogenic cells significantly decreased the microbiome gene expression associated with peptidoglycan biosynthesis and restored epithelial and endothelial gut barrier integrity. Also indicative of diabetic gut barrier dysfunction, increased levels of peptidoglycan and FABP-2 (intestinal fatty acid-binding protein 2) were observed in plasma of human subjects with type 1 diabetes mellitus (n=21) and type 2 diabetes mellitus (n=23) compared with nondiabetic controls (n=23). Using human retinal endothelial cells, we determined that peptidoglycan activates a noncanonical TLR-2 (Toll-like receptor 2) associated MyD88 (myeloid differentiation primary response protein 88)-ARNO (ADP-ribosylation factor nucleotide-binding site opener)-ARF6 (ADP-ribosylation factor 6) signaling cascade, resulting in destabilization of p120-catenin and internalization of VE-cadherin as a mechanism of deleterious impact of peptidoglycan on the endothelium. We demonstrate for the first time that the defect in gut barrier function and dysbiosis in ACE2-/y-Akita mice can be favorably impacted by exogenous administration of myeloid angiogenic cells.

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