PMID- 28450277
OWN - NLM
STAT- MEDLINE
DCOM- 20170816
LR  - 20170816
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Linking)
VI  - 313
IP  - 1
DP  - 2017 Jul 1
TI  - Absence of the NOD2 protein renders epithelia more susceptible to barrier 
      dysfunction due to mitochondrial dysfunction.
PG  - G26-G38
LID - 10.1152/ajpgi.00070.2017 [doi]
AB  - Irregular mitochondria structure and reduced ATP in some patients with IBD 
      suggest that metabolic stress contributes to disease. Loss-of-function mutation 
      in the nucleotide-binding oligomerization domain (NOD)-2 gene is a major 
      susceptibility trait for IBD. Hence, we assessed if loss of NOD2 further impairs 
      the epithelial barrier function instigated by disruption of mitochondrial ATP 
      synthesis via the hydrogen ionophore dinitrophenol (DNP). NOD2 protein (virtually 
      undetectable in epithelia under basal conditions) was increased in T84 (human 
      colon cell line) cells treated with noninvasive Escherichia coli + DNP (16 h). 
      Increased intracellular bacteria in wild-type (WT) and NOD2 knockdown (KD) cells 
      and colonoids from NOD2(-/-) mice were mediated by reactive oxygen species (ROS) 
      and the MAPK ERK1/2 pathways as determined by cotreatment with the antioxidant 
      mitoTEMPO and the ERK inhibitor U0126: ROS was upstream of ERK1/2 activation. 
      Despite increased E. coli in DNP-treated NOD2 KD compared with WT cells, there 
      were no differences in the internalization of fluorescent inert beads or dead E. 
      coli particles. This suggests that lack of killing in the NOD2 KD cells was 
      responsible for the increased numbers of viable intracellular bacteria; a 
      conclusion supported by evidence of reduced autophagy in NOD2 KD T84 epithelia. 
      Thus, in a two-hit hypothesis, decreased barrier function due to dysfunctional 
      mitochondrial is amplified by lack of NOD2 in transporting enterocytes: 
      subsequently, greater numbers of bacteria entering the mucosa would be a 
      significant inflammatory threat especially since individuals with NOD2 mutations 
      have compromised macrophage and Paneth cell responses to bacteria.NEW & 
      NOTEWORTHY Increased internalization of bacteria by epithelia with dysfunctional 
      mitochondria (reduced ATP) is potentiated if the cells lack nucleotide-binding 
      oligomerization domain 2 (NOD2), mutations in which are inflammatory bowel 
      disease-susceptibility traits. Uptake of bacteria was dependent on reactive 
      oxygen species and MAP-kinase activity, and the increased viable intracellular 
      bacteria in NOD2(-/-) cells likely reflect a reduced ability to recognize and 
      kill bacteria. Thus a significant barrier defect occurs with NOD2 deficiency in 
      conjunction with metabolic stress that could contribute to inflammation.
CI  - Copyright (c) 2017 the American Physiological Society.
FAU - Saxena, Alpana
AU  - Saxena A
AD  - Gastrointestinal Research Group, Department of Physiology and Pharmacology, 
      Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of 
      Medicine, University of Calgary, Calgary, Alberta, Canada.
FAU - Lopes, Fernando
AU  - Lopes F
AD  - Gastrointestinal Research Group, Department of Physiology and Pharmacology, 
      Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of 
      Medicine, University of Calgary, Calgary, Alberta, Canada.
FAU - Poon, Karen K H
AU  - Poon KKH
AD  - Gastrointestinal Research Group, Department of Physiology and Pharmacology, 
      Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of 
      Medicine, University of Calgary, Calgary, Alberta, Canada.
FAU - McKay, Derek M
AU  - McKay DM
AD  - Gastrointestinal Research Group, Department of Physiology and Pharmacology, 
      Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of 
      Medicine, University of Calgary, Calgary, Alberta, Canada dmckay@ucalgary.ca.
LA  - eng
PT  - Journal Article
DEP - 20170427
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Dinitrophenols)
RN  - 0 (Nod2 Signaling Adaptor Protein)
RN  - 0 (dinitrophenol-ovalbumin)
RN  - 9006-59-1 (Ovalbumin)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Dinitrophenols/pharmacology
MH  - Escherichia coli/physiology
MH  - Gene Expression Regulation/*physiology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Intestinal Mucosa/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/*metabolism
MH  - Mitochondrial Diseases/*metabolism
MH  - Nod2 Signaling Adaptor Protein/genetics/*metabolism
MH  - Organoids/physiology
MH  - Ovalbumin/pharmacology
MH  - Rats
MH  - Tissue Culture Techniques
OTO - NOTNLM
OT  - NOD2
OT  - barrier
OT  - commensal bacteria
OT  - epithelium
OT  - mitochondria
EDAT- 2017/04/30 06:00
MHDA- 2017/08/17 06:00
CRDT- 2017/04/29 06:00
PHST- 2017/02/28 00:00 [received]
PHST- 2017/04/07 00:00 [revised]
PHST- 2017/04/18 00:00 [accepted]
PHST- 2017/04/30 06:00 [pubmed]
PHST- 2017/08/17 06:00 [medline]
PHST- 2017/04/29 06:00 [entrez]
AID - ajpgi.00070.2017 [pii]
AID - 10.1152/ajpgi.00070.2017 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2017 Jul 1;313(1):G26-G38. doi: 
      10.1152/ajpgi.00070.2017. Epub 2017 Apr 27.