TY - JOUR
T1 - Campylobacter concisus Impairs Sodium Absorption in Colonic Epithelium via ENaC Dysfunction and Claudin-8 Disruption
AU - Nattramilarasu, Praveen Kumar
AU - Bücker, Roland
AU - Lobo de Sá, Fábia Daniela
AU - Fromm, Anja
AU - Nagel, Oliver
AU - Lee, In-Fah Maria
AU - Butkevych, Eduard
AU - Mousavi, Soraya
AU - Genger, Claudia
AU - Kløve, Sigri
AU - Heimesaat, Markus M
AU - Bereswill, Stefan
AU - Schweiger, Michal R
AU - Nielsen, Hans Linde
AU - Troeger, Hanno
AU - Schulzke, Jörg-Dieter
PY - 2020/1/7
Y1 - 2020/1/7
N2 - The epithelial sodium channel (ENaC) can increase the colonic absorptive capacity for salt and water. Campylobacter concisus is a common pathogenic epsilonproteobacterium, causing enteritis and diarrhea. It can induce barrier dysfunction in the intestine, but its influence on intestinal transport function is still unknown. Therefore, our study aimed to characterize C. concisus effects on ENaC using the HT-29/B6-GR/MR (epithelial cell line HT-29/B6 transfected with glucocorticoid and mineralocorticoid receptors) cell model and mouse colon. In Ussing chambers, C. concisus infection inhibited ENaC-dependent Na
+ transport as indicated by a reduction in amiloride-sensitive short circuit current (−55%, n = 15, p < 0.001). This occurred via down-regulation of β-and γ-ENaC mRNA expression and ENaC ubiquitination due to extracellular signal-regulated kinase (ERK)1/2 activation, predicted by Ingenuity Pathway Analysis (IPA). In parallel, C. concisus reduced the expression of the sealing tight junction (TJ) protein claudin-8 and induced claudin-8 redistribution off the TJ domain of the enterocytes, which facilitates the back leakage of Na
+ ions into the intestinal lumen. In conclusion, C. concisus caused ENaC dysfunction via interleukin-32-regulated ERK1/2, as well as claudin-8-dependent barrier dysfunction—both of which contribute to Na
+ malabsorption and diarrhea.
AB - The epithelial sodium channel (ENaC) can increase the colonic absorptive capacity for salt and water. Campylobacter concisus is a common pathogenic epsilonproteobacterium, causing enteritis and diarrhea. It can induce barrier dysfunction in the intestine, but its influence on intestinal transport function is still unknown. Therefore, our study aimed to characterize C. concisus effects on ENaC using the HT-29/B6-GR/MR (epithelial cell line HT-29/B6 transfected with glucocorticoid and mineralocorticoid receptors) cell model and mouse colon. In Ussing chambers, C. concisus infection inhibited ENaC-dependent Na
+ transport as indicated by a reduction in amiloride-sensitive short circuit current (−55%, n = 15, p < 0.001). This occurred via down-regulation of β-and γ-ENaC mRNA expression and ENaC ubiquitination due to extracellular signal-regulated kinase (ERK)1/2 activation, predicted by Ingenuity Pathway Analysis (IPA). In parallel, C. concisus reduced the expression of the sealing tight junction (TJ) protein claudin-8 and induced claudin-8 redistribution off the TJ domain of the enterocytes, which facilitates the back leakage of Na
+ ions into the intestinal lumen. In conclusion, C. concisus caused ENaC dysfunction via interleukin-32-regulated ERK1/2, as well as claudin-8-dependent barrier dysfunction—both of which contribute to Na
+ malabsorption and diarrhea.
KW - Campylobacter concisus
KW - Claudin-8
KW - Diarrhea
KW - Epithelial sodium channel
KW - Extracellular signal-regulated kinase
KW - Sodium transport
KW - Tight junction
UR - http://www.scopus.com/inward/record.url?scp=85077848194&partnerID=8YFLogxK
U2 - 10.3390/ijms21020373
DO - 10.3390/ijms21020373
M3 - Journal article
C2 - 31936044
SN - 1661-6596
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 2
M1 - 373
ER -