Campylobacter concisus Impairs Sodium Absorption in Colonic Epithelium via ENaC Dysfunction and Claudin-8 Disruption

Abstract

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.

Immune-Mediated Aggravation of the Campylobacter concisus-Induced Epithelial Barrier Dysfunction

“…We detected a decrease in the protein and mRNA expression of claudin-8 in HT-29/B6-GR/MR cell monolayers 48 h after C. concisus infection in our previous study, in which regulation of claudin-8 expression was influenced by stimulation with dexamethasone (D), butyrate-sodium salt (B), and aldosterone (A) [ 5 ]. In our present study, claudin-8 protein expression remained unaltered 48 h after C. concisus infection in HT-29/B6-GR/MR cell monolayers, presumably because they were not pre-stimulated with DBA.…”

“…The cell monolayers were infected with C. concisus ( C. concisus AAuH 37 UC oral [ 40 ]) on the apical and basal sides of the cell monolayers at a multiplicity of infection (MOI) of 200 ( Figure 9 ). After infection, the cell monolayers were incubated in a microaerophilic and H 2 -containing atmospheric condition at 37 °C, as described in our previous study [ 5 ]. TER was recorded at 24 h and 48 h p.i..…”

“…Most importantly, one clinical study with a large cohort of diarrheal patients discovered that C. concisus induced prolonged diarrhea with less fever, unlike zoonotic diarrheal pathogens Campylobacter coli and Campylobacter jejuni , which cause short-term diarrhea with more often fever and increased C-Reactive Protein (CRP) levels [ 4 ]. In our previous study, we reported that C. concisus impaired epithelial sodium channel (ENaC) function via activation of extracellular signal-regulated kinase (ERK) and induced claudin-8-dependent barrier dysfunction, both of which contribute to sodium malabsorption and watery diarrhea [ 5 ]. The diarrheal mechanism of C. concisus correlates to the diarrheal pathomechanism of lymphocytic colitis, a subtype of microscopic colitis [ 6 ].…”

High risk of microscopic colitis after Campylobacter concisus infection: population-based cohort study

“…The same research group also showed an epithelial barrier dysfunction with downregulation of epithelial tight junctions, through downregulation of claudin-4, claudin-5 and claudin-8, and redistribution of claudin-5 and claudin-8 off the tight junction, which contributes to diarrhoea by a leak-flux mechanism 44. Quite recently, Nattramilarasu et al also showed that C. concisus caused epithelial sodium channel dysfunction, as well as claudin-8-dependent barrier dysfunction, both of which contribute to Na + malabsorption and the clinical manifestation of watery diarrhoea 45…”

Ion and Molecule Transport in Membrane Systems 2.0

“…The transport mechanisms in biomembrane systems are studied in [ 1 , 2 , 3 , 4 ]. The complicated transfer of keratinocyte toward the wound skin was studied by S. Hwang [ 1 ].…”