The pathogenesis of diarrhea related to inflammation in the colon is a multifactorial event
[1]. Understanding the ion-absorption/secretion mechanisms in the colon and the effects of inflammatory mediators on epithelial transport function is therefore of great importance.
Figure 1 depicts the major ion transportation pathways in the colon. Generally, normal stool is low in Cl
− and Na
+ and high in K
+ since reabsorption of Na
+ and secretion of K
+ (both active and passive) takes place in the colon
[2]. The reason for the low level of Cl
− in normal stool is that short-chain fatty acids (SCFA) produced in the colon can replace Cl
−, while luminal concentration of HCO
3− is similar to its concentration in plasma
[2]. In the colon, Na
+ gets absorbed through the stimulatory effect of SCFA, through an aldosterone-sensitive sodium absorption by the epithelial Na
+ channel (ENaC) in the distal colon
[3], and through an Na-H exchange parallel to a Cl-HCO
3− exchange (in the proximal colon) which is responsible for an electro-neutral Na-Cl absorption
[4]. SCFA are the primary anions in the lumen, which also contribute to Na absorption through apical Na-H, Cl-SCFA, and SCFA-HCO
3− exchanges; this type of Na
+ absorption is not hampered by cyclic adenosine monophosphate (cAMP)
[4]. Secondary messengers, such as cAMP, cyclic guanosine monophosphate (cGMP), intracellular calcium (Ca
+), and neurohumoral substances, can activate Na-H exchange (NHE) genes such as NHE3, which is involved in neutral absorption of sodium
[3]. However, increased mucosal cAMP and intracellular Ca
2+ concentration in the colon can inhibit apical Na-H and Cl-HCO
3− exchanges and reduce absorption of Na
+ and Cl
−, consequently reducing the water absorption
[4]. For apical exchange of Cl-HCO
3− in the colon, downregulation in adenoma (DRA or SLC26A3) is the major exchanger, which is a chloride-sulfate anion transporter in the upper crypt and surface epithelium of the colon
[1][5]. DRA activity was shown to be inhibited by increased cellular cAMP and Ca
2+ [6]. Moreover, the gene expression of DRA was reported to be heavily diminished in colonic inflammation as an effect of the interleukin-1β (IL-1β) cytokine, hence hampering Cl
− absorption
[1].
In animal studies, it has been shown that some bacterial pathogens, such as
Salmonella typhimurium [7],
Shigella dysenteriae toxin type 1
[8], and
Campylobacter jejuni, increase intracellular concentrations of Ca
2+, resulting in inhibition of NHE3 and stimulation of an excessive secretion of Na
+ and Cl
− [3]. Therefore, impaired Na
+ absorption and stimulation of Ca
2+ secretion can result in diarrhea
[3]. Excessive intracellular secretion of Ca
2+ could be a tertiary effect of microbial pathogenesis since pathogens first stimulate the enteric nervous system, then increase the release of neurotransmitters and, ultimately, enhance the secretion of Ca
2+ [8]. Increased levels of luminal ions can be expected as a result of inhibition of Na
+ and Cl
− absorption along with stimulation of excessive Cl
− secretion after disruption of the colonic mucus layer by either pathogen- and/or feed-induced inflammatory mediators
[9]. Quantification of recovered Cl
− from fecal samples
[10] of affected pigs can potentially be an indicator of an inflamed colonic epithelium of pigs with colitis.