A Review of Epithelial Ion Transporters and Their Roles in Equine Infectious Colitis

Abstract

Equine colitis is a devastating disease with a high mortality rate. Infectious pathogens associated with colitis in the adult horse include Clostridioides difficile, Clostridium perfringens, Salmonella spp., Neorickettsia risticii/findlaynesis, and equine coronavirus. Antimicrobial-associated colitis can be associated with the presence of infectious pathogens. Colitis can also be due to non-infectious causes, including non-steroidal anti-inflammatory drug administration, sand ingestion, and infiltrative bowel disease. Current treatments focus on symptomatic treatment (restoring fluid and electrolyte balance, preventing laminitis and sepsis). Intestinal epithelial ion channels are key regulators of electrolyte (especially sodium and chloride) and water movement into the lumen. Dysfunctional ion channels play a key role in the development of diarrhea. Infectious pathogens, including Salmonella spp. and C. difficile, have been shown to regulate ion channels in a variety of ways. In other species, there has been an increased interest in ion channel manipulation as an anti-diarrheal treatment. While targeting ion channels also represents a promising way to manage diarrhea associated with equine colitis, ion channels have not been well studied in the equine colon. This review provides an overview of what is known about colonic ion channels and their known or putative role in specific types of equine colitis due to various pathogens.

Keywords: colitis; diarrhea; equine; gastrointestinal; infectious disease; ion channels.

Figure 1

Localization of epithelial apical ion channels along the intestinal tract. (A) The epithelium of the small intestine is separated into crypt and villus regions, with absorptive ion channels (including NHE3, SGLT1, DRA) located along the villus tip and secretory ion channels (including CFTR, CaCC) within the crypt. (B) The colonic epithelium has secretory ion channels (including CFTR, CaCC) within the crypts and absorptive ion channels (including NHE3, SGLT1, DRA, ENaC) located at the mucosal surface. In the horse, DRA (anion-exchanger) is present on both the right ventral and right dorsal colons. Bicarbonate is also secreted via CFTR in the horse (primarily in the right dorsal colon). ENaC is more highly expressed in the distal colon of rodents and humans (and can be co-localized with CFTR), while NHE3 tends toward higher expression in the proximal colon of rodents and humans. Equine distribution of ENaC, NHE3, CFTR, and CaCC is unknown. (*) SGLT1 is present at low levels in colonic epithelium in rodents and humans. CaCC: Calcium-activated chloride channel; CFTR: Cystic fibrosis transmembrane conductance regulator; ENaC: Epithelial sodium channel; SGLT1: Sodium-glucose cotransporter 1; NHE3: Sodium-hydrogen antiporter 3; DRA: Down regulated in adenoma (also known as the anion exchanger). Image created with Biorender.

Figure 2

Absorptive and secretory ion channels of the intestinal epithelium and their regulation by pathogens or pathogen-secreted toxins. The red bars indicate inhibition of the targeted channel, while the green arrows indicate activation. The figure is not intended to imply that the ion channels are all expressed in the same cell but rather to demonstrate the potential conflicting influences of different pathogens on epithelial ion transport. References for each proposed target by the different pathogens are included in Table 1. (*) The proposed mechanism of action of ECoV is extrapolated from data on related pathogens (SARS-CoV and SARS-CoV-2). CaCC: Calcium-activated chloride channel; CFTR: Cystic fibrosis transmembrane conductance regulator; ENaC: Epithelial sodium channel; SGLT1: Sodium-glucose cotransporter; NHE3: Sodium-hydrogen antiporter 3; DRA: Down regulated in adenoma (also known as the anion exchanger), TcdB: Toxin B. Image created with Biorender.