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Page 6 of 19 Son et al. Microbiome Res Rep. 2025;4:29 https://dx.doi.org/10.20517/mrr.2025.14

pathway. Specifically, NF-κB suppresses tuberous sclerosis complex 2, a negative regulator of mTOR
[60]
[60]
complex 1 , thereby enhancing mTOR signaling and driving cell proliferation .
Peptidoglycan, another bacterial cell wall component, is found in both Gram-negative and Gram-positive
+
bacteria. However, in F18 E. coli, peptidoglycan is shielded by LPS and is therefore less effectively
recognized by PRRs in epithelial cells than in Gram-positive bacteria. The cell wall of Gram-positive
bacteria also contains teichoic acid and lipoteichoic acid, which are recognized by Toll-like receptor 2
(TLR2), either as TLR2/TLR1 or TLR2/TLR6 heterodimer located on the apical surface of epithelial
cells [61,62] . Thus, TLR2-mediated recognition is primarily associated with Gram-positive bacteria. This
recognition activates the MyD88-dependent signaling cascade and the extracellular signal-regulated kinase
(ERK) pathway, promoting the secretion of anti-inflammatory cytokines such as interleukin-10, which help
reduce intestinal inflammation.

MECHANISMS OF F18 E. coli -INDUCED PWD IN PIGS
+
F18 E. coli secretes several toxins in the small intestine, including heat-labile toxin (LT), heat-stable toxin
+
(ST), Shiga toxin, and enteroaggregative E. coli heat-stable enterotoxin . Among these, the major toxins
[11]
responsible for PWD are ST and LT, both of which disrupt electrolyte balance, ultimately leading to
diarrhea. ST toxins exist in two forms: heat-stable toxin a (STa) and heat-stable toxin b (STb). The receptor
for STa is located on the brush border membrane of enterocytes and is known as transmembrane guanylate
cyclase C [Figure 2A] . Upon STa binding, the intracellular catalytic domain of the receptor is activated,
[63]
converting guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). Increased cGMP
levels activate both cyclic adenosine monophosphate (cAMP)-dependent protein kinase A and cGMP-
dependent protein kinase II . These kinases phosphorylate the regulatory domain of cystic fibrosis
[64]
transmembrane conductance regulator (CFTR), altering its conformation and ion channel function. This
+
[65]
-
results in increased Cl secretion and decreased Na absorption . The resulting electrolyte imbalance
creates an osmotic gradient that drives water into the intestinal lumen, leading to watery diarrhea in pigs. In
contrast, the receptor for STb is sulfatide, an acidic glycosphingolipid located on the apical membrane of
enterocytes [Figure 2B] [66,67] . STb binding activates a GTP-binding regulatory protein, which increases
intracellular Ca levels through ligand-gated Ca channels . Elevated Ca activates calmodulin-dependent
2+
2+
2+
[66]
protein kinase II, which in turn phosphorylates CFTR and modulates electrolyte channels . This signaling
[68]
cascade enhances Cl efflux and promotes water movement into the intestinal lumen, contributing to PWD.
-
LT contributes to electrolyte imbalance and water secretion in a mechanism similar to that of ST, primarily
through CFTR activation in the small intestine. Structurally, LT consists of an A subunit and a pentameric B
subunit . The B subunit binds to the monosialotetrahexosylganglioside (GM1) receptor on the mucosal
[69]
surface of the small intestine , facilitating endocytosis of LT into epithelial cells [Figure 2C]. Inside the cell,
[70]
the A subunit is cleaved into A1 and A2 fragments . The A1 fragment increases intracellular cAMP levels
[70]
in the cytoplasm , which then activates protein kinase A. This kinase phosphorylates CFTR, leading to
[71]
altered electrolyte transport and ultimately causing PWD in nursery pigs.
F18 E. coli CHALLENGE MODEL AND ITS IMPORTANCE
+
F18 E. coli infection is commonly observed during the nursery phase on commercial pig farms. To mitigate
+
its negative impacts, researchers have developed dietary interventions targeting this pathogen [30,34,35,72,73] . The
efficacy of these interventions is typically evaluated using the F18 E. coli challenge model, which aims to
+
replicate conditions found in commercial settings. Several factors must be considered to accurately mimic
+
F18 E. coli infection under such conditions. Pigs used in the challenge model should express the F18
+
receptor, which facilitates the attachment and colonization of F18 E. coli. Previous studies have identified