## 3 Host-Pathogen Interactions in _Campylobacter_ Infections: Understanding the Link to PI-IBS
\begin{table}
\begin{tabular}{c c} \hline \hline
1. & Recurrent abdominal pain, on average at least 1 d/wk in the last 3 mo, with symptom onset at least 6 mo before diagnosis, associated with 2 or more of the following: \\ \(\bullet\) & Defecation \\ \(\bullet\) & Change in stool frequency \\ \(\bullet\) & Change in stool form (appearance) \\
2. & Should not meet IBS criteria before the onset of acute illness \\
3. & Symptoms appear either immediately after resolution of acute infectious gastroenteritis or within 30 d of resolution of acute symptoms \\
4. & Infectious gastroenteritis characterized by one of the following: \\ \(\bullet\) & Positive stool culture in a symptomatic individual (preferred) \\ \(\bullet\) & At least 2 of the following acute symptoms (when stool culture not available): \\ \(\bullet\) & Fever \\ \(\bullet\) & Vomiting \\ \(\bullet\) & Diarrhea \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Diagnostic criteria for PI-IBS based on Rome IV. testinal damage significantly compromises gut integrity, enabling both transcellular and paracellular internalization of _Campylobacter_ and its progression toward underlying connective tissues [34]. This damage facilitates the movement of _Campylobacter_ and triggers the translocation of luminal pathogenic bacteria, including _Salmonella_, _E. coli_[9] and _Clostidium_, into internal organ compartments [34]. The resultant breach in the intestinal barrier thus serves as a conduit for these pathogens, potentially leading to systemic infections and amplifying the inflammatory response within the gut environment. _HtrA_ plays a pivotal role in safeguarding _C. jejuni_ against the accumulation of denatured or improperly folded proteins in the periplasm under stress conditions [35]. Upon secretion into the extracellular space during infection, _HtrA_ directly interacts with host cell surface proteins, which have been shown to exert proteolytic activity. The initial identified target of _HtrA_ was the adherens junction protein and tumor suppressor, occludin, claudin-8 and E-cadherin, which _HtrA_ cleaves into various fragments [36]. Additionally, a more recently identified target of _HtrA_ is the tight junction protein occludin [35]. The cleavage of these key structural proteins by _HtrA_ results in the transient disruption of cell-to-cell junctions within the epithelium, facilitating the transmigration of _C. jejuni_ across epithelial barriers by moving between adjacent cells [35]. PI-IBS patients characterized by high fecal proteolytic activity demonstrate enhanced in vivo and ex vivo distal gut permeability, which appears to be directly proportional to the level of fecal proteolytic activity [10]. A distinct group of PI-IBS patients exhibited significantly enhanced in vivo intestinal permeability, as indicated by the lactose-mannitol excretion ratio [27]. Longitudinal studies following bacterial gastroenteritis have demonstrated that, although increased intestinal permeability generally decreases over time, it persists in those who develop PI-IBS [27]. Some clinical studies have shown that 5 out of 10 patients with _Campylobacter_-induced PI-IBS have increased intestinal permeability [10]. Furthermore, some PI-IBS patients exhibit elevated proteinase activity along with increased intestinal permeability. Specifically, elevation in serine proteinase activity may be responsible for the heightened intestinal permeability observed in a subset of PI-IBS patients [37]. These data suggest one or more mechanisms by which _Campylobacter_ infection may induce abnormal gut physiology and function, potentially explaining the symptoms frequently reported in patients with IBS-D. Additionally, robust case-control studies have shown that _Campylobacter_ and other enteric infections are associated with the development of PI-IBS [4; 38; 39], supporting the plausibility that _Campylobacter_ is a causative factor in PI-IBS.