## 3 Host-Pathogen Interactions in _Campylobacter_ Infections: Understanding the Link to PI-IBS
Additional mediators that could play a role include tumor necrosis factor-alpha (TNF-\(\alpha\)) and interferon-gamma (interferon-\(\gamma\)) [47]. Typically, inflammation is linked to activating cyclooxygenase-2 (COX-2) enzymes and the subsequent increase in prostaglandlannis, which sensitizes visceral afferents, stimulating secretion and promoting intestinal motility [47]. In cases of PI-IBS via _C. jejuni_ infection, the uptake of macromolecules through endocytosis increases, resulting in low-grade inflammation characterized by the release of pro-inflammatory cytokines [1]. Enhanced macromolecule permeability was evidenced by a temperature-dependent augmentation in horseradish peroxidase (HRP) absorption within the PI-IBS group. This phenomenon indicates the activation of the transcytotic pathway in colonic mucosa functional assessments of PI-IBS patients, shown by increased HRP transport at 37 \({}^{\circ}\)C but not at 12 \({}^{\circ}\)C causing the immune activation [48]. Such macromolecule uptake signifies the translocation of antigens from the intestinal lumen to the mucosa, presenting significant pathological implications for mucosal balance when this process is prompted [1]. Subsequent exposures to _C. jejuni_ have been shown to induce elevated levels of ileal \(\beta\)-defensin 2, IL-8, TLR-4 and \(\beta\)-defensin 6, persisting long after the initial infection has resolved [28]. This persistent inflammatory response suggests that low-grade inflammation may play an integral role in pathogenesis. [PERSON] and colleagues demonstrated in vitro that _Campylobacter_ strains linked to PI-IBS exhibit significantly higher levels of invasion and attachment to T84 cells than strains not associated with PI-IBS [9]. This suggests that individuals with higher exposure to particular _Campylobacter_ strains might be at an increased risk of developing PI-IBS, indicating the presence of a biological gradient where the extent of exposure to pathogenic strains correlates with the likelihood of PI-IBS development. Notably, inflammation and mucosal damage are significant markers in patients who have experienced prior infections, such as with _C. jejuni_. This observation is supported by a study which revealed a heightened presence of macrophages and T lymphocytes in consecutive intestinal biopsies [41]. In the context of IBS, it is posited that infection by _C. jejuni_ may precipitate the generation of autoantibodies, for instance, against vinculin [1]. As a PI-IBS rat model demonstrated, these autoantibodies can directly impact intestinal functions, leading to symptoms such as diarrhea resulting from destabilized TJs [1]. An additional pathway in PI-IBS could involve the discharge of histamine from mast cells situated in close proximity to nerve endings [1]. In PI-IBS subjects, there have been reports of activated mast cells around nerve fibers in the ileum [10]. These mast cells release tryptase, which can stimulate neuronal excitation by cleaving the protease-activated receptor-2 (PAR-2) correlated with heightened permeability and increased visceral sensitivity. Notably, neuronal activation in the submuc was significantly elevated in PI-IBS patients compared to healthy individuals, persisting even two years after the resolution of the initial infectious event [10]. The emission of histamine or prostaglandin E2 (PGE-2), coupled with a low-grade pro-inflammatory response, might contribute to visceral hypersensitivity and disruptions in intestinal barrier integrity, such as leaky gut syndrome. These mediators may also be responsible for hyperalgesia, a critical IBS symptom that warrants further investigation within the realm of PI-IBS research. Furthermore, elevated IL-1 expression in rectal specimens of PI-IBS patients underscores the pathophysiological significance of inflammation in developing PI-IBS [41]. The augmented presence of immune cells and intensified cytokine signaling are pivotal in the pathophysiological underpinnings of PI-IBS.