Autoimmunity Links Vinculin to the Pathophysiology of Chronic Functional Bowel Changes Following Campylobacter jejuni Infection in a Rat Model.

BACKGROUND: Acute gastroenteritis can precipitate irritable bowel syndrome (IBS) in humans. Cytolethal distending toxin is common to all pathogens causing gastroenteritis. Its active subunit, CdtB, is associated with post-infectious bowel changes in a rat model of Campylobacter jejuni infection, including small intestinal bacterial overgrowth (SIBO). AIM: To evaluate the role of host antibodies to CdtB in contributing to post-infectious functional sequelae in this rat model. METHODS: Ileal tissues from non-IBS human subjects, C. jejuni-infected and control rats were immunostained with antibodies to CdtB, c-Kit, S-100, PGP 9.5 and vinculin. Cytosolic and membrane proteins from mouse enteric neuronal cell lysates were immunoprecipitated with anti-CdtB and analyzed by mass spectrometry. ELISAs were performed on rat cardiac serum using CdtB or vinculin as antigens. RESULTS: Anti-CdtB antibodies bound to a cytosolic protein in interstitial cells of Cajal (ICC) and myenteric ganglia in C. jejuni-infected and naïve rats and human subjects. Mass spectrometry identified vinculin, confirmed by co-localization and ELISAs. Anti-CdtB antibodies were higher in C. jejuni-infected rats (1.27 ± 0.15) than controls (1.76 ± 0.12) (P < 0.05), and rats that developed SIBO (2.01 ± 0.18) vs. rats that did not (1.44 ± 0.11) (P = 0.019). Vinculin expression levels were reduced in C. jejuni-infected rats (0.058 ± 0.053) versus controls (0.087 ± 0.023) (P = 0.0001), with greater reductions in rats with two C. jejuni infections (P = 0.0001) and rats that developed SIBO (P = 0.001). CONCLUSIONS: Host anti-CdtB antibodies cross-react with vinculin in ICC and myenteric ganglia, required for normal gut motility. Circulating antibody levels and loss of vinculin expression correlate with number of C. jejuni exposures and SIBO, suggesting that effects on vinculin are important in the effects of C. jejuni infection on the host gut.

The colon: from banal to brilliant.

The colon serves as the habitat for trillions of microbes, which it must maintain, regulate, and sequester. This is managed by what is termed the mucosal barrier. The mucosal barrier separates the gut flora from the host tissues; regulates the absorption of water, electrolytes, minerals, and vitamins; and facilitates host-flora interactions. Colonic homeostasis depends on a complex interaction between the microflora and the mucosal epithelium, immune system, vasculature, stroma, and nervous system. Disruptions in the colonic microenvironment such as changes in microbial composition, epithelial cell function/proliferation/differentiation, mucus production/makeup, immune function, diet, motility, or blood flow may have substantial local and systemic consequences. Understanding the complex activities of the colon in health and disease is important in drug development, as xenobiotics can impact all segments of the colon. Direct and indirect effects of pharmaceuticals on intestinal function can produce adverse findings in laboratory animals and humans and can negatively impact drug development. This review will discuss normal colon homeostasis with examples, where applicable, of xenobiotics that disrupt normal function.