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Analysis of rats subjected to cold restraint stress (CRS) or restraint stress (RS) reveals that acute stressors exert significant influences such as enhanced permeability, activation of ion release and modified neural function on intestinal epithelial physiology. Jejunum from CRS and RS rats exhibits greater tissue conductance than that from unstressed control rats. Stress activates the release of Cl-.

A study of pertussis toxin involvement in the antigen-induced hypersensitivity reaction in Sprague-Dawley rats injected with the wild-type component of pertussin vaccine reveals that pertussis toxin activates hypersensitivity to co-administered antigens, increases neutrally regulated intake of antigen across the intestinal epithelium and reaginic antibodies and causes hyperplasia of mucosal mast cells. The recombinant wild type pertussis toxin-incited immunophysiological response lasts for more than 8 mo. Bacterial products are active mediators in the immunophysiological reactions to ingested antigens.

Purpose: We investigated the feasibility and safety of intraprostatic administration of bacillus Calmette-Guerin (BCG) and determined the histological changes induced by this approach., Materials and Methods: A total of 36 healthy male beagle dogs 2.2 to 3.6 years old weighing 10.0 to 14.8 kg were randomly assigned to 6 experimental groups. Four groups were given intradermal BCG vaccination and 6 weeks later they were given 0 (group 1), 10 (group 2), 5 x 10 (group 3) or 10 (group 4) BCG organisms intraprostatically. An additional group received prevaccination, followed 6 weeks later by a dose of 10 BCG organisms intraprostatically and then 6 weeks of antibiotics (group 5). Another group receiving no prevaccination and 5 x 10 BCG organisms intraprostatically at week 6 were included (group 6)., Results: Adverse reactions (ARs) were seen in 12 dogs, including inguinal lymphadenopathy in 3, an anal lesion in 5, constipation in 7 and dysuria in 3. There was a trend toward an increased incidence of ARs in high dose groups 3 and 4, fewer ARs in group 5 and no ARs in group 6. There was minimal evidence of systemic dissemination of BCG in any group. Post-necropsy histological analysis indicated higher inflammation as well as glandular destruction in high dose groups 3 and 4. Antibiotics did not seem to lessen the histological response to intraprostatic BCG injection (group 5). Interestingly in nonvaccinated group 6 the level of inflammation as well as glandular destruction was higher., Conclusions: Our results indicate that intraprostatic BCG administration in dogs is a safe and well tolerated procedure. It is free of major or long lasting serious complications.

Successful immune reconstitution would enhance resistance of beige/scid mice to chronic infection with Mycobacterium avium subspecies paratuberculosis, but may cause damage to intestinal tissue. Therefore, we investigated the effect of adoptive transfer of BALB/c mouse splenocytes on lesion severity and intestinal physiology in beige/scid mice infected with M. paratuberculosis. Mice were inoculated intraperitoneally (i.p.) with M. paratuberculosis, and two weeks later were inoculated i.p. with viable spleen cells from immune-competent BALB/c mice. Mice were necropsied 12 weeks after infection when engraftment of lymphocytes, clinical disease, pathologic lesions, and intestinal electrophysiologic parameters were evaluated. Lymphocytes were rare in control beige/scid mice not inoculated with spleen cells. In contrast, high numbers of CD4+, CD8+, and B220+ lymphocytes were detected in the spleen of all beige/scid mice (n = 24) inoculated with spleen cells, indicating that adoptive transfer resulted in successful engraftment of donor lymphocytes (immune reconstitution). Immune reconstitution of M. paratuberculosis-infected beige/ scid mice significantly reduced the severity of clinical disease and pathologic lesions, and numbers of bacteria in the liver. However, intestinal electrophysiologic parameters studied in vitro indicated that intestinal tissues from reconstituted beige/scid mice had reduced short-circuit current responses (due to reduced ion secretion) following electrical, glucose, and forskolin stimulation. These abnormal responses suggested that neural or epithelial cells in the intestine were damaged. We conclude that successful immune reconstitution of beige/scid mice enhance their resistance to M. paratuberculosis infection, but may cause pathophysiologic changes associated with intestinal inflammation.

We investigated whether infection of beige/scid mice with Mycobacterium avium subspecies paratuberculosis can induce intestinal pathophysiologic changes. Six-week-old beige/scid mice were inoculated intraperitoneally with M. paratuberculosis, then were killed 32 weeks after inoculation when the small intestine was evaluated for physiologic and morphologic abnormalities. All infected mice developed clinical disease. The lamina propria of the intestine from infected mice was mildly infiltrated with mononuclear cells containing acid-fast bacteria, and had significantly increased villus width. In vitro physiologic studies in Ussing chambers indicated that M. paratuberculosis infection caused significant abnormalities in intestinal transport parameters. Baseline short circuit current and potential difference were abnormally high in tissues from infected, compared with control mice, indicative of increased ion secretion. Baseline conductance was significantly decreased in infected mice, suggesting that intestinal tissue from infected mice was less permeable to ions. The change in short circuit current following transmural electrical and glucose stimulation was significantly reduced in intestines from infected mice, suggesting that inflamed intestine had neural and/or epithelial cell damage. We conclude that infection of beige/scid mice with M. paratuberculosis triggers significant intestinal pathophysiologic changes consistent with chronic inflammation. These functional abnormalities may contribute to the pathogenesis of the wasting syndrome seen in bovids with paratuberculosis. This animal model provides evidence that T cell-independent mechanisms are sufficient to cause mucosal pathophysiologic changes and inflammation in response to a specific pathogen, and may be of relevance to inflammatory bowel disease in humans.

In summary, immediate hypersensitivity reactions to luminal antigens occur in the intestine and result in pathophysiology including increased permeability and ion secretion. The mechanism involves activation of mast cells with neural amplification (FIG. 5). Released mediators/neurotransmitters may act independently or synergistically on the epithelium to elicit Cl ion secretion. In addition, a cyclooxygenase product of arachidonic acid metabolism, possibly of mesenchymal cell origin, may be a common mediator. However, additional effector cell(s) besides mast cells are undoubtedly involved. This system demonstrates undeniably the concept of neuro-immuno-physiology of gut mucosa.