Gastritis and Hypergastrinemia Due to Acinetobacter lwoffii

Y. Zavros,1 G. Rieder,2 Amy Ferguson,3 and J. L. Merchant1,2,4*

Howard Hughes Medical Institutethe Departments of,1 Internal Medicine,2 Physiology,4
Pathology, University of Michigan, Ann Arbor, Michigan3
*
Corresponding author. Mailing address: 1150 West Medical Center Dr., MSRB1, 35120, Ann
Arbor, MI 48109-0650. Phone: (734) 647-2944. Fax: (734) 936-1400. E-mail:
merchanj@umich.edu .
Received November 7, 2001; Revised January 23, 2002; Accepted February 13, 2002.
This article has been cited by other articles in PMC.

• OTHER SECTIONS▼
o ABSTRACT
o MATERIALS AND METHODS
o RESULTS
o DISCUSSION
o REFERENCES

ABSTRACT
In humans and mouse models, Helicobacter pylori is associated with an increase in serum gastrin
and gastrin-expressing (G) cells with a concomitant decrease in somatostatin-expressing D cells.
Inflammation of the gastric mucosa can progress to metaplastic changes in the stomach and to
decreased colonization by H. pylori and increased colonization by non-H. pylori organisms. In
addition, about 20% of individuals with chronic gastritis are H. pylori negative, suggesting that
other organisms may induce gastritis. Consistent with this hypothesis, we report here that
Acinetobacter lwoffii causes the same histologic changes as does H. pylori. Gastric epithelial
cells were isolated from the entire stomach by an enzymatic method for quantitation by both
flow cytometry and morphometric analysis. Two months after mice were inoculated with H.
pylori or A. lwoffii, the mucosal T- and B-cell numbers significantly increased. After 4 months of
infection, there was a threefold increase in the number of G cells and a doubling in the number of
parietal cells. A threefold decrease in the number of D cells occurred in H. pylori- and A. lwoffii-
infected mice. Plasma gastrin levels increased after both H. pylori and A. lwoffii infection.
Histology revealed the presence of inflammation in the gastric mucosa with both A. lwoffii and
H. pylori infection. A periodic acid-Schiff stain-alcian blue stain revealed mucous gland
metaplasia of the corpus. Collectively, the results demonstrate that gastritis and hypergastrinemia
are not specific for H. pylori but can be induced by other gram-negative bacteria capable of
infecting the mouse stomach.

• OTHER SECTIONS▼
o ABSTRACT
o MATERIALS AND METHODS
o RESULTS
o DISCUSSION
o REFERENCES
Helicobacter pylori causes chronic atrophic gastritis, and its presence is correlated with the
development of peptic ulcer disease and gastric adenocarcinoma (19, 25, 27). However, there is
also an association between colonization of the stomach by non-Helicobacter organisms and
chronic atrophic gastritis (7, 9, 30). Approximately 25% of gastric cancer patients have no
evidence of previous or current H. pylori infection based on serology (12). In addition, during
long-term acid suppression, the presence of H. pylori and that of non -H. pylori bacteria are
independent risk factors for the development of atrophic gastritis (29). Studies of several animal
models and humans have clearly shown that bacteria are important in triggering mucosal damage
and inflammation in the stomach (15, 20, 42). In addition, under hypochlorhydric conditions it is
known that bacterial overgrowth by non-Helicobacter organisms triggers perturbations in the
neuroendocrine and epithelial cell populations (42). The implications are that the pathology
observed may not be specific for H. pylori but instead is the general response of the gastric
mucosa to colonization by bacteria.
H. pylori is characterized by its ability to survive in the low-pH milieu of the stomach by
generating an alkaline microenvironment. With reduced levels of acid (hypochlorhydria or
achlorhydria), the competitive niche established by H. pylori dissipates and the human stomach
becomes susceptible to colonization by other organisms (9, 18). Gastric colonization by gram-
negative bacteria other than H. pylori is common in intensive care unit patients, who often have
an alkaline gastric pH due to routine treatment with antacids, proton pump inhibitors, and
histamine 2 receptor antagonists. Antiulcer medications are known to increase the gastric pH and
permit colonization of the stomach by opportunistic pathogens, such as Acinetobacter
baumannii, Klebsiella pneumoniae, and Pseudomonas spp., believed to contribute to the
development of nosocomial pneumonia (8, 36). Patients with pernicious anemia are colonized by
organisms other than H. pylori and develop atrophic gastritis and elevated levels of gastrin in
serum (9, 18). Moreover, 2 weeks of proton pump therapy reduces gastric acid by 75% and is
sufficient to permit bacterial colonization of the stomach in healthy volunteers (23). In addition,
our recent studies have demonstrated that the rise in plasma gastrin levels in mice with chronic
gastritis is the result of inflammation and not gastric pH (42). The genera of bacteria isolated
from these stomachs include gram-positive and gram-negative organisms, e.g., Neisseria and
Acinetobacter species (34, 35). In addition, about 20% of individuals with chronic gastritis are
H. pylori negative, suggesting that organisms other than H. pylori induce changes in the normal
stomach.
The study described here tests the hypothesis that inflammation in the stomach may be caused by
organisms other than H. pylori. We have recently shown that a mixed microaerophilic culture of
Acinetobacter, Pseudomonas, and a gram-positive species stimulates an increase in serum gastrin
levels when inoculated into the mouse stomach (26). In addition, live cultures of the bacteria
stimulated gastrin and interleukin-8 promoter activity. We found that the protein mediating the
promoter activation is a major outer membrane protein (OmpA-like protein) from the
Acinetobacter lwoffii family. Therefore, we analyzed whether oral inoculation by A. lwoffii alone
is sufficient to trigger gastritis, hypergastrinemia, and the same neuroendocrine cell changes as
those observed with H. pylori.