- Helicobacter pylori has received much attention as the
cause of stomach ulcers, but new research by scientists at the Howard Hughes
Medical Institute (HHMI) at the University of Michigan shows that many
other types of bacteria can cause the gastritis and ulcers that can ultimately
lead to cancer.
- The new research suggests that gastritis and ulcers are
triggered by bacterial overgrowth, rather than by stomach acidity.
- The researchers say their work suggests that long-term
treatment of patients with potent acid blockers, called proton pump inhibitors,
which produce a more alkaline environment that is unfriendly to acid-tolerant
Helicobacter pylori, may actually allow the overgrowth of other types of
bacteria, including Lactobacillus, Enterobacter, Staphylococcus and Probionibacterium.
- Overgrowth is excessive proliferation of bacteria. Proton
pump inhibitors dissipate stomach acid, which serves an important anti-microbial
function and protects the body from ingested microorganisms.
- The findings were published in articles in the January
2002 issues of Gastroenterology and the American Journal of Physiology
- Gastrointestinal and Liver Physiology by HHMI investigator Juanita L.
Merchant and colleagues at the University of Michigan.
- The researchers were studying the action of the hormone
gastrin, which is produced by specific cells in the stomach called G-cells.
Gastrin stimulates growth and acid secretion in parietal cells, another
set of cells found in the stomach.
- "The textbook understanding of how acid secretion
is regulated is that an alkaline pH in the stomach triggers gastrin release,"
said Merchant. "Once gastrin has restored an acid pH by stimulating
parietal cells, acid production is supposed to shut down by way of a feedback
control mechanism in which the suppressing hormone somatostatin is secreted
from D-cells that sense the low pH.
- "The problem is that when the stomach is infected,
gastrin levels rise, and it wasn't clear why," she said. "We
wanted to understand what was happening during bacterial infection of the
stomach that caused this feedback mechanism not to kick in to prevent development
of duodenal ulcers by preventing the production of excess acid."
- To determine whether gastrin itself was really central
to the damage caused by bacterial infection in the stomach, the researchers
studied mice in which the gene for gastrin had been knocked out, leaving
the animals with insufficient acid production, which led to stomach inflammation,
- An important puzzle, said Merchant, was that these knockout
mice could not readily be infected with Helicobacter.
- "Initially we hit a wall, but we realized we actually
had a means to an important insight," said Merchant. "The reason
we weren't able to infect the gastrin-deficient animals with Helicobacter
was that they were already colonized with large numbers of bacteria.
- "This led us to understand more clearly that pH
is regulating the types of organisms that colonize the stomach-Helicobacter
at low pH; mixed flora at high pH."
- When the researchers treated the gastrin-deficient animals
with antibiotics, the inflammation decreased, as did the bacterial overgrowth.
The scientists also noticed that inflammation triggered an increase in
the number of parietal and G-cells.
- When the researchers treated normal mice with the proton
pump inhibitor omeprazole for two months, they noticed that these mice
also developed stomach inflammation that was due to bacterial overgrowth.
- Treating these animals with antibiotics reduced inflammation
and the amount of gastric bacteria. The PPI-treated animals also showed
an increase in gastrin production, as well as an increase in the number
of G-cells and parietal cells, indicating that their stomachs were attempting
to generate acid to battle the bacterial infection.
- When the omeprazole-treated mice were given antibiotics,
gastrin production decreased, as did the number of G-cells and parietal
cells in these animals.
- "A key finding is that we showed that these abnormal
gastrin levels dropped down in omeprazole-treated mice just by giving them
antibiotics," said Merchant. "The question has always been whether
this elevation and regulation of gastrin levels was because the secreting
cells were regulated by the acid concentration. It turns out that's not
the case, because treating these animals with antibiotics caused their
gastrin and parietal cells to return to baseline levels. The elevation
was due to inflammation."
- In the American Journal of Physiology article, Merchant
and her colleagues demonstrated in mice that gastrin overproduction itself
suppresses the ability of the D-cells to secrete somatostatin, which acts
to shut down acid production in the stomach.
- "The dogma in this field has been that the increase
in stomach acid secretion in people infected with Helicobacter was because
the infection was destroying D-cells," said Merchant. "We showed
that this is not correct. At the same time gastrin is stimulating acid
production, it is also inhibiting the D-cell population. Thus, at the same
time that the stomach is making efforts to increase acid secretion, it
blocks the release of the inhibitor of gastrin and acid secretion."
- Merchant said that her group's studies showing that omeprazole
promotes bacterial overgrowth suggest that physicians should prescribe
this class of drugs with caution. Proton pump inhibitors include drugs
marketed under the trade names Prilosec® and Prevacid®.
- "In treating patients with gastrointestinal disorders,
physicians usually aim to increase the pH of the stomach, particularly
in patients who are in the intensive care unit, to try to protect their
stomach linings from ulceration -- which physicians initially believed
was due only to stomach acid," said Merchant. "There is also
the dogma that most ulcers are due to infections by Helicobacter.
- "But one important take-home point from our papers
is that you don't want to block acid secretion over the long term just
to treat either the bacterial overgrowth or the Helicobacter infection,
because that's going to potentially create other problems."
- Antibiotics should be used to treat such bacterial overgrowth,
which will restore the normal acid-control mechanism, Merchant said.
- According to Merchant, many physicians do seem to be
limiting prescription of acid-reducing drugs. But proton pump inhibitors
may eventually be sold over-the-counter, which could lead to chronic use
of the drugs by people who are not being treated by a physician.
- Merchant emphasized, however, that current over-the-counter
acid blockers such as Pepcid AC®, Zantac® and Tagamet®, a class
of drugs called H2 receptor antagonists, will not trigger significant bacterial
overgrowth because they do not suppress acid as completely as proton pump
- "In general, the medical community needs to think
more broadly about chronic infections in the stomach, colon, bladder and
liver, because inflammation in all of these organs can lead to cancer,"
Merchant said. "Helicobacter has quite correctly been labeled as a
significant carcinogen, but our papers emphasize that other organisms can
also cause chronic gastritis that may ultimately lead to cancer."
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