January 15, 2002
Excessive Growth of Bacteria May Also Be Major Cause of Stomach Ulcers
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.
“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.”
Juanita L. Merchant
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, called gastritis. 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 like
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 inhibitors.
“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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