Pain In The Gut? Don't Blame Stomach Acid

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Date: Posted 1/15/2002

Pain In The Gut? Don't Blame Stomach Acid; University Of Michigan Scientists

Show Why Inhibiting Acid Production Could Make Gastritis Worse

ANN ARBOR, Mich. - When it comes to cooling the burning pain of gastritis or an

inflamed stomach lining, reducing the amount of acid in the stomach may seem

like a good idea. But two new studies with laboratory mice, conducted by

Medical Institute scientists at the University of Michigan Medical

School, indicate it could be exactly the wrong thing to do.

U-M scientists found that antibiotics were the best way to kill the bacteria

that cause gastritis and eliminate stomach inflammation in their experimental

mice. Mice treated with prescription drugs called proton pump inhibitors or

PPIs, which block acid production, acquired more bacteria and developed more

inflammatory changes in their stomach linings than untreated mice.

" These animal studies indicate that it is the inflammatory response - triggering

the overproduction of hydrochloric acid - which is the stomach's primary

response to bacterial colonization, " says ita L. Merchant, M.D., Ph.D., an

HHMI assistant investigator and U-M associate professor of internal medicine and

physiology. " Inflammation of the stomach lining coincides with production of

peptides called cytokines, which stimulate production of a hormone called

gastrin. Gastrin triggers parietal cells in the stomach lining to produce more

hydrochloric acid, which kills off most invading microbes. If you inhibit

gastric acid production, you interfere with the stomach's natural defense

mechanism. "

Merchant cautions that without controlled clinical trials, it is impossible to

know whether the results would be exactly the same in humans. She also

emphasizes that a type of bacteria called Helicobacter pylori, the most common

cause of gastritis, was excluded from these studies. Since reduced gastric

acidity does appear to make the mammalian stomach more vulnerable to bacterial

invasion and gastritis, however, Merchant says physicians may want to

re-evaluate the long-term use of omeprazole and other proton-pump-inhibiting

drugs in their patients.

Together with Yana Zavros, Ph.D., an HHMI post-doctoral fellow, Merchant and

colleagues compared stomach cells from normal mice with those from a strain of

transgenic mice, developed at U-M, that lack the gene for producing gastrin.

Their goal was to understand the feedback relationship between bacteria,

pro-inflammatory factors, hormones and acid secretion in the stomach. Results

are published in the January 2002 issues of Gastroenterology and The American

Journal of Physiology.

Mice in the U-M studies contracted gastritis just like people do - from eating

food or drinking water contaminated with bacteria. While 75 percent of people

with gastritis test positive for Helicobacter pylori, many other species of

bacteria can trigger inflammatory changes, too, and often co-exist with

Helicobacter. No matter what type of bacteria causes the problem, it is a

serious medical condition. If untreated, chronic gastritis can lead to peptic

ulcers and stomach cancer.

H. pylori is the only bacterial organism in the stomach that cannot be killed by

hydrochloric acid. Since Merchant wanted to study the relationship between other

bacteria and gastric acid, she needed to exclude the presence of H. pylori. U-M

scientists cultured and analyzed bacteria from stomach washings of all normal

and gastrin-deficient mice to confirm the absence of Helicobacter. Major types

of bacteria identified included Lactobacillus, Enterobacter and Staphylococcus.

U-M scientists treated infected gastrin-deficient mice and normal control mice

with antibiotics for 20 days. Other mice were treated for two months with a

proton-pump-inhibiting drug called omeprazole or with a combination of

omeprazole and antibiotics. At the end of the treatment period, researchers

compared cell changes and bacterial counts from the stomach linings of all mice.

Major findings from the U-M studies include:

* Stomach cell samples from both the transgenic gastrin-deficient mice and the

normal mice whose ability to produce gastric acid was inhibited by omeprazole

all showed significant inflammatory changes -- including more immune cells

called lymphocytes -- and greater numbers of bacteria.

* Gastritis that developed in mice on omeprazole resolved after 20 days of

antibiotic treatment, despite continued omeprazole treatment and low stomach

acidity.

* The number of acid-producing parietal cells and gastrin-secreting G-cells in

the stomach increased in all mice with abnormally low levels of hydrochloric

acid. Elevated numbers of parietal and G-cells correlated with the presence of

inflammation, not with stomach acidity.

* Elevated levels of gastrin during chronic inflammation suppressed production

of a growth hormone called somatostatin, which inhibits parietal and G-cell

function. When the inflammation subsided following antibiotic treatment, gastrin

levels returned to normal releasing the hormonal brake inhibiting somatostatin.

" Our findings show that changes observed in gastrin-deficient mice are caused by

inflammation triggered by an overgrowth of many bacterial species, " Zavros

explains. " An abnormally low level of acidity in the stomach is the factor

initiating all these events. "

" The bottom-line message is that a two-week course of antibiotics to treat the

inflammation is essential for a successful cure, " Merchant adds. " Once you get

rid of the inflammation, the gastric acid levels should return to normal. It is

crucial to take antibiotics for the entire two weeks exactly as your physician

has prescribed, however. People often stop taking their medication early or skip

doses, which helps the bacteria to develop antibiotic resistance. "

In addition to the Medical Institute, this research was supported

by the National Institutes of Health. C. son, Ph.D., an associate

professor of physiology in the Medical School, developed the strain of

transgenic mice used in the experiments. Former U-M post-doctoral fellows

e Rieder, Ph.D., and Amy Ferguson, Ph.D., collaborated in the study.