杏吧原创

ONE winter morning 17 years ago, a little-known trainee doctor in a
little-known hospital in what is perhaps the most isolated city in the world
swallowed a broth of microbe-laced water. For a week he felt fine, but then he
began suffering headaches and stomach pains. He had hunger pangs even when he
was full. He felt nauseous, and even vomited a few times.

Barry Marshall, then working in Perth, Western Australia, had made his point.
An examination of the lining of his stomach revealed the telltale signs of
gastritis, the first step towards a potentially life-threatening ulcer, or even
stomach cancer.

Thankfully, Marshall recovered. Rather than inflicting death and disease, his
self-induced infection launched him on a high-profile research career, complete
with big grants, his own biotech company, and a Lasker Award鈥攁 frequent
harbinger of a Nobel prize. For Marshall鈥檚 dangerous experiment turned out to be
the turning point in his dogged campaign to convince the medical establishment
that gastric ulcers are caused not by stress or spicy foods but by a bacterium,
Helicobacter pylori.

Because of that campaign, ulcer patients who were once condemned to taking
medicines for life can now be cured with a one-off course of antibiotics.
Meanwhile, a race by labs around the world to develop a vaccine promises to wipe
out H. pylori once and for all, preventing not only ulcers, but also stomach
cancer, which claims more lives than any other cancer except lung cancer.

But just as the tale appears to have reached a happy ending, along come fresh
doubts about whether H. pylori is quite the bacterial bad guy it鈥檚 been cracked
up to be. Some dissenters suspect that it may not be the root cause of ulcers
after all, and others go even further. They say that H. pylori, like many germs,
has lived so intimately with humans for so long that it may now contribute to
our well-being. They point to emerging evidence that H. pylori may protect us
from diarrhoea, as well as a rare cancer now rising fast and mysteriously
throughout the Western world.

鈥淲e鈥檙e so afraid of the bad guys, we鈥檙e trying to live in a germ-free world,
and that鈥檚 fraught with hazard,鈥� says Martin Blaser, a microbiologist at New
York University鈥檚 School of Medicine, who鈥檚 leading the campaign in defence of
the 鈥渦lcer bug鈥�. 鈥淚n a world of black and white, H. pylori is grey.鈥�

So what does this mean for people鈥檚 health? Before searchlights fell on H.
pylori, doctors believed that ulcers were caused when excess acid brought on by
stress or spicy foods eroded the lining of the stomach or the duodenum, the
upper part of the intestine. Bed rest and lots of milk were the standard
treatment until the 1970s, when new acid-blocking drugs like Tagamet and Zantac
became household names. But though these drugs were effective at easing
symptoms, they failed to prevent ulcers from coming back. This was great for the
drugs company, but bad news for the patients and healthcare providers who paid
the bills.

When Marshall first suggested that it was a small spiral bacterium, not
excess stomach acid, that caused ulcers, most experts dismissed the notion
outright. Back then, bacteria were thought to cause only short bouts of
infection, not chronic diseases, and were deemed too fragile to survive in the
stomach, an environment acidic enough to corrode metal.

Then came Marshall鈥檚 self-inoculation. Since then, several studies have found
that treating ulcers with antibiotics makes them go away鈥攁nd stay away.
Further proof that Marshall was right comes from numerous studies showing that
90 per cent of people with duodenal ulcers, and 70 per cent of people with
gastric ulcers, are infected with H. pylori. Aspirin and similar drugs are
thought to cause the rest. Stress and diet have faded from the picture.

Most wanted

As for cancer, the association between H. pylori infection and gastric
carcinoma, which kills hundreds of thousands of people each year, is deemed so
strong that in 1994 the World Health Organization designated H. pylori a
鈥渃ategory 1 carcinogen鈥�, a title reserved for the most dangerous cancer-causing
agents. The bug is reckoned to be responsible for up to 60 per cent of
these cancers, which are particularly prevalent in Asia and many developing
countries. The push is now on to eradicate the infection completely, with
improved hygiene, antibiotics or, if one can be developed, a vaccine.

But despite the confidence with which the war on H. pylori is proceeding, a
number of inconvenient facts are starting to cast doubt on its evil image. The
most glaring is that even though around half the world鈥檚 population is infected
with H. pylori, only a fraction of these people ever get sick. Then there are
the observations of doctors who treat people with ulcers. In one practice in
Maitland, Florida, for instance, only 30 per cent of ulcer patients carry H.
pylori鈥攁n infection rate barely higher than that of the rest of the local
population. The same study found H. pylori in the stomachs of only two of 36
patients with stomach cancer. Similarly troubling observations are popping up in
Japan and other parts of the US. Other doctors claim to have seen ulcer
flare-ups after H. pylori has been banished from their patients鈥� stomachs with
antibiotics. 鈥淭he impression from this is that it鈥檚 not a big bad bug,鈥� says
Douglas Sprung, who ran the Maitland study.

Body of evidence

Doubts about H. pylori鈥檚 guilt also stem from failed attempts to fulfil
Koch鈥檚 postulates. Laid down in the 1800s by German bacteriologist Robert Koch,
these four rules are used to work out whether a particular organism is
responsible for a particular disease. One of the trickiest to fulfil is the
third postulate: the guilty germ should cause the disease when a susceptible lab
animal is inoculated with it. Marshall鈥檚 dramatic experiment is for many the
ultimate proof of Koch鈥檚 third postulate. But his critics point out that
Marshall only came down with mild gastritis. He never gave himself an ulcer.
This distinction is important, they say, because we now know that gastritis is
common in perfectly healthy H. pylori carriers who never go on to develop
ulcers.

To make matters worse, for a long while no one could get H. pylori to trigger
ulcers and stomach cancer in lab animals, though eventually a Japanese team
managed to give Mongolian gerbils both diseases. 鈥淎ll the animals had ulcers
after six months,鈥� says Marshall, 鈥渁nd about a quarter of them had cancer at 12
months.鈥� Others, though, claim the gerbil diseases are not similar enough to the
human conditions to be counted. 鈥淜och鈥檚 postulates have never been proven, not
to this day,鈥� maintains John Graham, a gastroenterologist at Sydney Hospital in
Australia.

Marshall and his allies point out that it is notoriously hard to fulfil
Koch鈥檚 postulates; for a long while, no one could show that HIV causes AIDS in
an animal. But the critics say there could be a simpler explanation: that
triggering disease with H. pylori is so difficult because it鈥檚 not a pathogen
but a 鈥渃ommensal鈥濃�攁 bug that has co-evolved alongside humans for so long
that it is perfectly benign under most circumstances.

Certainly H. pylori has adapted well to life in this seething pit of
digestive juices and hydrochloric acid. Equipped with four whip-like flagella
and a spiral-shaped body, it can propel itself deep into the stomach lining鈥檚
thick, gooey layer of mucus. It converts urea, a gastric waste product, into
ammonia, which may provide shelter from its environment by enveloping it in a
protective alkaline bubble. And it thrives best in 5 per cent
oxygen鈥攅xactly the level found in the stomach鈥檚 mucous layer.

But perhaps the best evidence that humans and H. pylori learned to get along
aeons ago, says Blaser, is the bug鈥檚 worldwide prevalence. It has been found in
mummies dated at thousands of years old. And while H. pylori infection rates
have fallen dramatically in industrialised countries during the past four
decades, thanks to improved hygiene and antibiotics, in parts of the developing
world as many as 90 per cent of the population carries the bug. Most other
mammals appear to carry their own versions of H. pylori. 鈥淵ou could argue that
Helicobacters have always been in mammals, and as our stomachs diverged so did
our stomach flora,鈥� says Blaser.

What鈥檚 more, most infected people have become infected during childhood and
stay that way for life. Recent DNA fingerprinting investigations aimed at
following the bug鈥檚 movements suggest that it鈥檚 normally passed from mother to
child and between siblings, but not between adults. No pathogenic bacterium is
known to do such a poor job at transmission. 鈥淰ertical inheritance from mother
to child, almost by definition means commensal,鈥� says Page Caufield, a
microbiologist at the University of Alabama in Birmingham.

The anti-H. pylori camp interpret things differently. Because the bugs are so
well adapted to living in the stomach, they can afford to cause very little
disease, says Julie Parsonnet, an expert in infectious diseases at Stanford
University in California. 鈥淭hey鈥檝e figured out a strategy where they can live in
the body for a long time. They only have to be transmitted on rare
辞肠肠补蝉颈辞苍蝉.鈥�

Another expert who claims not to be fooled by H. pylori鈥檚 low profile is
David Graham, an H. pylori specialist at the Veterans Affairs Medical Center in
Houston, Texas. 鈥淥ne characteristic of a real commensal is you can鈥檛 get rid of
it,鈥� he says. 鈥淏ut if you clean up the environment just a little, H. pylori
starts to disappear.鈥� Nor is it unusual, he says, for pathogens to inhabit
humans without causing disease. 鈥淲alk around a school yard and you鈥檒l find a
culture for Neisseria meningitidis. It鈥檚 very common, but only a very few
[children] get meningitis.鈥�

In fact, it鈥檚 H. pylori鈥檚 potential for living in the human body while only
occasionally causing disease that brings the two sides closest to agreement. The
bug鈥檚 supporters are prepared to concede that, like other commensal bacteria, it
may turn nasty when something upsets the balance between it and its host, just
as bacteria in the mouth only rot teeth when fed a modern diet high in sugar.
But rather than wage all-out war on the bug, they say we should find out what
turns H. pylori bad and deal with that. In a curious turnabout, the first hints
suggest that those factors might be stress and diet.

鈥淚鈥檒l be a total pariah and say that when you talk to patients you know that
stress plays a big role in duodenol ulcer disease,鈥� says Sprung. 鈥淲hether H.
pylori has any role, I鈥檓 not sure.鈥� He still prescribes antibiotics because
that鈥檚 the recommended treatment, but John Graham does not. He uses acid
blockers instead. 鈥淚鈥檝e got as good a healing rate as any of my colleagues in
Australia, if not better,鈥� he claims.

Stress could also explain why a rash of ulcers followed the 1995 earthquake
in Kobe, Japan, especially among patients who had previously suffered ulcers but
had failed to rid themselves of H. pylori. And diet could explain why people in
the warm regions of both China and Colombia, where fresh fruit and vegetables
are available all year round, are less likely to suffer stomach cancer than
their compatriots in cooler regions, where salt-cured meats are eaten more
often, even though H. pylori infection rates are universally high in both
countries.

For researchers like Parsonnet that is not reason enough to ease up the war
on H. pylori. 鈥淲e have far greater success treating infectious agents than we do
changing people鈥檚 diets,鈥� she points out. In the other camp, those who stand
firm in their belief that H. pylori is commensal argue that getting rid of it is
akin to amputation. It鈥檚 now a part of the body, they say, and one we may not
want to be without.

The first important clue that this might be the case came in 1999, when
Swedish researchers discovered that H. pylori produces substances that kill
bacteria such as E. coli (Nature, vol 398, p 671). Then, last year, researchers
in Germany examined the medical histories of more than 2400 schoolchildren, and
found that 76 per cent of those who were H. pylori-positive had been
diarrhoea-free during the previous three months, compared to 54 per cent of
those who were not infected with the bacterium. 鈥淲e have now found the same
association in an adult population,鈥� says epidemiologist Dietrich Rothenbacher
of the University of Heidelberg, who headed the study.

But by far the biggest splash has come from reports that H. pylori may
protect against oesophageal adenocarcinoma. This form of cancer is still rare,
but its incidence is rising at an astonishing rate鈥攂y 17 per cent a year
in Australia and 11 per cent a year in the US, where it kills 5000 people
annually. The cancer is also on the march in Britain, Norway, France,
Switzerland and New Zealand鈥攁ll nations where H. pylori infection rates
have plummeted.

Still, such a vague association would not have sounded the alert without a
second curious discovery: patients who take antibiotics to rid themselves of H.
pylori have an unusually high incidence of gastro-oesophageal reflux disease, in
which stomach acid gurgles up into the oesophagus, sometimes causing hardening
of the oesophageal lining. That hardening, known as Barrett鈥檚 oesophagus, is a
major risk factor for oesophageal cancer. Other studies suggest that people
infected with certain strains of H. pylori are less likely to develop
oesophageal cancer. The evidence isn鈥檛 conclusive, but the suspicion is there:
the elimination of H. pylori just might be causing the rise in oesophageal
cancer.

Despite those qualms, Marshall, for one, has no regrets at having inspired
the crusade against H. pylori. 鈥淭he risk from H. pylori is still four times
greater than the risk from eradicating it,鈥� he says. And if you ask David Graham
whether he would rid the world of H. pylori if a vaccine were available, he
says: 鈥淚 wouldn鈥檛 hesitate.鈥�

Unfortunately for H. pylori, it seems that the jury is still set against it,
despite what some see as growing cause for reasonable doubt. Commercial
development of vaccines for clinical testing is now under way, and most
indications suggest the death penalty will stand. In the war on germs, it鈥檚
guilty until proven innocent.