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H. pylori — Old Foe or Friend?

About 10 years ago, I had stomach ulcers and GERD.  At that time, my old family doctor had prescribed antacids and drugs that interfered with acid production (i.e., proton pump inhibitors).  However, that didn't cure my stomach symptoms. Whenever I discontinued the use of those drugs, the symptoms recurred.

5 years later, my current family doctor had found that I had Helicobacter pylori (H. pylori; a helix-shaped bacterium of the stomach).  He then prescribed antibiotics to eradicate the bug and my stomach symptoms were finally put into remission.

In some case studies, it shows that autoimmune disease— type-1 diabetes, rheumatoid arthritis, and Crohn's disease — has flared immediately after patients eradicated the bug.  In this article, we will examine any relation between H. pylori and autoimmune diseases and allergies.

What's H. pylori?

More than 50% of the world's population harbor H. pylori in their upper gastrointestinal tract[1]. Infection is more prevalent in developing countries, and incidence is decreasing in Western countries.  In India, four of five people had the bacterium; in Denmark, just one of four did.  Countries in transition fell somewhere in between, with the upper classes, who usually benefited from improvements in hygiene earlier than the lower classes, losing H. pylori first[2].

Some facts about the bacterium :
  • It's tough to cultivate the bacterium on petri dishes (i.e., outside the stomach's acidic environment)
  • (1982) The bacterium was linked to gastric ulcers by Australian scientists Barry Marshall and Robin Warren, who were awarded the 2005 Nobel Prize in Medicine.
  • Although the bacterium doesn't prompt ulcerations in the majority of those who harbored it, it almost always incites gastritis, a low-grade inflammation of the stomach
  • H. pylori's helix shape is thought to have evolved to penetrate the mucoid lining of the stomach
  • The lifetime of inflammation elicited by the bacterium predisposes stomach cancer
    • H. pylori is blamed for about 63% of all stomach cancers
    • Strains endowed with CagA (or cytotoxin-associated gene A) incited greater inflammation[3].  
      • Harboring a CagA-positive strain roughly doubled your risk of gastric cancer compared with strains without the gene.
    • Gastric cancer generally struck after age 65.
  • Children who acquire the bacterium grow more slowly than their H. pylori-free peers
  • (1994) the World Health Organization's International Agency for Research on Cancer classified H. pylori as a group 1 carcinogen
Old Foe or Old Friend?

Our association with the bacterium was ancient—In 2007, scientists put a date on the most recent common ancestor of all human H. pylori strains: 58,000 years ago in East Africa.

H. pylori-related diseases were by and large afflictions of old age.  Two-thirds of gastric cancer cases occurred in people aged 65 or older.[8]  But we'd only recently begun living past age sixty en masse.  For the great extent of human evolution, H. pylori wouldn't have caused cancer, and natural selection would have therefore been mostly blind to its presence. Which raised the question: In the lifetime of coexistence before disease arose—six or seven decades, in some cases—what was the bacterium doing?  Was it benefitting the host somehow?

Scientists had penned report after report on inflammation elicited by the bacterium that, over a lifetime, added up to gastritis, ulcers, and cancer.  But, plenty of people—the majority, in fact—harbored the bacterium without complications.  Later researches have also shown some protective benefits against allergies and auto-immune diseases for people harboring the bacterium.  Are the bacteria our old foes or friends?

At beginning, most scientists thought the bacteria our foes, which can cause gastritis, ulcers and ultimately cancer. However, microbiologist Stanley Falkow strove to think about disease-causing pathogens in a larger evolutionary context. And in the broad view, if a bacterium had infected humans for many tens of thousands of years, and, as was the case with H. pylori, caused disease only 10 to 15% of those it colonized, it wasn't strictly speaking a pathogen—a harmful bacterium. That relationship bordered on commensalism and, maybe even mutualism.

"We truly believe that H. pylori has advantage, that it's not a pathogen," says Sabine Kienesberger at NYU's School of Medicine, referring to the bacterium's talent for surviving where little else can.  She's arguing that its dominance of the gastric niche suggests that it belongs there—that we, the hosts, need it there.  Dr. Blaser has also described the relationship between H. pylori and its human host was a biological Nash equilibrium. This Nash equilibrium involved some amount of mutual tweaking.

For Blaser, our longstanding association with the bacterium meant that "gastritis" was likely the evolutionary norm. Now, for the first time in human evolution, most children — more than 90% in the developed world—found themselves without this immune activation.  The new "postmodern" stomach would, he predicted, have consequences.

Regulatory T Cells

If the bug is more mutualist than parasite, how does it actively contribute to the greater whole?  The cardinal rule of coevolution: any commensal tolerated by its host likely engages the host's regulatory immune circuits[6]. And as we've seen repeatedly, strengthening those circuits incidentally prevents inflammatory disorders.

The bacterium as we know now turns up the dial on the very cells that prevented allergic and autoimmune disease: regulatory T cells.  So it will probably come as no surprise that, in addition to warding off allergic disorders, H. pylori may protect against autoimmune diseases, such as lupus, multiple sclerosis, IBD, and perhaps even heart disease.  In summary, scientists have found that:
  • Those with H. pylori infections had much less GERD and fewer cancers of the esophagus (vs. gastric cancer).
    • The association is strongest with the most virulent, CagA-positive strains.
    • The more the bacterium interacted with your stomach lining, the more it wards off GERD and associated malignancies (i.e., esophagus cancer).
  • Those harboring H. pylori had less allergic disease.
    • Youngsters who harbored the bacterium were 1/3 less likely to wheeze, and nearly half as likely to have sinus allergies.
    • For children under age 5, the protective effect of H. pylori infection was stronger still — a 40% reduction in the risk of allergic disease compared with children who did not have H. pylori.
    • The more virulent CagA-positive strains lessened the risk of asthma most effectively.
    • The more the bacterium interacted with your immune system, it seemed, the less your chances of allergic disease.
    • With each course of antibiotics, the odds of losing H. pylori fall between 15 and 50%
      • The more people use antibiotics early in life, the greater their chances of asthma as adults.
      • Similar patterns have emerged for IBD.
      • Children exposed to seven or more courses of antibiotics had nearly triple the risk of developing Crohn's disease compared with those who never took such drugs, and double the risk compared with those who'd taken just one or two courses.
  • Plenty of people are asymptomatic carriers
    • The majority harbored the bug without complications for decades[8]
    • Peptic-ulcer patients vs. asymptomatic carriers
      • Peptic-ulcer patients had 60% fewer T-regs than asymptomatic carriers.
    • Asymptomatic carriers vs. noninfected controls
      • Infected patients had nearly triple the number of circulating T-regs compared with those without the bacterium.
    • Scientists found that acquiring H. pylori early in life reduced the risk of developing eczema and respiratory allergies by more than half.
    • Anne Müller at the University of Zurich found that the earlier H. pylori colonized its host, the better the host tolerated
      • Mice colonized as newborns suffered far less damage from H. pylori than mice colonized later.  Presumably, they'd be less prone to stomach cancer in old age as well.
  • Harboring H. pylori protected against active TB in the Gambia and Pakistan
    • Those with H. pylori were just as likely to carry tuberculosis.  However, they were far less likely to develop active tubercular disease.
    • By activating antimicrobial aspects of the immune system—especially interferon gamma, which was also, incidentally, so important in protection against allergy—H. pylori helped its host manage the tuberculosis infection.
  • One bacterium helped control a second
    • German schoolchildren harboring the bacterium were nearly 1/3 as likely to suffer from diarrhea compared with their helicobacter-free peers.
    • Israeli soldiers hosting H. pylori were less susceptible to diarrheal disease than those without. 

Time of Colonization Is the Key

Anne Müller has found out: The outcome of host-pathogen interaction is extremely different depending on the time of colonization

Studying asthma with mice, she has found that timing was important in preventing allergic disease. Asthma-prone mice that acquired the bacterium earliest were the most protected from wheezing later. Essentially, an early arrival vigorously engaged the host's regulatory circuity, while prompting comparatively little inflammation. With later colonization and more inflammation, the host response became less protective against allergic disease, and more predictive of cancer. The equivalent period in humans, she says, might be the first year of life—the period during which, in many less-developed countries, children still acquire H. pylori.

As affluence increased and sanitary reforms went into effect, colonization by H. pylori occurred later and later.  Delay it a little, and your risk of stomach cancer goes up.  Delay it a little more, and your risk of stomach cancer declines, the odds that you'll develop ulcers increases.

Some scientists also think: If you're exposed to a variety of H. pylori strains, you may harbor a more diverse helicobacter ecosystem, one that inhabits your stomach more peaceably.

Bottom Line

The bacterium can either hurt or help, depending on the greater context of the superorganism.  The only rule here is that insofar as the bacterium elicits damaging inflammation, it will worsen health.  But, to the degree that it strenthens immune regulation, it will prevent diseases of immune dysregulation.  It can do both.

Stomach cancer is a maligancy you want to avoid.  A century ago, it killed more American men than any other cancer, and it remains a major killer of men over 65 in developing countries.  So, it's a good idea to eradicate the bacterium if you:
  • Are older
  • Harbor the more virulent CagA-positive strains
  • Are not an asymptomatic carriers who harbor the bacterium without complications
In parasitology, there's an old rule of thumb: hangers-on that travel from parent to offspring are more likely to confer benefit than parasite that travel horizontally.  If parasites need their current host to reproduce so they can find a home for their own offspring, the thinking goes, then their interests and the host's align.


References
  1. Helicobacter pylori (Wikipedia)
  2. An Epidemic of Absence by Moises Velasquez-Manoff 
    • An excellent book on which this article is mainly based.
  3. Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host
  4. Can Parasites Heal the Gut?
  5. Are Dogs More Protective For Children’s Health?
  6. The secret of the legume: Bond Life Sciences Center researchers pinpoint how some plants fix nitrogen while others do not
    • “There’s this back and forth battle between a plant and a pathogen,” said Yan Liang, a co-author of the study and post-doctoral fellow at MU. “Rhizobia eventually developed a chemical to inhibit the defense response in legumes and make those plants recognize it as a friend.
  7. Gut Bacteria May Be Implicated in Rheumatoid Arthritis
  8. Did Microbes Shape the Human Life Span?
    • "I began thinking that a real symbiont (e.g., H. pylori) is an organism that keeps you alive when you are young and kills you when you are old. That’s not particularly good for you, but it’s good for the species," Blaser said.
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