Beloved Enemy
What the stomach bacterium Helicobacter pylori can teach us.
When I was a child, I had stomach pains from time to time. They were annoying, but over time I got used to them and didn't waste much thought on them. My father believed that I had a nervous stomach and had to watch out for stress. As a student, however, I realized that, unlike my fellow students, I could drink less cocktails at various parties if I wanted to still feel good the next day. This was a drastic experience, because I usually overlooked the point of no return and had to pay for it the next day with an over-acidified stomach and severe pain. That was the moment when I decided to see a doctor. After a gastroscopy I received the diagnosis: I had the stomach bacterium Helicobacter pylori.
My attending physician advised me to take an antibiotic. The name of the drug sounded as if the marketing department of the pharmaceutical company had collectively smoked a joint: ZacPac. I could picture them searching for a name for their newest antibiotic and an imaginary Peter, intern and break clown who had been through a long evening before, shouted into the room, "And how about ZacPac? Silence. While suggestions like Panamoxiclari or Claripantamo had come in from various earned employees so far, this name seemed like a joke. ZacPac? Was that serious? And then the manager, who wanted to leave early for the weekend that Friday because he still had a date with his girlfriend at a bar that night, decided: make it so!
I took the drug for a week
So I looked at the desk where, as if by magic, the medication had already been put down by my doctor and said yes.
ZacPac is - contrary to the name - not a fancy candy but a pretty tough mixture of Pantoprazole, an acid inhibitor, and the antibiotics Amoxicillin and Clarithromycin.
I took the drug for a week and since there was no final checkup scheduled afterwards, I forgot all about it and assumed that I no longer had a stomach bacterium. I devoted myself fully to my wild student life again.
What is Helicobacter?
Helicobacter pylori is a gram negative bacterium that is present in half of the earth's population.
It is microaerophilic, meaning it can tolerate only very small amounts of oxygen, and lives in the human stomach. The cell has the shape of a drill. With its coils, it can bore into the stomach mucosa and settle there. At the same time, the stomach, with its high content of corrosive acid, is not a particularly nice home for bacteria. A pH of 1-1.5 means an extremely hostile environment for any form of life. Only the stomach mucosa prevents the stomach from digesting itself.
H. pylori was discovered late. Australians Warren and Marshall were able to isolate the S-shaped bacteria in 1982. Both suspected a link between these bacteria and the often observed gastritis, the inflammation of the stomach mucosa. The question, however, was whether these bacteria caused gastritis or merely accompanied it. To find out, Marshall launched a spectacular self-experiment. After demonstrating that his stomach was free of Helicobacter, he swallowed a whole load of these microorganisms. After only a few days, a biopsy showed that Helicobacter had settled in his stomach. In addition, he had developed gastritis. When he subsequently treated the bacteria with antibiotics, his gastritis disappeared again. He had thus proven that Helicobacter was responsible for the gastritis. This was groundbreaking, because until then it had been thought that stress and poor nutrition were the cause. In the years that followed, scientists from all over the world showed that ulcers and stomach cancer were caused by this stomach germ. Stomach cancer is extremely deadly. Only 10% of people diagnosed with it survive the following five years.
Both researchers therefore received the Nobel Prize for their discovery in 2005, and in 1994 the WHO declared Helicobacter pylori a public enemy: it was classified as a cancer-causing agent - the worldwide hunt for this bacterium had thus begun.
Many questions remained open
The WHO judgment was also the opening of a gigantic market for the pharmaceutical industry. We remember: 50% of people have Helicobacter and it should now be eradicated. There are rarely target groups for the pharmaceutical industry that are so huge.
So, while doctors around the world were trying to eradicate the germ, some questions still remained unanswered. Why did only a fraction of people carrying H. pylori develop ulcers and stomach cancer? And why had researchers in the 19th century demonstrated that eventually these S-shaped bacteria could be seen in everyone's stomach? After all, even if Warren and Marshall had been able to culture the bacteria, their presence had been known 100 years earlier. So if everyone had carried this bacteria before and now only 50% did, then the germ was already disappearing.
Helicobacter is transmitted through feces or excretions via the throat, e.g. when kissing.
The subsequent studies were able to show that the reason for the strong decrease of H. pylori was the increasing improved hygienic conditions. Helicobacter is transmitted through feces or excretions via the throat, e.g. when kissing. Most transmission occurs in childhood. So improved hygiene at least greatly reduced transmission through feces.
Also, the cells must carry certain genes to be pathogenic. The environment too seems to play a role in whether or not a disease breaks out. The situation was not as clear and straightforward as the WHO had seen it at the time.
My re-encounter with H. pylori
When I underwent a colonoscopy and gastroscopy many years after my ZacPac experience, I had not bothered about Helicobacter until then. The gastroenterologist surprised me with the finding that my Helicobacter had returned and recommended immediate eradication. By now I was a trained microbiologist who didn't easily fall for fancy marketing names from pharmaceutical companies and decided against it, much to my doctor's displeasure. Instead, I wanted to persuade "my" Helicobacter to say goodbye to me voluntarily. Over the course of two years, I ate Manuka honey from New Zealand, which is said to have anti-inflammatory properties and is recommended by many as an alternative method for Helicobacter eradication. At the end of this path, I had subsidized the honey business in New Zealand with several hundreds of EUROs, only to learn from my doctor that I was still H. pylori positive.
The quadruple therapy applied swept over me like a thunderous whirlwind and paralyzed me.
It came again to an argument, in which I tried to convince my physician that Helicobacter was a part of me and we had already made intimate friendship. Meanwhile, it was suspected that I carried a stubborn Eastern European strain that had survived the attack of the standard French triple therapy ZacPac. Since I was born in former Czechoslovakia, it was not a surprising realization. Eventually, I got tired of always arguing with my gastroenterologist and agreed to a second eradication attempt.
The quadruple therapy applied swept over me like a thunderous whirlwind and paralyzed me. A combination of proton pump inhibitor (PPI), bismuth potassium salt and the antibiotics tetracycline and metronidazole were used. For ten long days I had side effects such as restlessness, shortness of breath and sleep disturbance until the pack was finally empty. The subsequent success control at the doctor's confirmed it: Helicobacter had left me. This also ended the years-long argument with my doctor. But already when I left the practice, I felt a certain uneasiness.
Our oldest companion
Helicobacter is one of the oldest companions of humans. Genetic analyses confirm that we have carried the germ inside us for at least 100,000 years. Since the methods cannot look further back, it is strongly suspected that already since the origin of Homo Sapiens, H. pylori has been our constant companion. As a microbiologist whose specialty is microbial ecology, it is very difficult for me to imagine that this germ has survived in us for so long without also having positive effects. Communities, whether microorganisms, animals or humans, only last when everyone not only takes but also gives! Real win-win relationships, which also form the basis of every management theory for successful cooperation.
And with H. pylori should it be different? Helicobacter was the parasite that had managed to settle in us for 200,000 years and only cause damage? That would be difficult to imagine ecologically.
The decrease in the risk of developing stomach cancer was therefore bought with an increase in the risk of developing GERD, esophageal cancer or asthma.
And in fact it is known that Helicobacter has not only negative but also positive effect. People in whom Helicobacter has been eliminated suffer more from reflux. In this case, the muscles at the end of the esophagus no longer close properly and stomach acid can be pushed up into the esophagus. This causes an unpleasant and burning sensation. If reflux becomes chronic, then GERD can develop: Gastroesophageal Reflux Disease. GERD causes nausea, vomiting, difficulty swallowing and chest pain. It now affects between 10-20% of adults in the United States. Additionally, it is known that due to constant irritation from stomach acid, the lower part of the esophagus can change in 10% of reflux sufferers, resulting in a certain type of esophageal cancer. This particular form of cancer, also called esophageal adenocarcinoma, is the fastest growing cancer of all known cancers and now accounts for 80% of all cancers of the esophagus.
Asthma is also thought to be caused, at least partly, by the absence of H. pylori. It is now known that H. pylori positive people have a much lower risk of developing it.
The decrease in the risk of developing stomach cancer was therefore bought with an increase in the risk of developing GERD, esophageal cancer or asthma.
The bigger picture
But how does it come to this? In short, Helicobacter cannot be considered isolated either. Like all bacteria of the microbiome, it is involved in various processes of the body. Here, the immune system also plays an essential role, which is activated in a special way by the gastritis caused by Helicobacter. This activation results in H. pylori positive individuals being far less vulnerable to asthma than H. pylori negative individuals.
If Helicobacter is eradicated, ecological niches are created that are taken over by other bacteria.
In addition, H. pylori activates hormones that play an important role in gastric acid production via the inflammation it causes in the stomach mucosa. If the bacterium is absent, gastric acid continues to be produced almost indefinitely, even in advanced age, and can cause the problems and diseases mentioned above.
But Helicobacter is also in constant exchange with other bacteria. It is now known that the stomach also has its own microbiome. If Helicobacter is eradicated, ecological niches are created that are taken over by other bacteria. In addition, the drugs used harm the microbiome and drastically reduce its diversity. The so-called alpha diversity, the measure of species diversity, is further reduced. However, reduced diversity is destabilizing to a community.
Helicobacter and neurodegenerative diseases
Research on Helicobacter is in full progress. The interaction with our body and the other microorganisms as part of the microbiome is still far from being understood. Eradication with quadruple therapy is radical and can cause great damage to our microbiome.
New research also shows an involvement of H. pylori in Parkinson's disease. Currently, it appears that H. pylori promotes Parkinson's disease. But who can say what future research will find out? There are studies showing that people with Parkinson's who also have H. pylori have worse symptoms than patients without the bacteria. But the mechanisms are largely not yet understood.
We will certainly have to expect sensational findings
So is Helicobacter involved in the pathogenesis? Or might it be that eradication promotes the disease? It is now suspected that the disease originates in the gut and spreads to the brain via the gut-brain connection. But is Helicobacter the essential parameter here, or is it not rather the change in the microbiome that causes people to develop the disease or not? Particularly in the development of neurodegenerative diseases, we will certainly have to expect sensational findings with regard to the microbiome.
To eradicate or not?
The Helicobacter story has not yet been written in its entirety. It is quite possible that the evil Helicobacter will become a real hero in the end. The increase in various types of cancer after the eradication of Helicobacter at least speaks against a one-sided view of what is happening.
If I had to decide again, then from today's point of view and with my knowledge as a microbiologist, I would no longer eradicate H.pylori from my body. This opinion will not be shared by the majority of doctors and scientists, as it is still fashionable today to attribute the role of evil to Helicobacter.
But the fight against H. pylori is also a big market for the pharmaceutical industry. This influences decisions and studies. And we still know far too little about the true role of the microbiome to make generalized judgments.
Further reading:
Martin J. Blaser, Missing Microbes; How the overuse of antibiotics is fueling our modern plagues, Henry Holt and Company, New York.
Pero R, Brancaccio M, Laneri S, et al (2019) A Novel View of Human Helicobacter pylori Infections: Interplay between Microbiota and Beta-Defensins. Biomol 9:237. https://doi.org/10.3390/biom9060237
Engstrand L, Graham DY. Microbiome and Gastric Cancer. Digest Dis Sci. 2020;65(3):865-873. doi:10.1007/s10620-020-06101-z
McGee, D. J., Lu, X.-H., & Disbrow, E. A. 2018. Stomaching the Possibility of a Pathogenic Role for Helicobacter pylori in Parkinson’s Disease. Journal of Parkinson’s Disease, 8(3): 367–374.
Ye Q, Shao X, Shen R, Chen D, Shen J. Changes in the human gut microbiota composition caused by Helicobacter pylori eradication therapy: A systematic review and meta‐analysis. Helicobacter. 2020;25(4):e12713. doi:10.1111/hel.12713
Suerbaum (2002) Review Article Medical Progress Helicobacter pylori Infection