Most people know that asthma, a disease known since ancient times, has become a serious health problem. Statistics from developed countries, which are at least seventy years old, show that the incidence has doubled, if not tripled. The graphs are similar to the retirement savings of your dreams, but actually show an increase in the amount of terrible suffering and, in some cases, premature deaths.
Doctors have known for many years that asthma is somehow connected with gastroesophageal reflux disease. Many people have siping, coughing and shortening of the respiratory tract, characteristic of asthma attacks. And when people with asthma receive medicines from GERD to reduce the acidity in the stomach, and breathing improves. Despite the obvious connection, many doctors believe that reflux disease is the cause of only a small percentage of asthma.
One theory explaining how these two diseases are related is purely mechanical. When gastric juice rises through the esophagus, it can get into the respiratory tract and cause irritation. But this explanation does not take into account allergies and hay fever, often developing against the background of asthma – the main representative of the group of related diseases, which are characterized by increased sensitivity to foreign substances.
After research showed that H. pylori can protect us from GERD, I wondered if it can protect us from asthma. Perhaps the increase in the number of cases of this disease is due to the fact that now fewer children receive the bacterium in childhood, and many accidentally destroy it in the treatment with antibiotics. Could subclinical unrecognized cases of GERD caused by the absence of H. pylori be the main cause of an asthma epidemic?
Although the idea seemed quite reasonable and fit into what we learned in the mid-90s, many considered the conclusion hasty. A decrease in the amount of H. pylori and an increase in asthma cases are undeniable facts, but they could not be related. The increase in the incidence of asthma is correlated with, for example, an increase in the number of TVs in homes or “Volkswagen” on the roads.
I tried to convince a few colleagues who worked with lung disease to explore this potential connection with me, but it seemed too far-fetched. In addition, the medical community was primarily interested in the danger presented by H. pylori. To prove his hypothesis, it was necessary to study the population of patients with asthma, but without the cooperation of a clinical scientist I would not have succeeded.
Then, in 2000, I moved from Vanderbilt University in Tennessee to new York, where I headed the new York University school of medicine. I was very happy to be able to return to my Alma mater and gather a strong team at the faculty. But despite the administrative tasks and pressure, I did not want to give up research. In a new place it was necessary to look for new chances. So my colleagues were asked, ” which one of you is working with asthma?»
All pointed to Dr. Joanna Reibman, a lung specialist, who opened a clinic for adults with asthma at Bellevue hospital in 1991. She politely, but without much enthusiasm, listened to my ideas. One of Joanna’s intellectual strengths is her skepticism. Wild ideas come up all the time, and the woman wasn’t going to believe my idea without proof. Fairly.
Dr. Reibman agreed to attract research patients of his clinic. Their healthy friends and relatives served as a control group. She conducted numerous tests to identify pulmonary functionality and allergies. Fortunately for me, since 2002 she has been collecting and freezing blood samples from participants that could be used for testing on H. pylori. Joanna’s support has become key to testing the hypothesis; she has always been looking for and is still looking for ways to improve the lives of asthma patients.
By 2004, the team of Joanna was in the presence of the blood samples of over 500 people. We agreed that she would send my team some blood serum under code names so that we wouldn’t know who was sick and who wasn’t. This reduced the chances of bias. Guillermo did blood tests, and then we divided the results into positive, negative and unclear. Using re-analyses from almost all unclear managed to get rid of.
Later that year, we sent the results to Joanna and her team, which included Michael Marmor, an experienced epidemiologist. He was doing just the statistical analysis we needed. A few weeks later, Dr. Reibman called and reported that, to her surprise, there was an inverse proportion between the presence of H. pylori and asthma. Nevertheless, she still doubted. After all, how can a stomach microbe protect against lung disease?
We agreed to meet and discuss the results. A week later, Joanna, Mike and the rest of the team arrived at a small hospital of the veteran organization, where my laboratory and a small private office are located. She told about the participants of the experiment-318 patients with asthma and 208 healthy people from the control group – and announced the results of statistical analysis.
The experiment showed that people with a positive test for H. pylori have 30% less chances to get asthma than those who do not have bacteria in the body. Statistics remained even after they took into account other variables that explain the possible predisposition to the disease.
This was the first confirmation of my theory. Nevertheless, the data could be interpreted in different ways.
- What about cagA? I asked. We also tested for the presence of this strain, as in tests for peptic ulcer, gastric cancer and esophageal diseases.
“We haven’t analyzed it yet,” Joanna said.
I was disappointed because the key marker is the garden. It is he who has the worst effect on the ulcer and best of all on the health of the esophagus. If it were possible to predict which story about asthma would be the most spectacular, I was willing to bet that it would become sada as the best indicator of protection from asthma.
“Well,” said Joanna, ” we’ll see.”
Mike stepped in.
– Wait a minute! he said. – I can probably calculate that.
With that, he started typing something on his laptop. We watched in silence. Thirty seconds later, with a sweeping gesture, he pressed the last button and read from the screen.:
– Garden+: probability of 0.6.
Eureka! These words meant that people with this strain are 40% less likely to suffer from asthma.
Amazing strains directly related to ulcers and stomach cancer, as it turned out, it is best protected from GERD, and now from asthma. The paradox, but now the result can be explained by the fact that the Garden most closely interact with their carriers. By that time, we already understood the system of these strains {128}: constant injection of their material into human gastric cells. As if there are two different populations of H. pylori strains. Some-energetic and sociable, cagA-positive. Others, cagA-negative, can be considered more lazy: they are much less likely to contact the cells of the carrier-human.
These strains are likely to live closer to our cells, and others – further, in the stomach cavity. Thus, it is not surprising that it is cagA-positive that most damage the walls. But since they are the most “sociable”, potentially can bring the greatest benefit to the regulation of physiology.
Joanna then looked at the patients ‘ medical records to see when the disease was diagnosed. In childhood appeared the first symptoms or in adulthood? It was found that patients with H. pylori had asthma at an average age of twenty-one. Who did not have it – at eleven. Striking difference. This showed that the absence of H. pylori is more often associated with childhood asthma, and the presence of postponing its onset. A couple of years later, a large study involving children was conducted in canadian Manitoba. It was found that the use of antibiotics in the first year of life leads to a significant increase in the chance of asthma in seven years {129}. They did not specifically search for H. pylori, but their results correlated with my General hypothesis.
A summary of our findings was presented at The annual meeting of the American society of thoracic diseases in may 2005. Unfortunately, we met him with a yawn. Our work did not belong to the main area of study of asthma, and even specialists in pulmonary diseases from the team Joanna was much less impressed with the result than I was.
In Joanna’s study, blood samples were also tested for allergen antibodies to check whether H. pylori is associated with allergic reactions. And there was a connection: the presence of bacteria was associated with fewer reactions to allergens. This indicated that the microorganism protects against allergies.
I continued to work. Will we be able to repeat our results in another population? If we’ve really attacked something worthwhile, we’ll see it again. I wondered if I should use the data from a large study called NHANES III: 20,000 Americans were selected as “representatives of the country”, and from 1988 to 1994, several medical examinations were held with their participation.
Blood test results were still available, including on H. pylori. Sitting in the same small office in the building of the veteran organization, in March 2006, I suggested to the epidemiologist Dr. Yu Chen, a young specialist who recently moved to new York University, to use this data to test the hypothesis of inverse proportionality between the presence of H. pylori and asthma incidence. She agreed and was able to find NHANES III data on 7,600 people with asthma and tests on H. pylori. Joanna’s previous study of 500 people was in itself quite large, but here the sample was fifteen times larger.
On may 5, 2006, Yu sent me an email. “I analyzed the NHANES data… they’re kind of weird.”
In my hurry to catch a plane to Chicago, I put the printed tables in my suitcase. A few hours later, sitting quietly in the cabin, finally considered them. Everything was clear: the data showed that there is indeed an inversely proportional relationship between the presence of H. pylori and asthma. It was especially pronounced for the garden-positive strains. Moreover, the incidence rate was lower by about 40%, as in Joanna’s study.
This is the second large, independent, blind study that produced a result almost identical to the first. Is clearly not a coincidence. It was necessary, of course, to consider other issues, besides the data did not say anything about the absence of H. pylori prerequisite for the development of asthma or Vice versa. But at that moment, sitting in the plane, under the noise of engines and snoring neighbor in the chair, I realized that the hypothesis is true {132}. And he felt as if he had walked a long way and finally, barely breathing, wet with sweat, climbed to the top of the mountain – it was a moment of joyful excitement.
In the study of Yu found additional nuances. All inversely proportional relationships occurred in children under the age of fifteen. The effect was specific to childhood asthma and did not manifest itself in the adult state. Although the incidence has generally increased since the Second world war, it has been most common among children, both in urban and rural areas in all developed countries, but the poor are particularly vulnerable. There are many theories explaining this; one popular is that they are more common with cockroaches and other insects that can serve as important triggers of asthma. But not everyone in the house where cockroaches live has asthma, and many get sick, although they have never seen these small pests. For me, the main question is not even why someone is allergic and after a meeting with a cockroach breathing becomes hoarse. That’s what I understand. The question, rather, is why after this meeting, most children wheezing pass, but not at all.
In the records of NHANES III was information about hay fever, and allergic rhinitis. Again, we found the opposite effect, and again in children rather than adults, and it was stronger for cagA-positive strains. This work was the first evidence that the presence of H. pylori in the stomach of a child can protect it from hay fever. Like asthma, this disease with the gradual disappearance of H. pylori began to spread more and more.
NHANES III turned out to be a real Treasury (taxpayers ‘ money brought real benefits). Yu was able to link the tests on H. pylori with the results of skin Allergy tests in more than 24 000 people. For each of the six allergens considered, there was an inversely proportional dependence on the presence of bacteria, and for four of them (pollen, rye, Thistle, Alternaria) the difference was statistically significant. As with asthma and hay fever, people with H. pylori were less likely to show a skin reaction to allergens. Just to clarify the situation: I do not want to say that there is any direct link between our bacteria and, for example, thistles. Rather, it has some General effect on the immune system, on the ability of people to turn off an allergic reaction.
These additional results were very important because they showed a similar relationship with three different but related diseases: asthma, hay fever, and skin allergies. In addition, the results were confirmed in larger samples {133} when Yu and I conducted another large study. We used analyses taken from people in the NHANES program in 1999. Almost ten years later, the results were similar.
I started studying asthma because of her Association with GERD. At first, he agreed with the popular explanation that heartburn leads to asthma due to the fact that the lower part of the esophagus gets gastric juice, bile and other toxic substances, which then rise up and through the trachea are in the respiratory tract. But this theory does not explain the origin of hay fever and skin allergies, because they develop very far from the esophagus. Given that all these ailments are allergic in nature, the obvious question arose: does H. pylori affect the immune system? And how does a gastric microbe affect the immune system?
The answer I eventually came to is close to the initial observations of Robin Warren, an Australian pathologist who linked H. pylori to gastritis – a large cluster (more than considered normal) of inflammatory and immune cells on the stomach wall. But which wall is normal: modern, without H. pylori {134} and with a small number of the above cells (without gastritis), or more ancient, with H. pylori and a large number of them (gastritis)?
Like the intestine, the stomach wall is home to numerous types of cells involved in the immune system. Among them-white blood cells, fighting infections, and others that regulate immunity. In addition, there are so-called dendritic cells with long protruding processes, which feel the nearby bacteria and react to them. When activated, they transmit an alarm to lymphocytes, the white blood cells that make up the bulk of your body’s police force.
Lymphocytes in different ways strengthen the defense. And besides, they have a memory: most remember any chemical aspect of a particular event, for example, a component of the bacterial wall from a past infection. Every time a child becomes ill with streptococcal pharyngitis, his body remembers them better, and, in the end, with the next infection, symptoms cease to appear – immunity is produced. Vaccines and doses of antigens use such functions to make it strong.
You should not be surprised that the wall of the gastrointestinal tract, from the mouth to the anus, inhabited by cells-dendrites, which detect bacteria, and lymphocytes, which react to them. And on ordinary inhabitants, and on uninvited guests, but not always the same. Lymphocytes remember and intruders who need to catch immediately after detection, and guests who need to be treated very courteously.
In the wall of the stomach also live white blood cells: b-lymphocytes, which produce antibodies, and T-lymphocytes, which are engaged in complex protection. But immune cells can perform opposite functions: to be activators or suppressors. Some primarily trigger inflammation, while others, called regulatory T-lymphocytes or T-suppressors, modify and suppress reactions. We do not want any small incident to escalate into a full – scale war-it will be too destructive. We need a police force to regulate the army – something like a military police force to maintain order in the troops. This is one of the roles played by T-suppressors. Part of the” gastritis ” that pathologists see on the stomach wall during colonization of H. pylori is actually lymphocytes reacting to the bacterium. In the stomach with H. pylori lives more lymphocytes and much more T-suppressors than in the “modern” without this bacterium.
Thus, not every gastritis observed by pathologists is”bad”. It’s a paradigm shift. I believe that T-suppressors living in the stomach, with their functions protect us from asthma and allergic disorders. Pathologists and doctors should understand that “inflammation” of the stomach is normal. It has biological costs, particularly ulcer and cancer, but it also brings benefits that we are beginning to understand only now.
A group of Swiss scientists, led by Dr. Anna Muller, conducted experiments on mice to understand the importance of immune responses caused by H. pylori. Their work confirms its protective role in asthma. Muller with colleagues induced {135} in mice asthma, sprysnuv spray with allergen in the lungs. They showed that when H. pylori was infected, the reaction of mice to the allergen was reduced. Living bacteria in the stomachs protected; the dead did not help in any way. Moreover, mice infected in infancy received better protection. These results are similar to the epidemiological picture in humans. We have shown that the asthma protection provided by H. pylori works for the most part at the beginning of life.
Further experiments have shown that bacteria interact with sensitive dendritic cells of the stomach wall, forcing them to program the immune system to release T-suppressors. H. pylori chose a very clever strategy: T-suppressors suppress immune responses that must destroy bacteria. But this is a great deal, because along with this, they also suppress allergic reactions.
This theory, though not widely known, is valid from an evolutionary and physiological point of view; epidemiological, histological and experimental studies provide parallel evidence: populations of immune cells, the appearance of which provoke H. pylori, protect us from asthma. Again, the idea is not that bacteria are somehow related to cockroaches or pollen. Rather, their presence in early childhood ensures that when the carrier encounters these allergens, it will have time to turn off the immune response before the Allergy gets out of control. And this, most likely, are not only H. pylori. It is possible that there were other similar microbes that died, and with them the population of immune cells. H. pylori can be the leader, the leader of the pack, the main actor of the troupe, or a star in the play, or it is generally a theater of one actor. Yet known. But these “old soldiers” are now rapidly disappearing, which may be a sufficient explanation for the increase in the incidence of asthma.
My ideas about H. pylori – that at the beginning of life they are good for our health, but with age they become dangerous – were not well received by many colleagues. On the contrary, some even called me a heretic.
In many ways, the problem is that the whole doctrine has already been built around the idea of its harm. Part of the resistance stems from a logical scientific principle: to show correlation is not yet to prove causation. People who Rob banks may smoke more than those who live a normal life, but that doesn’t mean that Smoking makes them Rob banks. Moreover, there may be “reverse causation”: Bank robbery is a dangerous business, so people can smoke while struggling with stress.
Despite a considerable number of studies by different scientists, there is little direct evidence of the dual nature of H. pylori. However, the degree of skepticism is too disproportionate to what has already been clarified. By the way, there is no direct evidence that H. pylori causes peptic ulcer. Scientists have shown that its elimination significantly reduces the risk of recurrence, and this is a very important clinical result, but it does not say anything about the original cause.
Imagine I spilled gasoline on my hands and someone set it on fire. As a result, we get burns. Suppose we decided to conduct a study of different methods of treatment and on the right hand struck with an antibiotic ointment, and on the left there, and the right hand has healed better. What conclusion can be drawn? Obviously, the use of antibiotic led to the better outcome. If you run the same test on many people, and on average, an antibiotic-treated hand will heal better than an untreated one, it could be a new standard of treatment.
But such a test can not be considered proof that the burn is caused by bacteria. We see only that their removal contributes to better wound healing. The burn was caused by the interaction of match and gasoline. After action reviews research on the effects of eliminating H. pylori in people already with a history of ulcer, is a phenomenon of the same order. In fact, the only study I know that asked if H. pylori causes stomach ulcers is our own. Working with Abraham Nomura and the Japanese-American population in Hawaii, we have shown that the presence of bacteria in the 1960s is associated with an increased risk of ulcer twenty-one years later. So I’m not saying that her presence is harmless to us. Just the fact that, as in many complex problems of human biology, specific cause-and-effect relationships are difficult to establish. Although H. pylori is usually a necessary condition for the development of peptic ulcer disease, it is not enough. In 1998, I suggested that the ulcer is caused by a change in the microecology of the stomach, which leads to a change in the amount of H. pylori, the types and diversity of its strains, as well as a change in the number and distribution of other organisms. After sixteen years, the idea seems quite reasonable.
After the publication of the first work of Warren and Marshall appeared group “Helicobacter pylori”. Meetings were held all over the world, many of them received a lot of stamps in their passports. Each year, the European community convened a conference on H. pylori, attended by gastroenterologists, microbiologists, pathologists and their students; by the mid-1990s, the number of visitors was already in the thousands. Hot support for pharmaceutical companies ready to join the new “movement” has become an important incentive for meetings.
In 1996 and 1997, when I put forward the idea of “good” helicobacters, the range of reactions was somewhere between bewilderment and contempt. Remember: good H. pylori a dead H. pylori. The Nobel prize, received by Warren and Marshall in 2005, also did not help my case much, although the Committee gave a very thoughtful formulation related to the discovery of H. pylori and its role in the course of peptic ulcer disease. The great revolution, which made the discovery of the bacteria that have destroyed the dogma that the cause of ulcers is stress and its associated hyperactivity. But its place was taken by no less radical dogma: H. pylori must be destroyed.
Doctors who sincerely believed that they were doing a good deed by getting rid of H. pylori, patients who were worried about “infections”, and pharmaceutical companies who are always happy to distribute their products, in particular antacids (one of the most commercially successful drugs in the world), together created a skating rink, which is ready to crush the ancient microbe. Despite the fact that relatively few people suffer from peptic ulcer disease, the rink receives an increasingly powerful impulse to move.
However, I believe that in the end we will understand this: an environmental change of this magnitude – the disappearance of H. pylori – has many consequences, both good and bad. The work shaped my thoughts and made me who I am today: I worry about the disappearance of many microbes from our ancient bacterial heritage. How many other organisms are disappearing or have already disappeared?
Colleagues continue to organize “consensus conferences”, mainly sponsored by pharmaceutical companies, which constantly add new categories of people who need to eliminate H. pylori. The basic practice still sounds like”Identify and cure”. The military analogy for this phrase is”Find and destroy.” Everywhere people are afraid of the presence of bacteria in the stomach, and doctors consider themselves obliged to get rid of this pathogen. Despite the publication of our results in many leading journals, I could not change anything in practice.
Nevertheless, these ideas found a response in communities of microbiologists and ecologists. As my team has played an important role in proving that H. pylori is a pathogen, I am invited to many meetings, to universities, and also included in the composition of leading scientific societies. In his article, I stopped to call the infectious bacteria. This is the process of colonization-countless organisms do the same to our body and live happily there for many years. I’m sure of that.
In addition, time is on my side, the truth will come out, and we will learn how to prescribe personalized treatment: to decide who has H. pylori to destroy, who – to save, and who – to restore. We are moving in the right direction, but in modern medical practice there are too many counterproductive incentives, and it is too inertial – especially when it comes to “sacred cows”.