Uninvited tenants: a lung microbe

In May 2007, the National Institutes of Health — the highest authority in the United States in matters of medical research — announced the launch of a giant project called the “Human Microbiome”. The goal of this ambitious multibillion-dollar project was to identify and decipher the human microbial genome. Microbial? It looks like the name of a chain of diet food stores. What is it? In simple terms, a microbial is a collection of all useful, harmful and neutral inhabitants of the human body, mainly bacteria, as well as fungi and viruses. After the decoding of the human genome in 2000, the study of the microbiome should be the next milestone in finding out the causes of diseases.

Why such optimism? If we talk about genes and chronic diseases, the connection is obvious even to the layman. But germs? They cause only acute diseases! Or they just live in the body as tenants, feeding on the waste products of the body, but generally not causing any harm. Yes, it has been thought so for many decades. However, at the beginning of the XXI century, some bacteriologists tried to rise above these ideas. And what if the bacterial flora of a person has a much stronger impact on his health and is not limited only to “classic” infections? What if the billions of microorganisms on the skin, the lining of the intestines, in the mouth or in the nose are not just quiet parasites? What if microbes purposefully control or manipulate the immune system, and their signaling substances are able to cause certain reactions of the body? Can violations of the bacterial flora cause the development of chronic diseases, and not only in the intestine, but everywhere? Are they triggers for common diseases such as obesity and diabetes?

At first, these scientists were ignored and ridiculed. But improved molecular research methods have made it possible to study the microbiome in more detail, and the growing capabilities of computers have made it easier to sort and analyze giant databases. First of all, it was necessary to map microbes: what microorganisms live near us and in what quantity? On the surface of the human body immediately after birth, a characteristic flora of bacteria and fungi begins to gather. As with any flower bed, the combination of their types will be individual. Here are groundcover annuals, there are perennial grasses, in the shade a little moss, a mixture of hyacinths and gerberas, a little yarrow and in addition a couple of bushes-the flower garden is ready. As for the human bacterial flora, the diversity is simply huge: about 10 thousand different types of bacteria live in the intestines and on the skin. Each person has more bacteria in their body than the actual cells: 39 trillion bacteria and 30 trillion cells. The total weight of the bacteria is about 2 percent of the body weight! It has long been known that interference with this flora can cause the development of diseases. Treatment with antibiotics changes the flora of the mucous membranes and can lead to fungal diseases in the mouth, intestines or vagina, and in severe cases-cause inflammation of the intestine due to the uncontrolled proliferation of harmful bacteria. But until now, these side effects were considered acute and temporary disorders: as soon as the antibiotics were finished, the flora was restored to balance.

New trends in microbiology have forced researchers to dig deeper. What is the long-term effect of bacterial flora? Does a person have their own unique microflora, like a fingerprint? And if so, what is the reason for this? What role do the countless bacteria that are not included in the lists of common pathogens play? Do benign bacteria affect our immune system? And most importantly, can a change in the microflora cause or, conversely, prevent the development of chronic diseases?

Indeed, as the new millennium began, more and more information began to emerge about the relationship between microbiome disorders and chronic diseases. Gradually, certain patterns began to emerge. In healthy people, the bacterial flora is stable and diverse, while in patients its composition is poorer, but individual species dominate. There is such a term as “dysbiosis” – a violation of the normal composition of the bacterial flora, which does not cause any specific complaints, but contributes to the development of chronic diseases and can even cause them.

However, many doctors continued to be skeptical, interpreting the change in the composition of the microflora as a consequence of the underlying disease, and not as its cause. However, soon one clinical experiment made a sensation in the world of medicine. With the help of fecal transplantation, doctors transplanted the intestinal microflora of a healthy person to a patient with inflammatory bowel disease, after which the patient’s condition improved dramatically. This is the first time a direct link between dysbiosis and chronic disease has been confirmed. The implementation of the National Institute of Health’s “Human Microbiome” project has opened a new era in medical science. To begin with, scientists have identified which parts of the body can be expected to make the most progress in such studies: the intestine (clear), the skin (logical), the mouth (clear), the vagina (well, so be it). What else? Nothing, nothing at all. You heard right: not a single vote was cast for the lungs. What’s it? A conspiracy of cardiologists, who in this way tried to win back the fame of pulmonologists (and money for research)? The mistake of the pulmonologists themselves, who delayed the application deadline or did not collect all the necessary documents? The answer is simple: a few years ago, the lungs were considered sterile, they had no microflora at all. Why investigate a microbial organ that doesn’t exist?

However, this decision was soon recognized as wrong, and from today’s point of view it really seems a little naive. Already in 2007, voices began to be heard questioning the” sterility ” of the lungs. Why would they be sterile all of a sudden? More than 10 thousand liters of air are pumped through this organ every day. If every liter contains hundreds of bacteria, then some of them must settle in the lungs? However, no matter how hard scientists tried to grow bacterial crops from the mucus of the respiratory tract of healthy people, nothing grew: the soil continued to be barren, despite diligent watering and fertilization-not a stalk, not a leaf. The lungs remained the last stronghold of purity.

For the time being.

Tell me, do you run around the apartment all day for your household with a bottle of disinfectant? Are you wiping your laptop keyboard? And the TV remote? Then pull yourself together: it turns out that the lungs are not sterile, it is all dirt and infection, the same microbiological septic tank as the intestines, skin, mouth, nose or vagina. New methods adopted by molecular biology have revealed an ugly truth: the respiratory tract is teeming with bacteria. However, the lungs are still cleaner than other organs. Unlike the intestines or the oral cavity, there is only one bacterium for every tenth cell. Thus, the lungs are in relative order, there is no reason to call a cleaning team. But even with a sterile operating room, they can not be compared. And even with the villa, where after the murder, the criminals carefully washed everything to destroy the evidence. The lungs have to share the tragic but unavoidable hardships of life with the skin and intestines. Before a person is born, after the first breath, his lungs are already infected. But there is no cause for concern. The bronchi do not need to be cleaned with a disinfectant. On the contrary, most of the uninvited guests are good for our health, and some are simply necessary. Besides, you can’t see them. Nevertheless, you are still interested to know who lives there inside you? Okay, so be it.

Apartment owners always want to know who they rent their living space to. They ask for proof of solvency, inquire about the presence of children, smoking, pets, because all this is important. Our microscopic tenants can also be asked for recommendations, so be on your guard. However, in most cases, this is unlikely to help, since a significant part of them was inherited by us. In this case, the notary at the opening of the will does not ask you whether you agree to enter into inheritance rights. Everyone gets a mandatory share.

So who are your tenants and where did they come from? Their names are unlikely to tell you anything. Why? Imagine that you are a postman, and the lungs are a fourteen-story house in a residential area. The door signs are all unpronounceable names: Streptococcus, Veylonella, Prevotella, Fusobacteria, Pasteurella, Porphyromonade, Acinetobacter, Candida, Lactobacillus, Eurocyomycete, etc. So try to deliver registered letters here! Not an easy task. So you can safely forget all these names — the vast majority of residents with exotic names are completely harmless. But there are also negative characters, asocials, who are so eager for world domination, and they should be followed by public control. There is also a third group — harmless, in principle, creatures, but able to show the dark side of their personality, if they are in the majority or if you give them power. A familiar picture? No wonder they say that biology is a soap opera in miniature, in which new episodes are released every minute!

And where do all these inhabitants of the respiratory tract come from? Out of thin air? Only partially. Most of the microorganisms contained in the air are filtered out in the nose and remain there. Why would they want to go somewhere further, in the nose, too, is not bad. The lung microbiome originates mainly from the digestive tract, more precisely, from the mouth. Just before giving birth, the lungs are an uninhabited island. In the first months of life, tiny droplets of saliva enter the lower respiratory tract through the glottis and deliver the first settlers there. Welcome to the new world! The settlers grow, multiply, and within a few years they are a stable society with their own individual characteristics. The arrival of new residents and the departure of old ones only slightly change the composition, and the microbial lung remains as unique as a fingerprint. But be vigilant! Once formed, such a microbe is practically unchanged. Therefore, careful selection of the first inhabitants is very important. If you make a mistake here, it will affect you throughout your life.

If the lung microbiome is formed mainly from the microflora of the oral cavity, then where does it appear there? As you know, any show is preceded by a preliminary casting. Who conducts the selection of candidates? Parents. More precisely, the mother. The source of microflora in the mouth of a newborn is the mother’s microbe, the microorganisms are literally inherited from her through direct contact with the baby. Their places of origin are the vagina (contact during natural childbirth), the skin (breast-feeding and touching), the mouth (kissing and pre-chewing by the mother of food for the baby-ugh, disgusting!).

When your mother as a child wiped your mouth from chocolate with a handkerchief, which she previously moistened with saliva, it was not a hygienic procedure, but a microbiome transplant. I hated it, and so did millions of other children. Sorry, Mom. The transfer of the mother’s microbiome to the child is a very important and delicate process. Why? Because the lung microbiome stimulates, trains, and to a certain extent even corrects the immune system of the respiratory tract. A mature and strong immune system of the lungs is the result of a healthy microbiome, it consistently and powerfully fights pathogens and shows tolerance towards harmless bacteria and harmless substances such as allergens. If the microbiome is exposed to external influences or the mother transmits it already with dysbiosis, the child’s susceptibility to respiratory diseases increases. Children born as a result of cesarean section, that is, not in contact with the maternal vaginal flora, are later more likely to suffer from allergies and asthma. The risk of developing these diseases is also increased when mothers take antibiotics during pregnancy or immediately after delivery. Today we know that such children inherit from their mother a microbial disorder. Many generations of psychoanalysts really were not wrong: always and in everything the mother and father are to blame. Even in the composition of bacilli.

If there is a disturbed lung microbiome, then what should a normal and serviceable one look like? What does it consist of? Here the situation is the same as with making a list of guests for a party, success depends on the right combination. Two factors are particularly important: diversification (i.e., diversity) and homeostasis (i.e., balance). Thus, you equally need mumblers who fall asleep on the move, and inveterate freaks. The main thing is that some do not strongly dominate over others, unless you have decided in advance to start a fire in the house. But such scenarios are usually not provided for in biology. In people with healthy lungs, the diversity of bacterial species in the microbiome is very large. They get along very well with each other. Different bacteria mutually control each other’s growth, and no one, including possible pathogens, multiplies at the expense of others. At the same time, diversity provides balance, since none of the guests allows themselves too much. Even those who come to the party by accident, drink just enough beer so that it is not obvious, and do not turn on the music at full volume, so as not to give the neighbors a reason to call the police. The main thing is not to cross the border, and everything will be fine. But how to achieve this? How can the host influence what is happening? After all, everything is impossible to control. You can’t control everything, but you can control some things, such as the door and the bar, that is, the choice of guests and the number of drinks. Here you can not make mistakes, otherwise the holiday will get out of control and the house will burn down. Just keep in mind that diversity is great. If you close the door in the face of unwanted people, you will have to deal with the consequences. What can happen in this case is clearly demonstrated by some nationalities living in the far north. More precisely, in the northeast.

Have you heard about Karelia? No? In your opinion, this is the birthplace of Karel Gott? No, Karelia has nothing to do with him. If you have an atlas on hand, look for Scandinavia. Found it? Karelia is located where the isthmus connects the Scandinavian Peninsula with the mainland. Is it beautiful there? I don’t know, I’ve never been, and that’s not relevant. Why did I mention Karelia? Because this is a special region. It is special in ethnic, political, social and cultural terms, and in recent years also in medical terms. You should know that the Karelians traditionally live separately and therefore are a very homogeneous ethnic group in genetic terms. Unfortunately, their habitat is a territory to which neighboring countries show great geopolitical interest: Finland – in the north and Russia-in the south and east. Therefore, the Karelians did not know peace all their lives. In the Second World War, this territory changed hands more than once and was eventually forcibly divided. As a result, the Karelians, unwittingly, in the post-war years became the objects of a giant medical experiment. While the Finnish Karelians increasingly adopted the Western way of life and settled mainly in cities, the Soviet Karelians remained an agrarian people.

In the early 2000s, epidemiologists in the course of research encountered striking differences in the prevalence of respiratory diseases. If every third child in the Finnish Karelians suffered from asthma, hay fever and other allergic diseases, then only every fiftieth child in the Russian Karelians was ill. The scientists were puzzled. Is this an accident? Maybe during the political division, most allergy sufferers switched to the Finnish side and passed on their genes to subsequent generations? Doctors conducted research among the older generation and made an incredible discovery: in Karelians born in the 1940s, allergies and asthma practically did not occur — neither on the Finnish side, nor on the Russian side. The later the Finnish Karel was born after the partition, the more often he suffered from one of these ailments. In Russian patients, the incidence remained at a very low level. If the gene pool of the population on both sides of the border was the same, as well as geological and climatic conditions, it means that the reason for frequent allergies and asthma in Finnish Karelians were differences in the way of life. In 2008, researchers began a systematic search for the causes and found them. It turned out to be the microbiome.

The daily life of Russian Karelians still remains almost the same as at the beginning of the last century. People live on farms and are engaged in agriculture. Often, they share a fairly limited space with pigs, horses, cats, dogs, chickens and sheep. Their families usually have a large number of children. They take their drinking water from the pumps. Many people sleep in the hay. The nearest doctor is a few kilometers away. Finns perceive this way of life as a romance of long-past times. Life in the Russian part of Karelia is not easy, and it is not necessary to take an example from it, but such a habitat and lifestyle give people one thing in abundance: microbiological diversity! The microbiome of the Russian Karelians differs sharply from the Finnish one: the former have a much larger number of bacteria in their airways, and their species composition is much wider. Among them there are those that the Finns do not meet at all or are found in very limited quantities: lactococci, Acinetobacter, and even the bacterium Helicobacter, which has become notorious for its involvement in the occurrence of stomach ulcers. It turns out that this is the cause of allergies?

Scientists continued their search, determined to find out whether strains of these bacteria can influence and even control our immune system. It turned out that sowing lactococci and Acinetobacter on the mucous membranes of mice protects them from allergies and asthma. The bacteria produced substances that blocked the occurrence of allergic reactions. They distracted the immune cells, and they simply ignored the typical pathogens of allergies such as flower pollen or dust mites, ceasing to fight them. These findings fit perfectly into the so-called hygiene hypothesis, which has been discussed by allergists since the 1990s. According to it, the reason for the rapid increase in the incidence of various types of allergies and asthma in developed industrial countries is the Western way of life. People live in too clean conditions and are increasingly moving away from nature. Due to vaccinations and general hygiene measures, the child’s body gets few infections that train the immune system. As a result, she gets bored and tries to occupy herself by attacking harmless particles such as flower pollen, dust mites, or animal hair. So there is an allergy.

The publication of the data from Karelia caused a real euphoria among the supporters of this theory. Is it really possible to prevent allergies with the help of changes in the microbiome? For example, on special “resort” agricultural farms for mothers in the last stage of pregnancy and children immediately after childbirth? Maybe this way you can finally get rid of allergies and asthma, and even better-completely return to nature? Unfortunately, this is not possible. And first of all, because it is unlikely that any achievement in the last 200 years has saved as many human lives as hygiene in all its manifestations. As well as vaccination. Do we really have to throw these truly revolutionary inventions overboard and go back to public wells instead of running water for the sake of a few bacilli in the nose of the Russian Karelians? Of course not. The microbiome is an important, but not the only key to solving the mystery of the appearance of allergies. However, the beginning is made: bacteria are not accidentally found in the lung microbiome, they are not useless ballast and not parasites, some of their types are useful for health.

The research data obtained in Karelia shows how important it is to carefully select guests at the front door. The whole art is to recognize the beneficial bacteria and let them in, and it’s best to do this at the earliest stage of life. If children don’t grow up on farmsteads, the beneficial bacteria can be let in with probiotic-enriched yoghurts. What about adults? Is it really possible to correct the mistakes made in the selection of guests at the time? Yes, it is real. Research on the lung microbiome is still in its infancy, but it already offers hope for the future. So far, one thing is clear: diversity is good for us! Although it’s not just about him. Even if you have invited the right guests, the party can still go wild if you lose sight of the bar!

In April 2010, the doctors of the clinic in the Texas city of Carthage had an unusual patient. He was very drunk, but at the same time he convincingly proved that he did not drink alcohol. He had previously experienced cases of severe intoxication without the use of alcoholic beverages, and this led him to despair. Most of the doctors in the area considered the man a secret alcoholic, and even his wife began to doubt his veracity. The doctors asked when it all started. It turned out that the patient remembers this exactly — in 2004, when he underwent surgery for a broken bone. After surgery, the man took antibiotics for a long time to fight the infection. Hearing this, the doctors became wary. They analyzed the patient’s feces and found a large amount of the yeast Saccharomyces cerevisiae used in brewing! A follow-up examination made it completely clear: after taking the sugar-containing solution, the alcohol content in the man’s blood increased dramatically, because the brewer’s yeast in the intestine was doing its job, turning sugar into alcohol. The patient was prescribed antifungal medication and soon recovered.

What can be useful for yourself to learn from this case? That you can learn to get drunk cheap and thereby bankrupt the entire beer industry? And that, too. But in addition, this episode demonstrates how sensitive and dynamic the human microbiome is. Inconspicuous and harmless Saccharomyces took advantage of the weakness of competitors, which arose due to the use of antibiotics, and secured the most profitable place. An inconspicuous gray mouse, after a couple of drinks, quickly turned into a megalomaniac dictator, staged a beer putsch, and put an end to the fun party until the bouncer regained control. But Saccharomyces is a very harmless type that will not resist, and not all guests can be escorted out of the hall, especially uninvited ones. Unfortunately, some patients with lung diseases lack control at both the front door and the bar. In such cases, someone in the microbiome may secretly try to take over. With a fatal outcome.

With cystic fibrosis — a rare hereditary disease that affects about 10 thousand people in Germany, the production of mucus in the respiratory tract is disrupted. The thick and viscous mucus clogs the small pathways and becomes an ideal breeding ground for bacteria. If the disease is not detected immediately after birth, then sick children draw attention to themselves with frequent respiratory tract infections. Soon there is a vicious circle of inflammation and infection, which destroys a significant part of the child’s lungs. As of 1980, the average life expectancy for cystic fibrosis was only 17 years. Today, thanks to the improvement of treatment methods, most patients live to 30 or even 40 years. It all depends on the moment when one uninvited guest knocks on your door and enters the lung microbe. From this day on, your life will never be the same again.

In the respiratory tract, Pseudomonas aeruginosa settles, which leaves no stone unturned. Pseudomonas is not an ordinary harmless tenant with whom you can somehow get along. Wherever it appears, trouble immediately begins. From a biological point of view, this is a wonderful creature: it is characterized by villainy on a downright Shakespearean scale, and it can survive even in shampoo. Pseudomonas causes severe purulent infections, destroys organs, manipulates the immune system and is not afraid of even the most effective medications. The respiratory tract of patients suffering from cystic fibrosis is particularly attractive to it: the viscous mucus is an ideal nutrient soil for Pseudomonas and also protects it from attacks by the immune system.

There is no effective protection against this pathogen. Pseudomonas appears in the respiratory tract of a quarter of patients in the first year of life, and after twelve years, it is present in almost all without exception. The earlier Pseudomonas appears in the body of a patient with cystic fibrosis, the less likely it is to survive. At first, some help is provided by antibiotics, but after a few months, the causative agent of the disease begins to change and produces offspring that have a protective shell that neither the immune system nor antibiotics can overcome. Pseudomonas is rampant in the lungs, despite the losses, and mercilessly suppresses other types of bacteria. Within a few years, it makes up more than 80 percent of the entire microbiome. Diversity comes to an end, the invader colonies grow one by one. And if it is threatened by a lack of nutrition, it uses a clever trick: it encourages immune cells to create even more foci of inflammation and thereby destroy the lungs even more. It feeds on the resulting ruins. Antibiotics soon turn out to be useless. After each application, the offspring of the pathogen becomes even bolder, more determined, more aggressive. Any progress is only temporary. A patient with cystic fibrosis becomes a victim in an unequal struggle.

But there is still hope, and microbiome research suggests new ideas. The old truth: the enemy of my enemy is my friend. So why not search the microbiome for microbes that compete with the aggressor and make them your allies? Pseudomonas does not like an acidic environment, it does not feel well in it. But other bacteria have nothing against acid and even produce it in large quantities. For example, lactobacilli create an acidic environment in the vagina. If we can purposefully establish the reproduction of these bacteria in the lungs, it will be possible to suppress the spread of Pseudomonas. Perhaps this concept conceals a completely new approach to the fight against infections: to suppress the causative agents of diseases by natural means, using all the same principles of diversity and balance. And then soon Pseudomonas will have a “sour” appearance.

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