The continuing overuse of antibiotics in children and adults, changing birth practices, and the dosing of our farm animals with mountains of drugs inevitably have an effect on our bacteria, friend and foe alike. More than fifteen years ago, I began to think about what those effects might look like and to formulate the idea that the loss of our ancient, functionally conserved microbial inhabitants has led to the modern plagues I have mentioned: obesity, juvenile diabetes, asthma, and the rest.
The next five chapters explain the results of experiments I performed in my laboratory, first at Vanderbilt University and since 2000 at New York University, in an effort to confirm this hypothesis. The work has had many unexpected twists and turns, failures and successes, lots of hard work, and disappointments of every type. Still and all, the work is ongoing; the exciting days more than equal the busts, and we have been getting somewhere. Some days the results are so clear and so beautiful (thanks to great students who have learned to present their findings with artistry) that I can’t believe they are quite true. But the good ones keep happening again and again, and that’s how we know they are real. And I am running as fast as I can.
The ancient stomach bacteria Helicobacter pylori have been my guide for nearly thirty years. When they were discovered, or as you’ll soon see rediscovered, in 1979, their impact on human health was not obvious. Only later did it became clear that they led to specific diseases. But for the past eighteen years, my research has focused on how H. pylori keeps us healthy.
Making us sick/keeping us healthy—this may seem contradictory, but this dual nature has plenty of company in the natural world. More than fifty years ago the microbial ecologist Theodore Rosebury coined the term amphibiosis, the condition in which two life-forms create relationships that are either symbiotic or parasitic, depending on context. One day the organism is good for you—let’s say it fights off invaders. The next day it turns against you. Or, on any day, both happen simultaneously. Our colonization by the viridans streptococci discussed earlier is an example. Amphibiosis is all around us, including in our work relationships and marriages. It is at the heart of biology, in which the constancy of natural selection forces myriad nuanced interactions.
Amphibiosis is a more precise term than commensalism. Commensalism has been used to describe guests who come to the dinner table to eat; it’s not so hard to serve them an extra meal, but they don’t contribute much if anything to the upkeep of the kitchen. Until recently, that is more or less how we considered the microbes living in the human body, what we called the normal flora. Now we know that Rosebury’s amphibiosis better describes the more complex relationship between our bodies and our indigenous organisms. Helicobacter pylori is the best model I know for these interactions, and exploring its biological interface with humans can help us understand the wider world of our normal resident microbes.
H. pylori are curved bacteria found in essentially only one place: the human stomach. Billions of them live in a thick layer of protective mucus just inside the stomach wall. Mucus lines the gastrointestinal tract from your nose to your anus. It is a gel that helps food slide down and protects the walls of the GI tract from the digestive processes. In each part of the GI tract the locally produced mucus differs in its chemical composition, and, importantly, each zone has its own bacterial species. Your stomach mucus is particularly thick, forming a barrier against the highly acidic environment needed to break down food and repel pathogens. It’s here that we find H. pylori.
Helicobacter pylori have deep roots in evolution. The first primitive mammalian ancestor had a single stomach that laid the blueprint for all the stomachs that followed. As mice, monkeys, zebras, and dolphins radiated in separate directions, so did their stomachs, each with its own acid secretions, mucous layer, and the microbes evolved for that niche. Today we can recognize many Helicobacter species in mammals: H. suis in swine, H. acinonyx in cheetahs, H. cetorum in dolphins, and H. pylori in humans.
We know from genetic studies that humans have carried H. pylori for at least 100,000 years, which is as far back as we can determine using available methods. It’s reasonable to assume that we have had the microbe with us since the origin of Homo sapiens about 200,000 years ago in Africa. It’s been a long-term relationship, not a one-night stand.
Genetic analyses also tell us that all modern H. pylori populations derive from five ancestral populations: two from Africa, two strongly associated with Eurasia, and one with East Asia. We can trace the movement of H. pylori as people migrated around the world, carrying the organism as hidden passengers in their stomachs. Studies from my lab provide evidence that when humans crossed the Bering Strait from the Old World into the New World approximately eleven thousand years ago, they had East Asian strains of H. pylori in their stomachs. Nowadays, European strains predominate in South America’s coastal cities as a result of the racial mixing that occurred after the Spanish arrived. But pure East Asian strains can still be found among Amerindians living deep in the continent’s jungles and highlands.
Until recently H. pylori colonized virtually all children early in life, shaping the stomach’s immune responses in ways favorable to the microbes as well as to the child. Once H. pylori take hold, they are remarkably persistent. Many other microbes that we come into contact with, including bacteria in your dog’s mouth, bacteria in yogurt, and viruses that cause the common cold, are not. They pass through us transiently. But H. pylori have evolved a strategy for hanging on even as some of them are swept out of the body by peristalsis, the motion that pushes mucus, food, and wastes along your gastrointestinal tract and out your bottom. H. pylori can swim and multiply sufficiently rapidly to maintain their numbers for most of a person’s life. For millennia, these bacteria have fought successfully against the tide and until recently absolutely dominated the stomach. But nothing prepared H. pylori for the twentieth century, which is the setting of my main story. But first we must go back a little further in time.
In the nineteenth century, early pathologists used microscopes to compare normal and abnormal tissues in people who were ill. This was the beginning of the medical discipline of pathology, and they immediately saw differences. Normal tissues have regular shapes and great symmetry, lines and lines of cells in perfect rows. But infected tissues, such as a wound, an inflamed joint, or a swollen appendix, are infiltrated with white blood cells that sometimes form sheets, like an endless army of soldiers. Other times, the white blood cells form a rim around a space filled with pus, which contains remnants of tissue destroyed in the battle between the white blood cells and a pathogen.
Such infiltrations, called inflammation, correlate with the swelling, redness, heat, and tenderness that we experience with an infection or arthritis. Sometimes the inflammation is extensive, as in a raging abscess. Or it can be subtle, as in a muscle that has been overexercised and is sore the next day.
Those early pathologists and clinicians also looked in the stomach, where they observed, in essentially everyone, large numbers of bacteria that were curved like commas or were S-shaped like spirals. But these organisms were very particular in their growth requirements and could not be isolated in the kinds of cultures established by microbiologists on petri dishes. Because these organisms could never be grown in the lab, as could many other organisms in the gastrointestinal tract, their identity remained unknown and as a result they were ignored. They were deemed to be just some ordinary commensals that everyone shared, not long after which they were forgotten.
Within a few decades, physicians were being taught that the stomach is sterile and completely free of bacteria. Of course there had to be a reason why the stomach, which is next door to the bacteria-rich intestine, had no bacteria in it. And, having forgotten all about the curved bacteria, the professors invented a reason: obviously nothing could survive in the highly acidic stomach. Since stomach acid is similar in strength to the acid found in a car battery, it made sense to deduce that bacteria could not live in that environment. Our view of the bacterial world was then pretty limited; we had no idea that bacteria can thrive in volcanoes, hot springs, granite, deep-sea vents, and salt flats.
Doctors also knew that a highly acidic stomach can cause trouble. It can become injured and inflamed, and when that becomes particularly intense, the surface of the stomach wall can break, forming an ulcer. Ulcers, which also form in the duodenum, the first part of the small intestine just downstream from the stomach, can cause severe pain. They can erode into a blood vessel, causing substantial bleeding that sometimes is fatal. Or they may burrow through the stomach wall, creating a perforation connecting the stomach interior to the usually sterile space called the peritoneum. In the old days, that almost always was fatal as well. Between meals or in the middle of the night, people with ulcers can experience a gnawing or burning pain in their abdomen or have bloating or nausea. These ulcers can persist, or they can come and go.
In 1910 a German physiologist, Dragutin Schwarz, recognized that for an ulcer to occur, the stomach must contain acid. Elderly people whose stomach acid had naturally dissipated never got ulcers. Schwarz’s dictum was no acid, no ulcer. So doctors figured that the way to treat ulcers was to reduce stomach acidity. Generations of patients were advised to drink milk, take anti-acids, or undergo surgery that eliminated or reduced the stomach’s ability to produce acid. Moreover, stress seemed to make ulcers worse, which would explain why they waxed and waned. People were urged to control their stress along with their stomach acid. In fact, as a medical student I learned that men with ulcers had trouble getting along with their mothers and that ulcers were one of the best examples of psychosomatic illness. This particular lecture was given by a prominent psychiatrist whose ulcer treatment involved psychotherapy. Not surprisingly, each of the many popular remedies had important limitations, and peptic ulcer disease, as it came to be called, remained a major problem.
Then in 1979 Dr. Robin Warren, a pathologist in Perth, Australia, again noticed bacteria present in the mucous lining of the stomach. Using routine and later specialized stains, he could clearly see the comma and S-shaped bacteria. He further noted that stomach walls of people with bacteria showed signs of inflammation under the microscope or what pathologists like Warren typically call gastritis. Nearly a century after the initial discovery of bacteria in the stomach, Warren realized that the stomach was not sterile after all. It contained bacteria, and he correctly deduced that they must be involved somehow in the inflammation. But what kind of bacteria were they? Why didn’t stomach acid kill them off?
Within a few years, Warren shared his observations with Dr. Barry Marshall, a young trainee who had an “aha moment” of his own. He learned from reading the medical literature that almost everyone who has peptic ulcer disease also has gastritis. If the bacteria were related to gastritis, he reasoned, they also might be related to ulcers. They might even cause these peptic ulcers.
The two researchers studied biopsies from patients with and without ulcers. Nearly everyone with an ulcer had both the S-shaped bacteria and gastritis. But many people without an ulcer also had gastritis and bacteria. They concluded that the mysterious bacteria might be necessary but not sufficient to cause ulcers, just as in the case of gastric acidity.
Doctors (me included) were taught that gastritis is a pathological inflammation of the stomach. But hindsight allows me to question whether it really is pathological or instead a normal condition of the stomach in reaction to coexistence with bacteria. We’ll come back soon to this distinction, which is not just academic but is in fact central to understanding our relationship with H. pylori.
In April 1982, using methods developed over the previous few years to isolate Campylobacter organisms from fecal specimens, Warren and Marshall cultured the S-shaped gastric bacteria for the first time. They accomplished the feat that had eluded German, Dutch, and Japanese scientists nearly a century earlier. As noted in chapter 1, they first called these bacteria “gastric campylobacter-like organisms” (GCLO), then Campylobacter pyloridis, then Campylobacter pylori. Several years later, after more extensive study, it became clear that these organisms were not campylobacters at all but previously unknown cousins. That’s when they received their new name: Helicobacter pylori. Within months of Warren and Marshall’s first publication in 1983 in the Lancet, other investigators began finding these “new” organisms in the stomach and reporting their association with gastritis.
But Marshall wanted proof that these organisms could play a causal role in ulcers and were not just passengers. So in 1984 he used himself as a guinea pig. After testing showed that his stomach was H. pylori–free, he swallowed a culture of the organisms. At first nothing happened. But after a few days he developed indigestion. A new biopsy of his stomach revealed the presence of H. pylori, but even more important he had gastritis; his stomach hurt, and he had bad breath.
A few days later, a second biopsy showed that the gastritis was largely gone. But because Marshall worried that the organism might persist, he took a single antimicrobial agent, tinidazole, and, as far as what has been published, he was never bothered again by H. pylori.
Marshall’s self-experiment showed that H. pylori caused the gastritis rather than merely thriving in an environment created by it. But his acute gastritis lasted only a few days before getting better on its own. His condition was different from the usual chronic gastritis, which is present for decades in people with H. pylori in their stomachs. Moreover, Marshall took an antibiotic that we now know is ineffective in clearing H. pylori when taken alone. So with the benefit of hindsight we know that the infection and inflammation had spontaneously cleared. Most important, Marshall never developed an ulcer.
Nevertheless this dramatic experiment convinced most skeptics to accept the idea that this common organism was indeed a pathogen. Since H. pylori caused inflammation, it was obviously a bad microbe. Most people remember the experiment as one in which a crazy but brave Australian drank bacteria and caused an ulcer, thus proving his theory. Of course that is incorrect, but it caught the world’s attention.
Next, to see whether H. pylori might have a direct role in causing ulcers or might be just bystanders, Marshall and Warren treated ulcer patients with regimens containing bismuth, an antibacterial agent, or with regimens without bismuth. The results were clear: the rate of ulcer recurrence was much lower in the patients who received bismuth. And other investigators found the same relationships in their own studies.
Doctors could now treat ulcer patients with antibacterial agents, including antibiotics. This was revolutionary. Ulcers could be cured. Good-bye to the idea that stress caused ulcers; hello to microbes.
For their isolation of H. pylori in pure culture, for establishing its association with gastritis and with peptic ulcer disease, and for changing the treatment of ulcer disease, Marshall and Warren were awarded the Nobel Prize in Physiology or Medicine in 2005. This recognition solidified the notion that H. pylori was a major human pathogen and that anyone who had it their stomach would be better off without it.
But many mysteries about ulcer disease remained. Why does it affect men so much more than women, although they carry H. pylori at about the same frequency? Even though H. pylori is carried from early childhood to old age, why does ulcer disease start to appear in the third decade of life, peak over the next twenty years or so, and then decline? Why does an ulcer form and then heal after a few days or weeks and then recur weeks, months, or years later? Finding the link with H. pylori enabled us to better treat ulcers and to prevent their recurrence, yet we still understood little about the biology of the disease.
Having heard the first presentation of Warren and Marshall’s work at the International Campylobacter Workshop in Brussels in 1983, I was initially skeptical, in particular about Marshall’s assertions. Clearly they had discovered a new microbe, but Marshall’s claims about ulcers were not convincingly supported by the evidence he presented. Yet as Marshall and others in the field kept showing relationships between the organism and gastritis and ulcers, I decided that my lab should get involved. In 1985, we began to study the organisms themselves (still called campylobacters) and found that they were diverse, but that people who had them in their stomachs formed antibodies to them in their blood.
In 1987 my longtime collaborator Guillermo Pérez-Pérez and I developed the first blood test to accurately identify carriers of H. pylori based on their having antibodies to the organism. Like most scientists, we wanted to know our own status. One of the first things we discovered is that I was positive. I must admit, I was surprised. Like most people in the world who have H. pylori in their stomachs, I had no symptoms. My belly felt fine, although when I learned the test results I began to feel a little queasy. But the test opened many windows for us. We could obtain blood specimens from people of all ages all over the world, with different kinds of diseases or none, and, with our test, determine who had the organisms hidden in their stomachs, so we could look for relationships with various illnesses.
I wanted to know why only some of the people with the microbe developed ulcers. We had shown that H. pylori strains varied considerably, but we did not know whether these differences would determine whether or not a particular strain would cause disease. For example, nearly all of us carry E. coli, which is mostly harmless. Only a few types are very dangerous because they carry genes that code for particular proteins, called virulence factors, that make us sick. We wondered whether any H. pylori strains had virulence factors. Could such differences explain who got sick and who did not? Was the observed diversity clinically relevant?
After two years of study, we identified a protein in H. pylori that fit the bill. It was essentially always present in the strains found in people with ulcers. People without ulcers had it about 60 percent of the time. So while it seemed necessary for ulcers, it was not sufficient. Still it was a very good lead. Could we find the gene that encoded this protein? In 1989 we created a “library” of H. pylori genes within E. coli cells. This simply means that we could use the E. coli cells as microscopic factories to produce H. pylori proteins. Each cell churned out only one or two of the estimated 1,600 H. pylori proteins. Then we took the blood serum of a person who tested positive for the microbes (again it was me) and screened the library to see if any of the E. coli cells produced any proteins recognized by my antibodies. In other words, we went fishing, and we landed a big fish. The very first clone that my serum recognized coded for the same protein that we had associated with ulcers. We named it cagA, for cytotoxin-associated gene.
Later we learned how clever these microbes are. These virulent strains contain a cluster of genes that not only make highly interactive proteins, such as CagA, but also form a system for injecting these materials from the bacterial cells into host cells. This meant that my H. pylori cells were churning out the CagA protein and constantly injecting it into the cells of my stomach wall. This revved up inflammation, which as far as I was concerned at that time was not a good thing.
A second finding we made at that time was that all H. pylori strains possess a protein that in sufficient quantity pokes holes in the epithelial cells that line the stomach wall. Some strains make bigger holes than others by secreting a protein that we discovered and named VacA.
After studying Marshall and Warren’s work showing that H. pylori played a role in ulcer disease and gastritis, we had another relationship on our minds: whether the microbe was associated with stomach cancer. Cancer is the main scourge of the human stomach. It is an awful disease. After diagnosis, a person has less than a 10 percent chance of being alive five years later. In 1900 stomach cancer was the leading cause of cancer death in the United States. It still is the number-two cause of cancer death in the world, after lung cancer.
In 1987 we tried to convince the National Cancer Institute to work with us on a possible relationship between H. pylori and stomach cancer; however, we were turned down. But two years later I was contacted by Dr. Abraham Nomura, principal investigator of the Japan-Hawaii Cancer Study based in Honolulu. He and his colleagues had done pioneering work on the disease risks of Japanese-Americans living in Hawaii, and he wanted to use our blood test to study the risk for stomach cancer related to H. pylori. I jumped at the chance.
Between 1965 and 1968, more than 7,400 Japanese-American men born between 1900 and 1919 enrolled in the Honolulu Heart Study. These men, veterans of the 442nd Regiment who fought in the U.S. Army with great distinction during World War II, were heroes of mine ever since I had learned about them from reading James Michener’s book Hawaii as a boy. When Japanese-Americans were being rounded up and incarcerated on the West Coast of the United States, these men risked (and some lost) their lives and limbs to defend their country. The late Senator Daniel Inouye was one of them.
By 1989, blood samples from nearly 6,000 of these veterans had been obtained and frozen. During the interim, more than 137 men developed stomach cancer, and of these 109 could be studied. We matched them with 109 men who did not develop stomach cancer and examined their blood for antibodies to H. pylori. One strength of the study is that the blood specimens were obtained an average of more than twelve years before the cancer had been diagnosed. This window of time could help establish a causal relationship.
We asked two simple questions: who had H. pylori in their stomach in the 1960s, and did having the organism relate to getting cancer later on?
Our findings were dramatic. We discovered that those who carried H. pylori back then were six times more likely to develop stomach cancer over the next twenty-one years than those who were negative. I presented this finding as a “late breaker” at the same conference where Marshall had presented his findings about ulcers eight years earlier. Other parallel studies conducted in California and in England yielded similar results. Later we found that those who had the cagA-positive type of strains had double the risk.
It soon became clear that H. pylori was not just along for the ride. Carrying H. pylori preceded the development of stomach cancer. In 1994, based on our work and that of others, the World Health Organization declared H. pylori a Class 1 carcinogen for its relationship with stomach cancer. It was like smoking and lung cancer: no arguing about cause and effect.
No wonder doctors around the world began to believe that “the only good Helicobacter pylori is a dead one.” From ulcers to cancer, everything indicated that carrying H. pylori is costly to humans. Doctors everywhere started to look for it in patients who had any kind of gastrointestinal symptoms; and if they found it, they would eliminate it using antibiotic-based treatment regimens. Part of the rationale was the fear of the cancer, and part of it was to treat the symptoms that patients had. But except for ulcers, clinical trials did not show that symptoms improved any more than by chance alone. Still, everyone was happy to eliminate H. pylori whenever they found it.
Yet for years I kept returning to a question: Why did Warren discover the association of H. pylori with gastritis when it had been missed for so long? Eventually I remembered learning that nineteenth-century pathologists had found those curved and spiral organisms in the stomach of virtually everyone. By the 1970s, in the slice of Australia where Warren worked, only about half of the adults were positive. Pathologists in other developed countries saw the same thing: H. pylori and associated gastritis in a fraction of the people, not everyone.
However, in contemporary studies from Africa, Asia, and Latin America, nearly all adults carried H. pylori. It was as if they had nineteenth-century stomachs, while we “developed peoples” had twentieth-century stomachs.
I made a leap: Warren was able to find the association with gastritis because H. pylori was no longer universal; it was disappearing. This ancient organism was becoming extinct. Other researchers noticed that H. pylori was less common in younger people, but they all thought it was a sign of progress, and of course in a way it was.
Our more recent work shows that most people born in the United States in the early twentieth century carried the organism. But fewer than 6 percent of children born after 1995 have it in their stomachs. Similar trends have been documented in Germany and Scandinavia. In fact, wherever we look H. pylori is disappearing from humans, most rapidly in developed countries but also in developing areas. This variation is not based on geography but rather on socioeconomic status. Poor people tend to have H. pylori; wealthier people tend not to. We see this everywhere we look all over the world. The presumption has been that it’s better to be without H. pylori just as it is to be wealthier.
But why is H. pylori disappearing? Why is an organism that has survived so long in nearly all of our ancestors as the dominant bacteria in our stomachs been receding everywhere we look? The answer can be summarized in two words: modern life. A persistent colonizer like H. pylori must deal with two major biological problems: how it is transmitted to new hosts and how it is maintained until passed forward.
Transmission is the biggest bottleneck. H. pylori lives only in humans. As noted earlier, we do not get it from our pets, farm animals, or foods of animal origin, as we get other transient organisms such as Salmonella; nor do we get it from dirt. The major reservoir in the world for H. pylori is the human stomach. The microbe must pass from one stomach to another, and the only way to do that is to go either up or down the gastrointestinal tract.
H. pylori can easily travel up from the stomach to the mouth via burping or reflux. It can set up shop in dental plaque. In many parts of the world, mothers prechew food and pass it on to their babies’ mouths, thereby transmitting the microbe. When people vomit, H. pylori is present and can be carried by the air for several feet, contaminating the nearby environment—comforting thought.
Down is easier. Everything in the gastrointestinal tract has the potential to come out at the bottom in the feces, and both H. pylori DNA and live organisms have been detected there. Usually live H. pylori are excreted at very low levels, but more come out after a microbial bloom. When hygiene is bad, as has been the case most of the time we humans have been on the planet, feces contaminate food and water. Fecal H. pylori is thus transmitted to the next person.
Young children are the most susceptible to H. pylori. They seem to resist it in their first year of life, but after that, in countries where sanitation and hygiene are poor, about 20–30 percent acquire it every year. Between the ages of five and ten, most kids get colonized, often with several different strains. After that, the transmission frequency drops.
Why the decline over the past one hundred years? One obvious reason is sanitation. In the late nineteenth century, cities began to provide clean water for their citizens from watersheds that were not grossly contaminated with feces and with the important advance of chlorination. Such measures helped prevent the transmission of cholera, typhoid fever, hepatitis, and childhood diarrheal illnesses. Resounding public-health successes, they account for a major part of our improved health and longevity in the first half of the twentieth century. Yet in preventing the spread of pathogens, these practices also reduced transmission of our ancient colonizing microbes, like H. pylori. The benefit of clean water is so huge that we must not denigrate its importance, but we should also recognize the potential for hidden consequences that diminish our ancestral microbiome.
Drinking contaminated water is how a child could acquire H. pylori from a stranger, but most transmission occurs closer to home. As indicated above, a baby can get H. pylori from her mother chewing his or her food. We don’t know all the ways that children get H. pylori from their mothers, but studies have shown that the number-one predictor of whether a child has H. pylori is whether his mother has it.
Children also get H. pylori and other microbes from their older siblings. In a sense, the siblings amplify the transmission from mom, providing new opportunities for the organism to spread. Big families are an important reservoir for the organism, yet in developed countries families have been getting smaller. In a family with five children, 80 percent of kids have an older sibling. With two children, it is 50 percent. With an only child, it is zero. Before people became more prosperous, kids used to sleep in the same bed, sometimes with parents as well. Such close contact facilitated transmission of microbes, especially during critical windows, like early childhood.
Interestingly, when adults live together, as we showed in two studies, the risk of transmission of H. pylori to one another seems pretty low. We studied couples who were going to an infertility clinic, a group that might be having more physical contact than others; positivity in one member was no more likely to be associated with the same status in the other than by chance. We also looked at adults who came to a clinic for sexually transmitted diseases. With many organisms, such as the ones causing gonorrhea and syphilis, the more sexual partners you have, the more likely you are to acquire them. Not so with H. pylori; the organism hardly ever spreads from adult to adult.
If it is actually acquired in childhood, H. pylori must be maintained, so it can be transmitted to the next human generation. We know from both human and monkey experiments that the organism needs a period of time to adjust to its host. Some don’t make it, as in the case of Barry Marshall’s self-inoculation. If conditions are difficult for the organism, the success rate of transmission goes down.
Given the number of doses of antibiotics given to our children today, it’s easy to imagine that a major impact on H. pylori colonization comes from treating all those sore throats and earaches. A single course of an antibiotic will eliminate the microbe in 20–50 percent of patients. When children are given those same antibiotics, they stand a similar chance of losing their H. pylori.
It is my belief that each time they take a course of antibiotics, and with each course given in a population of children, a few more kids lose the organism. Across the whole population, the trend is cumulative. This practice is a paradigm for the disappearance of other of our ancient organisms. Fitness is not guaranteed. In its protected gastric niche for eons, H. pylori was not at all prepared for the onslaught of antibiotics in the last seventy years.
The loss is multigenerational. Studies show that if the mother has lost her H. pylori, chances are small that her child will acquire it. And so it will go, generation after generation. Starting with sulfa drugs in the 1930s and then penicillin and others in the 1940s, in the U.S. and western Europe we already are in the fourth or fifth generation of antibiotic users. Remember the recent data implying that young people have had about seventeen courses of antibiotics by the age of twenty, essentially when the women are starting their child-bearing years. And loss of H. pylori in an older sibling removes another opportunity for transmission. Clean water, smaller families, and lots of antibiotics create a triple whammy against H. pylori.
A final cause of its disappearance is that H. pylori like to have sex with other H. pylori. This is an essential part of their biology. Some bacteria are more reclusive, like the ones that cause anthrax or tuberculosis. For H. pylori, free love is a way of life. In the old days, the average person probably had several different H. pylori strains in his or her stomach, just as we see today in people in developing countries. Contaminated water is again part of the reason. These mixtures of H. pylori strains represent a robust community. With their constant exchange of genes with one another, their populations shift, reflecting the changing tides in the stomach. Such gene exchange makes the community very adaptable, so it can take advantage of all of the resources that a stomach can provide. The overall community can be sustained for years, even decades. This is the strategy that H. pylori have evolved over the millennia: organisms competing with one another as always but also cooperating to ensure transmission to a new host. But in recent years, as transmission and maintenance have become more and more difficult, the number of individual strains able to colonize the average stomach has declined from three to two to one to zero.
As I came to realize that in just a few generations the microbial ecology of the human stomach has changed markedly, I wavered from the conviction that H. pylori are only bad. I could see that while H. pylori caused inflammation, it had been with us for a very long time and that most people who became ill, especially with stomach cancer, were much older. The average patients were in their seventies, and the cancer rates were higher still among people in their eighties. Across our entire population, the cost of H. pylori was not as high as that for malaria or diphtheria, for example, which kill children.
I began to think that maybe under some circumstances the inflammation caused by H. pylori could be good for us. My original ideas were fuzzy; I didn’t know what good there could be. I only knew that when ancient dominant organisms disappear, there are bound to be consequences. This was heresy to most of my colleagues; having discovered H. pylori as a pathogen, they focused on the costs and considered it imperative to speed up its departure from this planet. They were not thinking about amphibiosis, just elimination.
Later we did find those benefits. In retrospect they seem obvious, but uncovering the answers took me years, and all the while most of my colleagues in the field did not agree with me. I failed to convince them, and in fact most physicians still see gastritis as a pathological condition. To them, a normal stomach should never show inflammation. The crux of the dilemma is simple: What is normal?
When pathologists see a stomach mucosa loaded with lymphocytes and macrophages, they call it chronic gastritis. But this condition can also be defined as the physiological response to our indigenous organisms. Just as there are inflammatory cells in your colon and in your mouth interacting with your friendly bacteria, your stomach has inflammatory cells interacting with its local bacteria. Thus the same question arises: Is the gastritis caused by H. pylori good for you or not? Pathologists, who characterize gastritis as a disease, classify H. pylori as a pathogen, whereas ecologists look at ancient organisms in an entirely different light.
The interaction between H. pylori and our ancestors evolved in ways that maintained persistence of the organism. Since there is little or no cost during childhood or young adulthood for carrying H. pylori, there is no selection against it. In contrast, malaria is so lethal to children that over the eons a whole set of human genes evolved to enable us to resist it.
We and our ancient, more quiet microbes like H. pylori are always adapting to each other, maintaining an equilibrium like artists on a tightrope, holding arms out as they cross to the other side; no missteps and they’re safely across. Our microbes take up residence in particular niches and send signals to our human cells, which signal the microbes back in the form of pressure, temperature, and chemical messages, including defense molecules. The microbes signal us, we signal them back—communication develops, a language. Within this equilibrium, there is a dynamic of up and down regulation of inflammation in specific locales. It’s like a marriage: we decide who does the dishes, who walks the dog. The conduct of one partner determines that of the other.
For example, the amount of inflammatory traffic in the stomach determines immune responses. Maybe the interactions early in life, when a baby is developing, also help determine immune tone. A person’s immunity can be twitchy, causing wheezing in response to an insect crawling across his or her arm, or it can be sluggish, with little response to a pathogen. There is no one universal tone in which one size fits all. Yet we have evolved over the millennia to have particular tones; it is not random. With our changing gastric microbiome, twitchier interactions seem to be increasing.
The loss of H. pylori from a person’s stomach has created a new milieu. Instead of the ancient equilibrium, now the regulation of immunity, hormones, and gastric acidity is a dance without a partner. And like the ending of most long-term relationships, the effects are not just immediate or local; they are lifelong.
The changes that have happened in this past century have bearing beyond the stomach. At the very least, they affect the nearby esophagus, the next stop in the saga. New diseases related to the loss of H. pylori are rising.