Unravelling the mysteries of Microbes and Man
When I was a Surgical Registrar in the ’70s, I spent a great deal of time in the operating theatre dealing with the complications of peptic ulcer. These could burst and cause peritonitis, or erode into an artery and cause major and sometimes fatal bleeding. They also caused severe chronic abdominal pain, and the usual medical treatment was diet, rest and antacids. All young doctors at the time knew quite clearly that the cause was Acid, Hydrochloric acid, produced by the stomach. So, us confident young surgeons knew that by removing half of the stomach, and or cutting the main nerve to the stomach, the vagus nerve, we could reduce gastric acid and cure our patients.
And indeed we did! No Acid, No Ulcer, was the dictum. I got very good at these operations and was quite pleased with myself. We understood that these operations had occasionally some nasty side effects. Explosive and uncontrollable diarrhoea was one of them. But how could anyone complain, if their ulcer was cured?
Parallel to all this, a group of physiologists and pharmacologists in London had been working on the problem. They found that gastric cells were stimulated by histamine. A blocker of this could thus reduce gastric acid production. They found one soon enough, and the famous drug “Tagamet” followed. The need for complex and dangerous operations was no more. Almost! I had to rapidly re-calibrate my surgical career.
The story gets more interesting. In 1982, a young gastro-enterology trainee was looking for a research project. Barry Marshall was learning to do gastroscopy (looking inside the stomach with a flexible tube), and had observed that patients with gastric and duodenal ulcers had visible inflammation, “gastritis” in the stomach. He took samples from these patients, and took these down to the pathology laboratory, where he had the help of a good pathologist Dr Warren. They discovered that most patients with ulcers and gastritis had a germ in these samples called Helicobacter Pylorii. Did the germ or the acid cause the gastritis and the ulcers?
This was tricky. To show that a germ causes a particular illness, it has to be collected from the patient with the disease, put into someone without the disease, the disease then forms in the non-diseased recipient, and the presence of this disease and germ, is proved in the new host. These are “Koch’s Postulates”. Now Barry Marshall could not ethically ask people to volunteer for this experiment as they could get serious illness. So, he volunteered himself. He had a gastroscopy and biopsy which showed he had neither gastritis nor helicobacter. He then swallowed a specimen containing helicobacter, and got quite sick. He was gastroscoped again where gastritis and helicobacter were found. He had fulfilled Koch’s postulates! It was also soon found that helicobacter was also associated with cancer of the stomach, and this could be now prevented, by eradicating HP.
Marshall and Warren then formulated the hypothesis that Helicobacter could cause gastritis and peptic ulcer, and later on cancer. This was initially ignored, then treated with skepticism and some hostility. But results came in from around the world; patients with ulcers had helicobacter, and if the germ could be eradicated with antibiotics, the ulcers could be cured. Permanently. No more tablets. This was transformative research, and Marshall and Warren duly received the Nobel Prize in 2005. Ulcers almost disappeared from surgical practice, and our surgical trainees hardly ever see those classical operations any more.
But questions remained. Most people in the developing world do have helicobacter. Only a very small number get either ulcers or cancer. In these communities transmission of the germ would occur at birth and infancy through the oral route. Evidence for human carriage of HP can be traced back 10,000 years. Could it have had a symbiotic relationship with human populations? Can it do any good?
Not surprisingly HP carriage in the developed world has steadily decreased, an observation I have been able to make in real time. The primary cause may well be the promiscuous use of antibiotics in the west. Improved hygiene, where familial transmission becomes less; and yes, Caesarean Section.
It did not take very long for doctors to notice that where HP had been eradicated patients started to get heartburn, the characteristic of acid reflux into the gullet. Now, this can be controlled well by the newer acid blocking agents. But more worryingly, what was a very rare cancer, adenocarcinoma of the oesophagus and upper stomach started to increase quite quickly, and indeed it is now regarded as the cancer with the rapidest increase in incidence. What about asthma? Yes, that as well.
In a previous article in MediScene (The Perils of Socrates) I briefly mentioned the importance of the Human Microbiome. HP is a small but important part of this. Traditional microbiological techniques, using culture and microscope was only able to identify 5% to 10% of bacteria. This has now been replaced by the new science of metagenomics which can count and classify communities of microbes by their genes. There are about 20,000 genes in human cells. We now learn there are 20 million bacterial genes, controlled and controlling, our physiology. What are some of the rules of this science. (See box)
Let’s return to HP. It turns out that most people develop HP as infants. The host defences, white blood cells, detect the HP, but the combination of HP with molecules of the defensive system render HP “invisible” to the host. So the host does not develop stomach inflammation, gastritis. These complex molecules drain from the stomach into their regional lymph glands. These are now accessible to the blood stream and circulate widely. One of the places they go to are the lungs, particularly the airways (bronchi), where they inhibit the allergic responses we associate with asthma; airway sensitivity and narrowing, and mucus production.
So as microbiota continue to diminish, we can expect more of our children to become asthmatic. This obviously suggests a treatment. Perhaps the children’s doctors of the future will be testing the nappies of infants for appropriate microbiota, and replacing them as appropriate. Perhaps this will involve deliberate dosing of infants with HP, then later on as adolescents eradicating the bug if it is shown to cause gastritis.
Aldous Huxley would have approved-“Brave New World” but Shakespeare I think would be appalled.
(The writer is Associate Professor of Surgery at James Cook University, Cairns, Queensland, Australia)
| Some of the Rules of Microbiota In humans different bugs populate different spaces-niche specific microbiota (helicobacter for instance in the stomach). The microbiota can change or can be transient. Eg after severe gastro-enteritis or antibiotics. Diet can also change the microbiota. The microbiota are ancient, and are vertically transmitted through the generations, along with the genes of their hosts. The structure of the microbiota is acquired in infancy, though it can be modified to an extent later on. The microbiota interact in many areas of human physiology to modify or produce disease. Asthma; but also diabetes, Multiple sclerosis, Rheumatoid arthritis. Other associations are constantly being added. | |