A paradigm shift in physiology

Print edition : November 18, 2005

Dr J. Robin Warren and Professor Barry J. Marshall celebrate after winning the Nobel Prize for Medicine for their breakthrough research on stomach ulcers. - ROB DUNCAN/WA NEWS

This year's Nobel Prize winners for Medicine and Physiology have paved the way for a better understanding of the link between chronic bacterial infection, inflammation and cancer.

JUST a little over two decades ago, medical - and hence also popular - belief was that gastritis (inflammation of the stomach) and ulceration of the stomach or duodenum (upper part of the intestine) were caused by excessive acid secretion due to stress or certain forms of diet (in particular spicy foods). The generally accepted treatment included acid-suppressing therapeutics, which made drugs like Zantac popular, and plenty of cold milk. This essentially symptomatic approach provided relief but only temporarily; there was often a relapse of symptoms and the chronic inflammatory condition remained.

This year's Nobel Prize in physiology and medicine has gone to clinicians from Perth in Australia - 68-year-old Robin Warren and 54-year-old Barry Marshall, who demolished this myth by postulating and subsequently proving that the causative agent of these ailments was, in fact, a bacterium called Helicobacter pylori. While Warren noticed the first evidence of the organism in biopsies of patients with these conditions, Marshall provided the "acid test" - in fact, literally - by actually swallowing a bacterial potion in water and developing the symptoms, after which he was duly cured by a dose of antibiotics. No one at that time thought along these lines; the prevalent scientific wisdom suggested that a bacterial colony could not survive in the highly acidic environment in the stomach.

As a pathologist, Warren found that in over 50 per cent of the patients, small curved bacteria had colonised the lower part of the stomach (antrum). More significantly, he made the crucial observation that there was inflammation in the gastric mucosa around the bacterial site. Marshall became interested in Warren's findings and together they undertook a study of biopsies from 100 patients. After some perseverance, Marshall was able to cultivate this hitherto unknown bacterial species (originally called Campylobacter pylori) from several of these biopsies.

The two found that the bacteria were present in almost all cases with gastric inflammation, and duodenal (peptic) or gastric ulcers. "Nobody believed that there were bacteria in the stomach until I saw them there," Warren said in an interview after the Nobel announcement. "And then it took a long time to convince everybody that they were there. It took about 15 years before it started appearing in textbooks," he added.

It is now known that the spiral-shaped bacterium, with its four flagella, is able to penetrate deep into the stomach lining's thick mucus where it converts urea, a waste product in the stomach, into ammonia. This provides the bacteria with the weapon to counter the acidic environment and enables them to colonise the lower stomach region. H. pylori needs an environment with only 5 per cent oxygen, the exact level of oxygen in the stomach.

Subsequent studies found that 90 per cent of people with duodenal ulcers and up to 80 per cent of people with gastric ulcers are infected with H. pylori. Infection, rather than lifestyle, was identified as the root cause of stomach ulcers. The findings also suggested that as long as the bacteria remained, the inflammatory condition would persist; ulcers could be cured only if the stomach could be rid totally of the bacteria. Thanks to this path-breaking discovery, which came in 1982, peptic ulcers, often resulting in severely disabling conditions including stomach cancer with life-long medication, are no longer a chronic ailment. It is now a disease that is curable with a regimen of antibiotics and acid blockers.

Though it seems well established that H. pylori infection is implicated in the development of gastritis and duodenal/gastric ulcer, it must be pointed out that subsequent research has led to a great deal of debate and controversy about the exact role of H. pylori in causing these conditions. Clinically it has been found that even though nearly 50 per cent of the human population are carriers of H. pylori, and in developing countries nearly the entire population is infected, only a fraction get the disease.

Most people contract the infection in early childhood, usually via mother-to-child transmission. Initiated in the antrum, it will remain a chronic infection in the stomach for the rest of the individual's life. However, the infection by and large remains benign, or causes mild gastritis. Only 10-15 per cent develop ulcers, mostly duodenal rather than in the stomach itself, resulting in excessive bleeding and perforation. The location of the infection and the severity of the inflammation that it leads to are crucial for the subsequent development of the disease into ulceration. The current view is that chronic inflammation in the distal part of the stomach results in increased acid production from the non-infected region of the stomach. This is believed to predispose the more vulnerable duodenum to ulceration.

An H. pylori infection may thus be necessary for but not sufficient to cause ulcers. What co-factors trigger the development of the disease is not very clear. Wide geographic and racial variability has also been observed in the extent of the role of H. pylori. Genetic variations among humans seem to affect the susceptibility to diseases caused by the organism. In fact, there have been studies in the United States that have claimed absence of H. pylori in association with ulcers in certain communities, thus raising questions about the necessity of the bacterium in promoting the disease.

The organism is found only in humans. Many scientists believe that H. pylori is "commensal", that is, it has co-evolved with humans. They do so for two reasons: firstly the bacterium causes disease in a low percentage of cases, and secondly the organism transmits from mother to child. In fact, only recently an animal model could be established, in the Mongolian gerbil by Japanese researchers - one of the three basic postulates of Koch that need to be satisfied to establish the causative organism of any disease.

In most circumstances, it appears that H. pylori does not cause disease unless the delicate balance between the host and the organism is disturbed by other factors. There is a lot of ongoing research to identify these; while some say that they may well include stress and diet, recent research also suggests that a human immune system dysfunction in recognising microbial products can result in disease development.

In certain individuals, H. pylori also infects the stomach proper when the inflammation is no longer localised to the antrum alone. This predisposes the individual not only to ulceration of the stomach but also to stomach cancer. Though the incidence of this cancer has declined in the last 50 years, it still ranks second in the number of cancer deaths around the world. As a result H. pylori was termed a Category 1 Carcinogen by the World Health Organisation in 1994.

Inflammation of the stomach caused by H. pylori can also predispose it to develop a special kind of lymphatic tumour in the stomach called MALT (Mucosa Associated Lymphoid Tissue). Since these lymphomas and tumours are seen to fade away as H. pylori is eradicated from the system with antibiotics, the organism stands well implicated in the development of these particulars as well.

According to B.S. Ramakrishna of Christian Medical College (CMC), Vellore, studies have shown that nearly 80 per cent of the Indian population is infected with the bacterium as against 50 per cent or less in the West. While most duodenal ulcers were seen to be in the young in the 1960s and 1970s, over the years the clinical profile seems to be displaying a demographic shift towards the elderly over the age of 50, a pattern also seen in the West. He attributes this to the changing nature of the disease given the high genetic variability of the organism itself. He rules out changing lifestyles and dietary habits in the Indian context.

Strains of H. pylori differ markedly in many respects, such as adherence to gastric mucosa and its ability to provoke severe inflammation. Even in a single infected individual, multiple strains can coexist and during the course of chronic infection the bacteria are known to adapt to the changing environment in the stomach. A certain strain found in Indian populations produced toxic proteins, points out Ramakrishna.

Helicobacter pylori, the bacterium found to be the cause of ailments such as gastritis and stomach ulcers.-

Duodenal ulcers have also been seen in people with a certain type of pancreatic tumour that causes excessive acid secretion in the stomach. Gastric ulcers, on the other hand, have always been found to be associated with H. pylori, says Ramakrishna. According to him, there is a North-South divide in the clinical profile of the organism - while in the South cases of duodenal ulcer develop more often, in the North gastric ulcers are more common.

Studies at the CMC have also found that in India H. pylori can also be associated with certain low-grade lymphomas in the stomach leading to gastric cancer. However, according to him, in nearly all cases antibiotic treatment has been found to be effective for long periods, though people can get re-infected with H. pylori very quickly because of poor sanitation and hygiene. Also, while antibiotics constitute effective treatment, indiscriminate use can also lead to resistance to antibiotics.

Notwithstanding the fact that the final word on the exact role of H. pylori in gastric and duodenal ulcers is perhaps yet to be said, the findings of Warren and Marshall marked a definitive paradigm shift in the understanding of these conditions by countering the prevalent dogma surrounding the involvement of bacterial infection. Their discovery has also opened up investigations into the microbial origin of other chronic inflammatory conditions such as Crohn's disease, ulcerative colitis, rheumatoid arthritis and atherosclerosis. What the duo's discovery of H. pylori has achieved, as the Nobel citation puts it, is to pave the way for a better understanding of the link between chronic infection, inflammation and cancer.

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