No cure in sight as IBD awaits its ‘H. pylori’ moment

While there have been considerable improvements in the treatment of IBD in recent years, a cure will remain out of reach until the biological mechanism for the condition is elucidated, according to Professor Arthur Kaser, University Chair of Gastroenterology  Cambridge University, UK.

Speaking at the opening of ECCO 2019 in Copenhagen, Professor Kaser said that Crohn’s and ulcerative colitis have yet to experience the critical breakthrough in understanding of disease causation equivalent to that seen with Helicobacter pylori and gastric ulceration, or the recent Nobel Prize for the CTLA-4 and PD-1 braking mechanisms on T cells that led to cancer checkpoint inhibitor therapy.

With current research focusing on genetic and environmental factors in the development of IBD, treatment still remained “distant from the source” of the disease biology, he said.

“We have made great progress over the last two decades and our treatments have become much better and much safer, but in essence they are still essentially based on generic dampening of immune system. And the reason is we just simply don’t know what causes Crohn’s and ulcerative colitis.”

Professor Kaser noted that even with the latest biologic immune therapies, only about 30% of patients achieve clinical remission and there is 15% loss of response per year. It was also questionable as to whether surgery rates for Crohn’s and ulcerative colitis had declined significantly in the biologic era, he added.

The current areas of focus for Crohn’s and colitis research spanned the range of genetic susceptibility, histopathological mechanisms such as autophagy and environmental triggers such as diet and the microbiome.

In terms of genetics, hundreds of possible sites in the genome have been linked to Crohn’s and ulcerative colitis and there may be ‘hub genes’ that have outsize effects rather than additive effects. But while there was promising work being done on genes such as IL-23A, this was shared with other conditions such as psoriasis and was not specific to Crohn’s, he noted.

And genetics alone is unlikely to provide the ‘cure’ for Crohn’s given that environment is clearly a factor in the disease, Professor Kaser said. The fact that Crohn’s disease is closely associated with industrialisation and is only now being seen in developing countries such as China shows that we need to look to a possible combination of environmental triggers and genetic susceptibility, he said.

Professor Kaser also sounded a note of caution on the potential role of the microbiome, pointing to the large overlap in microbial patterns between the healthy gut and that of people with IBD, as well as wide inter-individual variation. And while faecal microbiota transplantation (FMT) had shown ‘profound’ effects in some patients with ulcerative colitis, the intensity of treatment needed (daily enemas) limited its usefulness.

The focus on the microbiome role in IBD had yet to reveal exactly what factors were triggering the inflammation and pathology at the gut epithelium, he said. It was not yet clear if it was a bug such as Clostridium difficile, or something in the ileal  ‘soup’, such as oxazoles that triggered changes in the susceptible mucosa.

“When you look at the extreme diversity between individuals with regard to their microbiota environment and the two very distinct diseases Crohn’s and ulcerative colitis, I think we have definitely not yet found a smoking gun that comes close to the Helicobacter pylori of IBD,” he said.

“Are we anywhere near a cure for Crohn’s and ulcerative colitis? Certainly not. But we are clearly homing in on some of the central biologies of the disease. And I think that the search for some of the environmental triggers in population studies and also in biochemical studies could become incredibly powerful.

“What we need is this one critical discovery that essentially that changes everything. Whether this comes tomorrow, five years or fifty years we just don’t know.”

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