As a medical student, I learnt that Crohn’s Disease and Ulcerative Colitis, now lumped together as Inflammatory Bowel Disease (IBD) were serious, life threatening, long term conditions affecting the bowel. They needed to be controlled with powerful anti-inflammatory drugs and posed a significant risk for the development of bowel cancer. It was therefore important to make sure that any patient presenting with what we now recognise as Irritable Bowel Syndrome was investigated to rule out bowel inflammation. Later, as an NHS gastroenterologist, I occasionally saw patients with symptoms of diarrhoea and mucus, in whom I suspected colitis, but there was no obvious inflammation and no bleeding. Although I made a putative diagnosis of IBS, they responded to treatment with mesalazine (Asacol), first line treatment for inflammatory bowel disease (IBD). And then later still, while working as a psychotherapist, I recognised that the clients who came to see me with Ulcerative Colitis or Crohn’s Disease had suffered life trauma and responded to psychotherapy. This suggested to me some degree of overlap between IBS and IBD.
I was therefore very interested to read a paper by Professor Robin Spiller and Giles Major in September’s Nature Reviews, entitled ‘IBS and IBD: seperate entities or on a spectrum’. In what is a comprehensive review, the authors point out that diarrhoea predominant IBS, particularly the 17% that follow an attack of gastroenteritis, is associated with mild inflammation of the colon, increased permeability, proliferation of mast cells releasing histamine and serotonin*, abnormal enteric nerve function, physiological sensitivity and irritability, immune hyper-reactivity, microbial dysbiosis, and changes in the reactivity in the gut brain axis. Similar changes are seen in patients with IBD, prompting the suggestion that they might the same condition but existing at different loci along a spectrum.
Building their hypothesis, Spiller and Major cite evidence showing that a diagnosis of IBS increases the risk of developing IBD. Other patients have a brief attack of IBD, which goes into remission leaving persistent bowel abnormalities and symptoms of IBS. So we don’t only have post infectious IBS and post traumatic IBS, there is also post-inflammatory IBS. Patients in all three categories are more likely to be women and have higher levels and anxiety. Moreover, the role of environmental stress and emotional upset are well established in IBS, but they also play a major role in IBD. In the nineteen fifties, colitis was considered one of the ‘big five’ psychosomatic disorders. Finally, if IBD and IBD exists along a spectrum, then it would explain why so many patients with IBS have indeterminate values on Faecal Calprotectin testing, not low enough to be sure of IBS and not high enough to be definitely IBD.
Robin Spiller is a well-respected senior clinical scientist, who has spent over 20 years studying the role of inflammatory and immune processes in IBS. In this, his latest paper, he maintains that novel treatments for IBS should be oriented towards the suppression of inflammation and immune hyperactivity. This might include tachykinin inhibitors, histamine receptor antagonists and serotonin antagonists and faecal microbial transplants. Anti-inflammatory treatments, such as mesalazine, which is first line treatment for IBD, have been shown to be effective in IBS where there is evidence of bowel inflammation.
It seems a strong case, but let’s put it in perspective: using the author’s figures IBS is diagnosed in 1 in 10 people worldwide, while IBD is only found in 1-3 in 100,000. Moreover IBD is associated with cellular damage, major inflammatory reaction and a significant risk of cancer. These do not occur in post-infectious IBS. Faecal Calprotectin only works as a test for IBD because of the destructive nature of the inflammatory process. So there is therefore no strong evidence for a continuous spectrum of inflammation; just a big gap between the mild inflammation seen in some patients with IBS and the major destructive inflammation seen in IBD.
I have never quite understood why such seemingly different condtions as Crohn’s Disease and Ulcerative Colitis were lumped together as IBD. There is compelling evidence that the full thickness inflammation of Crohn’s Disease might be caused by an infection, whereas ulcerative colitis has been related to changes in the blood supply and nutrition to the bowel epithelium. Nevertheless, it seems a radical departure to suggest that IBS might be included in the IBD spectrum. What seems more likely is that some other factor turns on the cell destruction associated with IBD. Among possible candidates, there is evidence favouring a specific alteration in the colonic microbiome, specific changes in immunological mediators and particular genetic predisposition. The evidence for genetic factors is stronger for IBD than IBS.
As far as IBS is concerned, the notion that it may arise top down by environmental trauma or bottom up by infection, allergy or toxic effects on the gut might seem a useful distinction. It could be, for example that the case for an overlapping spectrum of IBS-D and IBD might just apply to those patients whose illness derives from a definite insult to the gut. There is some evidence for Crohn’s Disease arising after gastroenteritis and for colitis related to depletion of the colonic microbiome. Things are never that clear cut: several studies showing that stress, anxiety and depression at the time of infection predisposed to post infectious IBS.
Not all patients with IBS present like IBD. Many patients with constipation, for example exhibit reduced sensitivity and irritability and profound differences in colonic microflora compared with IBS-D. Moreover, not all patients diagnosed with IBS show increased inflammatory cells or immunological hyperreactivity.
It seems that the more we find out more about a certain disease, the less we know it. Old distinctions are becoming blurred. What was once seen as a diagnostic feature of a certain disease may be a non specific physiological reaction to inflammation or microbial depletion. As time passes , the textbooks may be rewritten to focus on a limited selection of disease mechanisms with multiple triggers and different expressions rather than an ever expanding host of specific diseases. GPs are only too aware of the concept of overlapping multi-morbidity in their aging practice, requiring not so much specific treatments for each disease but a more holistic interaction to calm the shared disease processes.
Just as genomics has caused dramatic revisions in taxonomy of species, so the new sciences of microbiomics and neuroimmunology may well alter the landscape of gastroenterology. Will doctors and their patients be flexible enough to accommodate the new knowledge?
*Several studies have noted an increase in immunoreactive mast cells in IBS. 25 years ago, Dr Philip Miner from the University of Oklahoma joined our group as a visiting research fellow. I asked him to attend my clinic. He listened carefully and as the last patient left, I asked him what he thought. Amazing, he exclaimed, you have three patients with Zinc deficiency and 6 with systemic mastocytosis. Now Systemic Mastocytosis is a serious disease affecting the bone marrow, but Phil had a point. Some patients with IBS-diarrhoea showed features that might increased release of chemical transmitters from mast cells. He was ahead of his time