Insights into IBD aetiology from China …

…returning once again feeling energised, revitalised and inspired. This year I have visited Guangzhou, Shanghai and Xi’an. The Chinese people are amongst the friendliest and hospitable I have ever come across. The country offers endless fascinations from almost unbelievable historical sites with exquisite artefacts to traditions and cultures that are alive and strong. Witness the 6000 strong life-size terra-cotta army, built by thousands of men over 40 years to protect an emperor in the after-life, only to be buried underground and lain undiscovered for over 2000 years. Along comes a peasant farmer in 1974 to make a most remarkable accidental find! What fascinates most in China is the rapidity of change. The cultural and environmental shifts taking place right now are quite startling. It is difficult to establish exactly when this started. Industrialisation has certainly been underway for a few decades now. But talking to the educated young locals in Xi’an this weekend one might suppose that the more obvious Westernisation has really taken foot in the past 5 years. To them this is a most welcome change, almost a necessity which feels like a certainty progressing relentlessly to a natural conclusion.

But my visits to China this year have not been about vacation. In Guangzhou in April we ran the first joint ECCO-CIMF international summer school in IBD. Over 40 of China’s most important IBD physicians came to learn with us … a humbling, engaging and inspiring experience over 3 residential days. This was as intense and rewarding a teaching experience as I have had the privilege of running. In September then to Shanghai for the World Congress of Gastroenterology, where I had the pleasure to speak on the future of biological therapies in IBD at the ECCO@WCOG symposium. We ran a most productive full-day face-2-face meeting of the International IBD Genetics Consortium (www.ibdgenetics.org). The geography allowed a major focus on the trans-ethnic studies underway. Genetic analysis of Asian and other populations are informative in their own right; coupled with the Caucasian studies already performed (Jostins et al Nature 2012) we are generating incredible power for fine-mapping efforts. Together, we hope to obtain sufficient resolution to fully map the genetic architecture in IBD.

The most recent trip to Xi’an has been for the Annual Chinese IBD Conference, attended by over 500 physicians from across the country. The success of this annual venture is of course thanks to the vision and energies of Professors PJ Hu (Guangzhou), Kaichun Wu (Xi’an) and Zhihua Ran (Shanghai), amongst others. But much more than this it reflects what can only be described as the most incredible explosion in IBD incidence across the country. The published epidemiological data is now starting to reflect this. But even so, it does not do justice to the rising incidence that becomes so apparent speaking to the physicians and surgeons in person. On recent trips I have been privileged to visit Ran’s hospital in Shanghai and Wu’s in Xi’an. There I saw the out-patient clinic full of IBD patients and vast wards where fully one third of gastroenterology in-patients have Crohn’s disease or colitis. In Xi’an they have an entire hospital covering 19 floors completely dedicated to digestive diseases! I spoke with 2 of Professor Wu’s patients suffering from as debilitating Crohn’s disease as I’ve ever seen in my clinical practice in Scotland.

So as we couple these two observations we are led to a rather obvious conclusion. In China, as in much of the developing world, the rapid Westernisation is in some way directly responsible for the dramatic rise in the incidence of IBD. This should be of no great surprise, as in the West we saw this in the second half of the 20th century. However what it now gives us is clues and opportunities. We can witness the environmental shifts in China. I have watched and marvelled with my own eyes at the seemingly real-time changes taking place. I saw clearly the juxtaposition of old and new on my first 24 hours in Guangzhou earlier this year : the peasant farm lady laden with fresh produce from the countryside sharing the same street corner with the young dude in jeans and trainers deep-frying chips on the same corner of the street. Where does this scene occur … right in front of a brand-new Starbucks of course. I have enjoyed the most marvellous of traditional Chinese breakfasts (noodle soup and rice congee – close to my daily fix of porridge!) whilst watching the young Chinese adults and children tucking into white ‘plastic’ bread and highly refined processed products laden with sugar and lacking in any non-digestive plant fibres. Over a lunch of the most impossibly delicious and intricately prepared steamed dumplings I look out across the central square in Xi’an to the hoardes queing up at McDonalds and KFC.

We cannot of course make establish causality with such casual observations. But whereas we presently lack a sufficient delta in the West to make underlying aetiologies clearly visible, we now perhaps witness a golden opportunity in China. And right now, as a pressing priority, I strongly urge my Chinese friends and collaborators to take up this challenge before it is too late and the change is complete. I do not suggest for a minute that we abandon efforts in the West. Indeed, I am presently in the advanced stages of planning for a large prospective study of environmental triggers in IBD across an inception cohort in Scotland. This follows on from our knowledge of disease genetics and will be accompanied by UK-wide studies of the gut microbiota. I would like to run a parallel study in China, also coupled with detailed sampling of gut microbiota and host genetics. The technological solution we are deploying across Scotland, with a web portal and smart phone app linked to NHS IT systems, is being designed with intrinsic scalability at heart. This will allow a rapid and economical roll-out across the rest of the UK, other Western populations, and with some further modifications, across to the far East.

This agenda will allow a systematic, robust and ultimately informative dissection of the diet-microbiota-genetic axis which I believe underpins IBD aetio-pathogenesis. What we eat affects our gut microbiota which in turn has differential effects, including the development of intestinal inflammation, depending on our genetic background. Occasionally there is an overwhelming genetic defect (e.g. loss of function XIAP or IL10R mutations in very early onset IBD). But mostly the individual genetic variants affect only subtle perturbations in immune responses. Kept in check during normal ‘physiologic’ conditions, a shift outside a controlled response zone in response to a dysbiosis may be triggered by an environmental insult. Further genetic, microbial or environmental conditions may then be needed for the inflammatory response to persist, thus tipping the balance from homeostasis to disease.

The work ethic in China is as exceptional as we might expect. The typical working day begins before 8am and finishes after 11pm for everyone from the junior research fellow to the senior chief. But sometimes I feel that the effort, especially across the research agenda, lacks focus and true ambition. So the visits to China have been deeply inspirational to me and together I feel we can affect major advances and ultimately improve knowledge for all of our patients.

I will return to China next year. And then I have one further ambition ... and that is not to run in a hotel gym in the middle of the night with no air conditioning. Next visit I want to go running in the real country … through the open fields, up the mountains and along the valleys. In the meantime we push ahead with the research agenda at home, and the Scottish trails beckon.  6 months until the http://www.zen31010.zen.co.uk/highlandflingrace/

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