The ENIGMA Study: Eastern Inflammatory Bowel Disease Gut Microbiota

The incidence of inflammatory bowel diseases, (IBD) including Crohn's disease (CD) and ulcerative colitis (UC), is increasing in the developing world. Our recent Asia-Pacific population-based study in 8 Asian countries and Australia have demonstrated that Hong Kong and China have amongst the highest disease incidences in Asia while Australia has the equal highest incidence of these diseases in the world. The incidence of IBD in Hong Kong and China has risen three-fold in the past decade.

Asian populations have genetic predispositions to develop IBD which are different to the West, but these genetic abnormalities are not obligatory for the development of IBD, with environmental factors playing a much more important pathogenic role. These factors include travel with exposure to a new population in childhood, diet, antibiotic use during childhood, socioeconomic status, and a rural versus urban upbringing, each of which alone, or in combination, are likely to affect the microbiome.

Compelling evidence suggests that gut microbes play a critical role in disease pathogenesis, while geographic, dietary and ethnic factors impact the microbial composition. In addition to broad changes in the microbial profile in IBD, a number of specific changes have been identified, such as a decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium Prausnitzii. Although the commensal gut microbiota is ecologically and functionally perturbed in IBD, there is unexplained heterogeneity among IBD subtypes and individual patients. In new-onset treatment naïve patients with CD, enrichment for the Enterobacteriaceae and depletion of Clades IV and XIVa Clostridia during disease-associated inflammation have been reported. Metagenomic studies and microarray analyses in Western populations and limited Asian data have demonstrated a reduction of Firmicutes, such as F. prausnitzii in Crohn's disease (CD), and an increased in Escherichia coli and Fusobacterium. It is unknown if the changes in putative pathogens and/or protective organisms identified in Western populations, such as E. coli and F. prausnitzii, respectively, are present in IBD patients in Asia. Information is also lacking about the degree of genetic variation between the bacteria assigned to these taxonomic groups from different ethnic and geographical regions. Most of the published work on these bacteria, and their potential pathogenic or protective role in CD, has been undertaken with isolates recovered from European and North American subjects. For these reasons, The investigators believe there is a need to firmly establish whether the microbial changes outlined above are also encountered in patients from other parts of the world, including Asian countries with high disease incidence and increasing disease incidence.

The Post-Operative Crohn's Endoscopic Recurrence (POCER) study was undertaken in 17 hospitals around Australia and New Zealand and recruited 174 patients who were then monitored for 18 months post-operatively. The microbiota analyses undertaken on a subset of the POCER study patient cohort showed that F. prausnitzii, previously identified as being capable of producing anti-inflammatory properties possible key organism in preventing active CD were decreased in abundance in active CD, in patients at the surgery who subsequently recurred, and in patients at the time of recurrence. Most of the published studies examining the anti-inflammatory properties of F. prausnitzii have been undertaken with a single strain of European origin. Despite the promise associated with the anti-inflammatory properties produced by F. prausnitzii it remains to be determined whether this bacterium is protective against inflammation, or diminishes subsequent to the onset of inflammation.

In summary, it is currently unclear if the changes in putative pathogens and protective organisms present in Western IBD populations are consistently observed with CD patients in Asia. Nor is it known whether the functional capabilities of these bacteria differ across ethnic and/or geographic regions.

In addition to the characteristics of these two bacterial families, the microbial environment interfacing with these organisms is likely to play a critical role in their expression and function. This will be examined in detail using broad sequencing techniques.

Microbial analyses will be undertaken in the context of a detailed examination of environmental risk factors for the development of CD, in the same patients.