Speakers: Dirk Haller (Germany), Balfour Sartor (USA)
Prof. Haller started his presentation by pointing out that “dysbiosis” is not a good term, because nobody knows what dysbiosis really means. To be able to understand what dysbiosis is, you would have to understand what the normal status quo is, and according to Prof. Haller that is not really well established. What is well established, as shown by a study with monozygotic twin cohorts, is a richness of gut bacteria in the healthy twins (cohorts from Germany and Lithuania), whereas in the ulcerative colitis-associated cohorts there is a dramatic decrease in bacterial richness. This drop in diversity can be observed in many inflammatory disease situations.
Prof. Haller also stressed that disease location matters, showing that ileal Crohn’s disease is associated with a dramatic loss of abundance of certain bacterial genera compared with colonic Crohn’s disease. He found it very stunning that, despite the fact that most of the bacteria are in the colon, the most pronounced effect of diversity loss was observed in the ileal phenotype. We have no real understanding yet of how different disease locations impact on the overall composition of bacteria in the gut.
There may also be a pre-selection, Prof. Haller indicated, referring to a German study with a combination of animal models and patients: it is not always good to look at end points only, prospective cohorts are important, too. A genetic predisposition could change the recruitment of bacteria. Though there is conflicting literature, this is a point to keep in mind. There is a possibility that patients who have a certain genetic variation may recruit a different microbiota from birth onwards – a concept that needs to be followed up in prospective cohorts.
The number of courses of antibiotic treatments before the age of 18 also plays an important part. According to Prof. Haller, the risk to develop Crohn’s disease increases tremendously with many rounds of antibiotics given during adolescence, because they leave a fingerprint in the gut microbiota that can never be erased completely. However, to follow up these studies, clinicians now have to work together with epidemiologists to put up large prospective cohorts with a population-based selection of people, the first ones already being underway in the UK and in Germany.
From a basic scientist’s perspective, Prof. Haller then spoke about animal models. He pointed out that it is a tragedy that, while there are more than 100 animal model systems to study chronic inflammation, most of them concern the inflamed colon, ignoring the inflamed ileum. Experimental animal studies co-conducted by Prof. Haller showed that diet matters and that there is a time window where treatment with certain dietary components could be effective. His group identified gluten as a potential trigger in ileal inflammation. Furthermore, as luminal iron can be quite aggressive at the epithelial interface, the depletion of luminal iron dramatically changes the gut microbial composition and antagonises Crohn’s disease-like ileitis.
In conclusion, Prof. Haller stated that everyone has a genotype variant that predisposes for one disease or another. But the translation from this genotype to phenotype is not always towards a disease endpoint. Rather, these phenotypes could grow out into the disease in the context of a certain environment. Nutrition and the gut microbiota are key environmental factors, but infections, smoking, antibiotics, and living on a farm also change your environment. Nutrition and the gut microbiota both are components that are inherently there every day: nutrition can influence the phenotype, but the question is whether nutrition can directly influence disease. The gut microbiota can certainly influence the disease, and the disease can feed back onto the microbiota and make it more aggressive. These fluxes are going to be the research targets of the next ten years.
Speaking from a clinician’s point of view, Prof. Balfour Sartor then explored what we can do about microbial dysbiosis in IBD. Even if it is a secondary phenomenon, it still may be pathogenic in that it might perpetuate disease, once initiated.
To start with, Prof. Sartor presented various forms of, predominantly correlative, clinical evidence that enteric bacteria, viruses or fungi can cause chronic, immune-mediated intestinal inflammation. These included the fact that IBD is usually located in areas with the highest concentrations of bacteria, such as the distal ileum and the colon. A study showed that a third of Crohn’s disease and a quarter of ulcerative colitis patients had a clearly divergent microbiota, results which have been replicated in many studies. The Lachnospiraceae Clostridia groups IV and XIVa and Bacteroidetes were dramatically decreased, while there was a substantial increase of Proteobacteria. This leads to two possibilities: losing beneficial function or gaining detrimental function by dysbiosis. Prof. Sartor believes that actually both might be occurring, because many of the Proteobacteria that increase include an enteroadherent, invasive phenotype of E. coli. In the gut, there is a balance of protective bacteria that predominate in the normal situation and of injurious, pro-inflammatory bacteria that have been implicated in experimental colitis or in human disorders. This balance is unique in each individual, and each individual responds differently to various bacterial species.
Prof. Sartor discussed several ways of therapeutically manipulating intestinal bacteria in case of a microbial imbalance in IBD: by selectively eliminating injurious bacteria with antibiotics or other, more thoughtful ways, or by augmenting either the number of protective bacteria or their function (perhaps by interesting ways beyond just probiotics). The tools on offer are selective and broad-spectrum antibiotics; traditional, commensal and genetically engineered probiotics; prebiotics and regular diet; combinations of antibiotics and probiotics or of probiotics and prebiotics; and microbial transplantation that can either be bacteriotherapy or complex groups of defined bacterial species.
Prof. Sartor said it is important to ask ourselves whether we should use beneficial commensals rather than traditional probiotic strains. We know that there are protective activities of some of our own commensal bacteria and that these are more likely to grow, persist and function in the intestine than those organisms grown in fermented milk.
As regards faecal microbiota transplantation, Prof. Sartor noted its effectiveness in preventing recurrent C. difficile toxin-induced colitis. However, he questioned whether the approach would be as effective in IBD as it is in C. difficile, because, despite small series of reports of success with IBD, these are no trials. It also needs to be determined whether it will be effective as induction or maintenance therapy. Other questions that need to be answered are whether the transplantation’s effects will have staying power, how the patient should be prepared, and what the optimal donor source is. Theoretically, you could develop obesity by a faecal transplant, so you might have to choose your donor wisely, and a family member may not always be the right person –– certainly not your identical twin if you have ulcerative colitis. There may be a need to match genetics, just like we need to match genetics for an organ transplant. Answering all these questions will require long-term longitudinal studies in well-characterised patients with microbiologists, immunologists and clinicians working together.
Dietary approaches, too, may alter the composition and function of the gut microbiota in a therapeutic or even preventive manner. Sucrose, fructose, iron and saturated fats increase the growth and function of aggressive bacterial species. Complex carbohydrates such as fibre, on the other hand, increase protective bacteria. Fibres are a non-absorbed carbohydrate that then is metabolised by bacteria.
To conclude, in Prof. Sartor’s view, the most important concept is that everyone’s microbiota is different. He said it is naïve to think that one approach could fix everybody, calling instead for a customised approach based on an analysis of the individual’s microbiota pattern.
Written by Robin Jeganathan, impressum health & science communication
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