Inflammatory Bowel Disease And Microbiome
By Jun Kim Ph.D.
As discussed previously (here), the main difference between IBD and inflammatory bowel syndrome (IBS) is that in IBD there is pronounced inflammation, ulcers, or other damages to the bowel, and it is a much more serious problem. Although it is now widely accepted that IBD is associated with alterations in the gut microbes, the exact mechanism is not clear and is shown to be contributed by both environmental and genetic factors. Currently, there are no known medications that can cure IBD. Frequently used treatments involve anti-inflammatory drugs and antibiotics, but they can also lead to more infections or antibiotics resistance. Addressing dysbiosis in patients with IBD through probiotics may be a promising therapeutic route with low side effects.
Studies that analyze the genetic basis of IBD can reveal which biochemical pathways are clinically useful for therapeutic targeting. For example, the strongest determinant of susceptibility to Crohn’s disease is the NOD2 gene. A study has shown that carriage of two NOD2 variants has a 98% specificity of having a complicated disease course in patients with Crohn’s disease 1. NOD2 regulates the gut microbiota (by producing antibacterial defensin), the immune response, and intestinal angiogenesis. The discovery of NOD2 focused research interest on the innate and adaptive immune response to the gut microbiota. Other additional important genes include those that are functionally related to NOD2, such as RIPK2, ReLA, TLE1, CARD9, and CARD11 2. Variants of such genes that are involved in innate immunity alter the production of cytokines and lead to the defective killing of the intracellular bacteria, which in turn activates pathogenic T cells.
Crohn’s disease and ulcerative colitis (UC) preferentially occur in the colon and/or distal ileum, which is associated with the highest intestinal bacterial concentrations. Biopsies show that concentrations of bacteria are higher in IBD patients, and they increase as the disease progresses 3. Also, the abundance profile of the intestinal microbiota is different in IBD patients. For example, Bacteroidetes and Lachnospiraceae were significantly depleted in samples from IBD patients, whereas Actinobacteria and Proteobacteria were substantially more abundant 4. A report with 40 twin pairs shows decreased microbial diversity in patients with Crohn’s disease and increased Enterobacteriaceae 5. Among patients with ileal disease key symbiotic bacteria such as Faecalibacterium and Roseburia were decreased. Functionally, these bacteria are prominent producers of short-chain fatty acids, which play a role in protecting the intestine.
A major limitation of these studies that look at the differences between the microbiome of IBD and non-IBD patients is that they do not describe a causal relationship between two events. For example, it is still unclear how the inflammation changes the microbiome or how the microbiome changes the inflammation. Analyzing only the outcome will always raise the question of the chicken or the egg. If the microbiome changes are the consequence of inflammation, then the observations are useful for diagnosis. But if the microbiome is a driver of the inflammation then the microbiome-based approach can even treat or prevent IBD. To answer these questions there need to be more longitudinal studies that start monitoring microbiome before the pathological outcomes become obvious.
While treatment with broad immunosuppressive therapy can increase the risk for infection with opportunistic pathogens, more specific and mechanism-driven treatments, such as anti-TNF agents, and anti-integrin therapies 6 have been showing more promising results. Microbiome-based therapies need to take a similar approach. Studies that examine altering the GI microbiota in IBD patients with probiotics suggest the clinical utility of probiotics 7–9. But results are variable and different probiotic species/combinations probably have different therapeutic effects. With the causal relationships discovered, more focused microbiome-based therapeutics with higher and reliable efficacy and reduced side effects will be developed.
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