Marlies Meisel: Untangling cause and effect in immune diseases
Growing up in Grafensulz, Lower Austria, Marlies Meisel already had a deep interest in medical science and research. “I always wanted to know how the things work in the body and what happens when the body gets sick,” she says. Marlies had a strong personal incentive for understanding how the body works and why it gets sick. “I was diagnosed with celiac disease when I was a baby, and could feel that if I made a nutritional mistake, I would feel pain and would get sick … but my other family members were fine.” Despite coping with celiac disease, she became very involved in sports when she started graduate work at the University of Innsbruck, competing in swimming, and marathons, and even “a couple Half-Ironmans!” Since earning her PhD in molecular biology and oncology, she has pursued postdoctoral research at the University of Chicago, where she studies celiac disease and inflammatory bowel disease (IBD), with special focus on the host’s gastrointestinal microbiota (bacteria populating the digestive tract) and the role of the immune system in these diseases.
The research reported in Meisel’s poster at ARIT 2016 investigated interactions between interleukin-15 (IL-15), the intestinal microbiota, low butyrate levels in the intestines, and susceptibility to colitis. IL-15 is a protein whose release from cells often increases in “distressed” tissue. Interestingly, levels of IL-15 are abnormally high in the gut of patients with IBD or celiac disease. The microbiota in this study are bacterial populations in the mammalian intestine, whose composition varies from one intestinal region to another, and often changes if the host or its biochemistry are disrupted. An imbalance between protective and harmful bacteria – a situation called “dysbiosis” – can predispose an organism to autoimmune diseases like multiple sclerosis and rheumatoid arthritis, or to inflammatory disorders like IBD and celiac disease. And while normal intestinal bacteria usually produce plenty of butyrate, a short-chain fatty acid that intestinal cells use as an energy source, low levels of butyrate are thought to be a causative factor in IBD. In fact, treating IBD patients with butyrate relieves the inflammation. Yet, no one really knew whether dysbiosis causes intestinal inflammation or is a result of it!
Meisel’s study used specially bred mice (v-IL-15tg mice) that overexpress IL-15 in their intestinal epithelium, and found that their intestinal microbiota are very different from that of wild type mice. Even with no visible tissue damage, IL-15 overexpression reduced the population of a certain type of butyrate-producing bacteria in the feces and the cecum (a part of the colon). In one experiment, Meisel transplanted fecal microbiota from a) wild-type mice, or from b) mice overexpressing IL-15, into germ-free mice. The results confirmed that lower butyrate levels in the intestines resulted from the dysbiosis induced by overexpression of IL-15. Moreover, mice that overexpressed IL-15 were also more susceptible to a type of chemically-induced colitis. And when mice with induced colitis were treated with butyrate, Meisel observed (unpublished data) that their signs of intestinal inflammation and disease severity decreased! “We also have preliminary data that reveal that a diet high in pectin (water soluble fiber that is enriched in the skin of apples or cranberries) is able to increase butyrate levels in the intestine of mice,” said Meisel. “This finding, that the diet is able to impact the function of the microbiome, is very interesting, as this could be a potential non-invasive treatment plan for patients with inflammatory intestinal diseases!”
Overall, Meisel’s studies indicate that IL-15 reduces the population of butyrate-producing bacteria, decreasing butyrate levels in the feces and cecum. Studies are now underway to investigate the links between low butyrate levels and occurrence of intestinal inflammatory disease. By revealing a new pathway by which IL-15 can promote intestinal inflammatory disease, Meisel’s study has increased our understanding of the disease mechanisms, and supports the possibility that celiac disease, and related disorders such as IBD, could be treated by intervening in this pathway, e.g., neutralizing or blocking the effects of IL-15, supplementing butyrate levels, or increasing the intake of dietary fibers (e.g. pectin). For patients who, like Meisel, have celiac disease or another inflammatory intestinal disorder, her study offers lots of hope, especially regarding the future options for non-invasive treatment.
The preceding article is part of a series featuring the scientific work of 20 young Austrian researchers, all who are active members of the OSTA's Research and Innovation Network Austria. The initial presentation of their work took place at the ASCINA poster session under the auspices of the "Austrian Research and Innovation Talk" in Toronto on October 21, 2016. Three of these scientists were subsequently awarded the ASCINA award the same evening, honoring their outstanding scientific work.