Challenges remain, but microbiome may hold guide to inflammatory disease
CHICAGO — Inflammatory bowel disease is known as a prototype for new-age diseases. It grew out of industrializing countries a little more than a century ago and the prevalence grew as populations exploded and lifestyles changed. Now, it is growing in countries with emerging industrialization, mirroring its original growth.
“This tells us that there are environmental influences on these types of disorders probably based on some kind of genetic background,” Eugene B. Chang, MD, professor of medicine at the University of Chicago, said in his presentation at IAS 2019. “What causes these diseases? Why do only a small fraction of individuals that have genetic variants that are known to be associated with increased risk of disease get these diseases?”
Chang said there currently are no good answers for these questions, as well as questions about whether a pathogen can cause IBD, or if the disease can be predicted or cured. While the microbiome is increasingly seen as an influential factor in the development of the immune system, assessing its direct role in the development of autoimmune disease, like IBD, remains difficult.
Beyond factors like patient-related variables and study design, Chang said the makeup of the microbiome limits what researchers can accomplish.
“Everybody’s microbiome is different,” Chang said. “You are getting down to a level below the genus level, at a species and strain level, we are just so different. If you try to study a population of individuals ... it is very difficult to determine what are meaningful changes.”
Limits on technology and investigational tools have created a “bottle-neck” and limited how far investigators can dive into genetic factors that impact autoimmune diseases.
Additionally, Chang said the cross-sectional design of current studies in IBD have proved to be a built-in disadvantage when trying to explore the role of the microbiome.
“They are done after the disease develops,” he said. “Once the disease develops, you can’t figure out what the events were that led to the development of disease. The disease process, particularly immune activation and inflammation have consequences that make looking at the microbiome very difficult. You cannot determine what is cause or effect.”
Chang and others have started looking for new ways to get around these study design problems to explore the role of the microbiome. For instance, Chang described a study of patients with ulcerative colitis who underwent colectomy followed by ileal pouch anal anastomosis and compared them with patients who underwent IPAA after familial adenoma polyposis. Although the pouch is made of small intestine, patients can still develop pouchitis with features that mimic UC, which only occurs in the colon.
“You can look at events before they happen,” Chang said. “When the pouch is created and before it is functionalized, that is time zero. No one has disease at that point. Once the pouch is created, it is very easy to sample.”
Researchers took pouch samples at 4, 8 and 12 months to study the microbiome, as well as gene expression. They found that the pouches of patients with UC had more than 6,000 different genes when compared with the pre-pouch area, which does not get pouchitis.
To find exactly how the microbiome impacts IBD, Chang said researchers will have to go down deeper into the strain level of bacteria and explore what genes are at play. However, once there is a target, it opens up the possibility of assessing risk and maybe even preventing disease.
“We have to be much smarter about this,” he said. “Now that we’re doing deeper dives into the microbiome and human responses, I think we are beginning to see it’s not that simple.” – by Alex Young
Chang EB. “Microbiome in Inflammatory Disease. Presented at: Interdisciplinary Autoimmune Summit; April 5-7, 2019; Chicago, Illinois.
Disclosures: Chang reports no relevant financial disclosures.