June 11, 2019
In this Q&A, Darrell S. Pardi, M.D., discusses the role that the microbiome plays in inflammatory bowel disease (IBD) and how this knowledge is guiding new approaches to treatment using fecal microbiota transplants and other microbiome replacement therapies. Dr. Pardi is a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, whose research focuses on the clinical features, epidemiology and treatment of IBD.
What's the relationship between bacterial dysbiosis and inflammation?
It's unclear if bacterial dysbiosis is the cause or effect of inflammation. We also do not know if IBD arises in a setting with too few "good" bugs or too many "bad" bugs. And we still don't know whether the primary problem is with the organisms or rather the products they produce. However, it is possible that disturbances in the microbiome may be a common pathway for a number of putative IBD etiologies, including diet, smoking, antibiotics and socioeconomic status.
What do we know about the microbiome in IBD?
There's ample evidence that abnormal interactions between gut microbes, environmental triggers and the immune system can lead to chronic intestinal inflammation. Patients with IBD, either Crohn's disease (CD) or ulcerative colitis (UC), have a microbiome that is different from individuals in healthy populations, with decreased overall diversity as well as alterations in the proportions of bacterial taxa.
Do viral and fungal dysbiosis have a role in IBD?
Both have been described in IBD, although not much is known about the role that they might play in these conditions.
What role does genetics play in the microbiome and IBD?
We have also learned that certain genetic loci for IBD are involved in mucosal immunity. While their exact mechanisms are still not well understood, we know that some of these loci have roles in barrier function and microbe recognition.
How can fecal microbial transplant (FMT) be harnessed to treat IBD?
The rationale behind FMT for the treatment of C. difficile infection is reasonably well understood. In addition, FMT can reduce permeability and increase production of short-chain fatty acids, especially butyrate, which help maintain epithelial integrity. FMT also inhibits Th1 cell differentiation, activity of T cells, leukocyte adhesion and production of inflammatory factors. These mechanistic effects of FMT coupled with our emerging understanding of the role of dysbiosis in IBD make FMT a promising option for treating IBD.
What has available research data shown us about the efficacy of FMT as a treatment for IBD?
Despite many different types of medical therapy for IBD, there are patients who do not respond. Microbiome treatments such as FMT have proved very effective and have helped countless individuals overcome infection with C. difficile.
However, the most recent draft of the Food and Drug Administration guidance for fecal transplant does not yet recognize the use of FMT to treat conditions other than C. difficile infection, since FMT is still considered experimental for the treatment of other conditions such as IBD. Some published studies have provided evidence demonstrating the efficacy of FMT as a treatment for UC, while others have not. One study published in JAMA in 2019 involving 73 patients with mild to moderate UC yielded encouraging results. The number of patients who experienced steroid-free remission at week eight was higher in the group treated with FMT than in the control group (32% versus 9%, P = 0.03). Overall response was also higher in the FMT treatment group than in the control group (55% versus 23%, P = 0.007). However, other studies of FMT in UC have been less encouraging. Moreover, based on experience, one notes that even among many who do respond initially, recurrence of disease activity occurs. In other words, FMT in UC may not lead to a sustained response.
There is less evidence supporting the use of FMT as a treatment for CD. To date, only a handful of small, uncontrolled trials and studies have been conducted. Therefore, further work is needed to define the role of FMT in UC and CD.
Given our knowledge of the pathophysiology of IBD, manipulating the microbiome is a promising option that merits additional studies. Many are optimistic that there will be a role for these types of therapies for subsets of patients with IBD in the future and that the work conducted at Mayo Clinic will add to our understanding and help our patients with IBD.
What is known about standard microbiome replacement therapies?
Multiple standardized microbiome replacement therapies (MRT) are being studied in clinical trials, and the preliminary results look promising. I am Mayo Clinic's lead investigator on a multicenter, randomized, double-blind, controlled phase 2b trial studying the MRT known as SER-287 in approximately 201 adults with mild to moderate UC.
This trial is designed to assess the efficacy and safety of SER-287 after 10 weeks of induction dosing (after pre-treatment with vancomycin) in achieving clinical remission. Secondary objectives include evaluating the efficacy in achieving endoscopic remission, histological mucosal healing, normalization of stool frequency, symptomatic remission, and the engraftment of SER-287 bacteria from each treatment arm into the intestinal microbial community over time.
We also plan to conduct another study of an alternative MRT product for use in UC, so our patients desiring this type of treatment will have options to choose from.
For more information
Costello SP, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: A randomized clinical trial. JAMA. 2019;321:156.