While nearly every adult and child experiences stomach issues once in a while, millions suffer from serious autoimmune problems in the intestine, such as celiac disease, and inflammatory bowel disorders, including Crohn’s disease and ulcerative colitis. These chronic digestive diseases, which have no known medical cure, commonly require a lifetime of care for patients.
Ongoing research at Stanford and elsewhere aims to forge new avenues for the diagnosis, therapy and prevention of these diseases. At Stanford, KT Park, MD, an instructor in pediatric gastroenterology, studies the pharmaco-economics of various therapeutic and diagnostic strategies for chronic gastrointestinal diseases, with particular interests in Crohn’s disease, ulcerative colitis, celiac disease and chronic abdominal pain. He is also an attending physician for the gastroenterology and hepatology services at Lucile Packard Children’s Hospital.
For this month's Ask Stanford Med, we asked Park to answer your questions on advancements in research and treatments for pediatric gastrointestinal diseases. He responds to your questions in a two-part Q&A, first discussing research on fecal microbiota transplantation, the role of diet in treating Crohn's, and IBD in the developing world.
Migdalia Ramos asks: Why isn’t fecal microbiota transplantation (FMT) seriously researched as a treatment for children with IBD?
You are correct in that the representative literature on fecal microbiota transplantation in IBD is lacking, although one small observational study in children was recently published. The paucity of data doesn't mean that scientists and IBD clinicians aren’t thinking about it. As you may know, FMT – after much advocacy by patients, various advocacy groups, and gastroenterology societies such as the American Gastroenterological Association – is now approved by the U.S. Food and Drug Administration for recurrent Clostridium difficile (C. difficile) infections and colitis, subject to ongoing regulatory oversight. Over 14,000 Americans die from C. diff annually. In fact, almost all major FMT literature is in the treatment of recurrent C. difficile colitis, which has over a 90 percent efficacy rate. Despite the success in eradicating C. difficile, FMT cannot be assumed to be safe or effective as a first-line therapy option in IBD, much less IBD in children. A recent systematic review (subscription required) which summarizes what is known and studied regarding FMT and IBD is published in Aliment Pharmacol Therapeutics and available (login required) for free on Medscape.
For now, I offer two additional items to consider. First, in the United States, FMT as per the FDA is considered an investigational new drug. As such, researchers are subject to the same jurisdiction as with any novel pharmacological agent. For clinicians, patient safety has to always take priority. At the moment, I know of one phase I study, which was approved by the FDA for research after two years of rigorous review, evaluating the safety and efficacy of FMT in ulcerative colitis in adults led by researchers at the University of Chicago. Second, despite the seemingly slow beginnings, I think there will be a future for FMT in IBD, but only after experience and applicability have been shown in recalcitrant C. difficile infections. Consider an editorial earlier this year in the New England Journal of Medicine, discussing the history and the future potential of FMT in gastrointestinal diseases. Like you, I'm hoping for and working to support the data needed to establish safety and standardization of FMT for adults and children with IBD in the foreseeable future.
EC Smit asks: Why isn’t diet part of the treatment plan for Crohn’s disease when people who have excluded known gastrointestinal irritants, such as gluten and carrageenan, have found relief and remission?
Let me first try to address your concerns and questions with a concession. Interventional dietary alternatives in the treatment of IBD are often underemphasized. Knowing this, our Stanford group is longitudinally recording and making some headway in characterizing how specific and modified carbohydrate diets have impacted health for patients with Crohn’s disease. We're still in the early phases of our prospective study, but we hope to gain more momentum.
With that said, I understand your perspective. Presently, the medical community in the United States can place more focus on pharmacological therapies than nutritional ones. I think this tendency may have to do with two important considerations. First, although Crohn’s disease is a gastrointestinal disease, it is in essence an autoimmune problem. Conventional and experiential wisdom tells us that controlling immune dysregulation requires immune-modulating agents, such as drugs that can help the body stop attacking its own cells or block the biological response that causes inflammation. And historically, we have found success with this established framework – as most Crohn’s patients achieve sustained remission following an evidence-based treatment plan. Despite the potential severity of the initial disease presentation, most patients return to living life without a noticeable difference in their overall quality-of-life.
Second, patient tolerance and continued adherence to the type of diet programs shown to be potentially effective in Crohn’s disease are difficult, to say the least. As you may know, the Specific Carbohydrate Diet (SCD) is one purported dietary intervention for Crohn’s disease. Although substantially more efficacy data are needed, we know that the SCD dietary plan is a very restrictive low carbohydrate diet, which is difficult to maintain strict adherence for patients, especially among children and adolescents. Similarly, elemental or polymeric diets, which have been reported to be helpful in active Crohn’s disease, are also difficult to perpetuate on a day-to-day basis for long-term disease management. For clinicians, we have to do our part in informing patients of all the alternatives while helping patients and their family to optimize daily quality-of-life.
Antonio Murcia asks: I want know what is known about ketogenic diet and very low carb diet (like paleo diet) to prevent inflammation in Crohn's disease. Can they be a good way to manage the condition?
Very low carbohydrate diets, like the paleo diet, or the ketogenic diet have not been proven to be effective in the maintenance of Crohn’s disease, and there is one study reporting disease non-response. Most evidence in dietary therapy for Crohn’s lies in the elemental formula diet. Also, there are case reports of the Specific Carbohydrate Diet inducing Crohn’s disease remission. Please refer to my more detailed answer to the previous question regarding therapeutic diets and IBD.
Raj Kmar asks: Is there a difference in the presentation of IBD among children in developing and developed countries?
This is a great question. In developing countries where access to care is difficult, we are not able to precisely estimate even the prevalence of IBD, let alone accurately describe any potential differences in the clincal presentation. In developed countries, the prevalence of IBD may be as high as 200 per 100,000 persons. My guess is that the overall presentation developing countries is similar to that of Crohn’s and ulcerative colitis presentation in the United States – abdominal pain, diarrhea, bloody stools and various signs of underlying inflammation.
However, marked differences could happen in the overall management of IBD, from initial diagnosis to ongoing maintenance treatment. For example, there have been case reports from developing countries of children with underlying IBD who were initially misdiagnosed for infectious colitis (e.g., parasites, tuberculosis, and enteric bacterial pathogens). I can see how this could be quite common because clinical intuition tells us that common things occur more commonly. In the developing world, infections rather than autoimmune diseases continue to be the primary cause of mortality and morbidity. In the case reports above, these patients often had concomitant gastrointestinal infection and underlying gut inflammation from undiagnosed IBD. The available literature also suggests that medical management is not always readily available. Patients who have been diagnosed may not have access to maintenance medications, and may have to rely more on steroids and surgery.
Sher Curly asks: I am also interested in FMT for treatment. I am curious whether you feel the potential for side effects is more, less or the same than traditional medications especially anti-tnf and 5ASAs.
This is a great question, but I don’t think anyone can offer any specifics at this time regarding the comparative effectiveness between FMT versus other conventional therapeutics. As remarked in my answer above, there is no consensus about how FMT might work best in the management of IBD. (Please refer to the previous systematic review I referenced.)
Standardization in FMT is lacking at the moment. So it is difficult to predict what type of maintenance FMT schedule (for example one-time vs. serial therapy), routes of delivery (naso-duodenal or gastric tube versus colonoscopic introduction versus enema) and donor screening regimens, and fecal preparation protocols are optimal for the various types of IBD. Different people have different disease severity with different areas of gastrointestinal tract affected. Similar to when classical pharamco-therapy options in IBD are considered, the goal of future FMT use in IBD should be to tailor an individualized treatment strategy that is specific to the unique patient profile and preferences – minimizing side-effects and risks while maximizing chances for sustained disease remission.
As you know, pseudotumor cerebri is a condition where the intracranial (inside the skull) pressure increases, often without an identifiable cause. Pseudotumor cerebri is associated with severe headaches, among other neurological symptoms. While pseudotumor cerebri is not identified as one of the common extra-intestinal manifestations of IBD, there have been multiple case reports and editorials of pseudotumor cerebri occurring in the context of IBD, most often as a potential side-effect from corticosteroids (or steroids) and mesalamine.
If you’re not having a known IBD medication-related pseudotumor cerebri, it’s important to have a full consultation with a neurologist. Recurring headaches and pseudotumor cerebri are non-specific, and can occur from multiple triggering factors. A final note is that IBD can elevate systemic inflammation within the body’s blood vessels, even those that supply the brain, which can potentiate pseudotumor cerebri or even more serious vascular complications. So, the best advice is to make sure that the IBD is as well controlled as possible to avoid the systemic inflammatory effects itself.
Previously: Ask Stanford Med: Pediatric gastroenterologist taking questions on inflammatory bowel diseases, Chat with Stanford pediatric gastroenterologist on celiac disease research archived on Storify, Living the gluten-free life, Spreading awareness of inflammatory bowel disease, one bathroom stall at a time and Getting to know – and thanking – the faces of Crohn’s disease
Photo by Loren Kerns