See “Too Early to Determine Whether Fecal Microbiota Transplant has Therapeutic Promise for Ulcerative Colitis?” by Russell on page 3.
Ulcerative colitis (UC) is a chronic inflammatory disease of the large intestine. A variety of human and animal data support the hypothesis that UC is a result of immune responses to the fecal microbiota in genetically susceptible individuals. Such immune responses may alter the microbiota resulting in dysbiosis, which can further lead to increased inflammatory responses. Such dysbiosis in patients with UC has been better defined in recent years with the advent of nonculturable techniques, such as 16S RNA sequencing for the identification of species within the fecal microbiota. The dysbiosis in UC has been characterized by low phylotype diversity and decreased depletion of commensal bacteria and overrepresentation of Enterobacteriaceae and Enterococcus and underrepresentation of Ruminococcus and Bacteroides(1–3). Numerous clinical studies have attempted to change or modulate the fecal microbiome to decrease the inflammatory immune response using fecal microbial transplantation (FMT) therapy via enema and colonoscopy. The outcomes of these trials, however, have had mixed results.
The possibility of modifying the human gastrointestinal microbiome to replace harmful bacteria with more favorable microbes via FMT was first reported by Eiseman et al (4) in the treatment of fulminant pseudomembranous enterocolitis. For the next 50 years, many case reports and case series of fecal transplantation were noted in the literature. This included treatment for Clostridium difficile, constipation, irritable bowel syndrome, and inflammatory bowel disease (IBD). FMT has been described in patients as young as 2 years of age and patients >90 years of age. Given the efficacy of this therapy in C difficile infections, the American Gastroenterology Association published a position paper on the use of FMT including the preparation, dosage, patient, and donor evaluations (5). Given the etiologic role of fecal dysbiosis in UC, we performed a prospective study of FMT via nasogastric (NG) tube in pediatric patients with active UC to assess the efficacy of FMT.
This is a single-center, exploratory open-label study examining the effect of FMT in pediatric patients with active UC. Patients with mild-to-moderate UC, as defined by the Pediatric Ulcerative colitis Activity Index (PUCAI), ages 12 to 21 years were enrolled in this study. Each participant was studied for 12 weeks.
The protocol was approved by the institutional review board at Seattle Children's Hospital. All of the patients/participants gave written informed consent or assent. Approval from the US Food and Drug Administration (investigational new drug number 14942) was obtained. Study subjects were recruited from Seattle Children's Hospital outpatient gastroenterology clinics.
Study subject recipient had laboratory tests including complete blood cell count with differential and platelets, C-reactive protein, albumin, and stool testing for C difficile, bacterial culture and ova and parasite. The American Association of Blood Banks Donor History Questionnaire was used to evaluate study subject donors. Study subject donor laboratory studies included HAV immunoglobulin (Ig) G and IgM, hepatitis B virus serum antigen and antibody and core antibody, hepatitis C virus IgG, HIV1 and 2 IgG, human immunodeficiency virus-1 and -2 IgG, rapid plasma reagin and Epstein-Barr virus, cytomegalovirus IgG and IgM, as well as stool testing for C difficile, bacterial culture, ova and parasite. Study subject donors were not allowed to have antibiotics 3 months before procedure.
Study subject recipients received premedication before fecal transplant, which included rifaximin 200 mg 3 times daily for 3 days, with the last dose given on the evening before procedure. Study subject recipients also received omeprazole (1 mg/kg orally) on the day before and morning of procedure. Transplant recipient also received 17 g of MiraLAX (Merck, Whitehouse Station, NJ) in 8 oz of water 3 times per day for 2 days before FMT. For the FMT, an NG tube was placed and the location confirmed by x-ray. Approximately 30 g of donor stool was mixed with 100 mL of normal saline and blenderized until a homogenous texture was achieved. The stool suspension was then filtered using a 4 × 4 gauze. Infusion of 30 mL was slowly performed via NG tube for a 3-minute period. The NG tube was flushed with 15 mL of normal saline for 1 minute. After 15 minutes, the NG tube was removed. Once the subject was observed for another 30 minutes, the subject was discharged home.
Study subject recipients were called 2 days after transplantation. Study subject recipients had clinical follow-up at 2, 6, and 12 weeks. Standardized questionnaires and the PUCAI were completed during each study visit. A PUCAI score of <10 denotes remission, 10 to 35 mild disease, 35 to 64 denotes moderate activity, and >65 severe disease activity. Study subject recipients’/patient's families were provided diary cards to assess possible adverse effects.
Standard descriptive statistics, such as mean, median, range, and standard deviation, were computed for continuous variables.
A total of 4 subjects were enrolled in FMT in the study. The mean age of FMT recipients was 14.5 ± 1.7 years (range 13–16 years). All were boys. Disease duration before FMT was 1.0 year for all of the participants. All of the patients had pancolitis (classified as E4 S0 under the Paris classification) (6). At time of transplant, 3 subjects were taking oral mesalamine, 2 were taking VSL#3, and 1 was receiving azathioprine (Table 1).
All reported adverse events were graded as mild and self-resolving. After the FMT, 1 patient had nasal stuffiness likely related to NG tube placement. One patient had bloating, possibly related to FMT. One individual had mild increase flatulence. Two individuals had vomiting after FMT; both episodes were greater than 4 hours after FMT and without fecal matter noted in vomitus. One episode was associated with a 3-hour car ride after FMT; the other was associated with eating a large greasy meal.
Two patients developed C difficile diarrhea after FMT. Stool donors did not have evidence of C difficile in their stool before FMT by either standard PCR or microbiome analysis. The first case of C difficile infection occurred in a 13-year-old boy with a history of 3 episodes of C difficile diarrhea before FMT. At screening for the study, the patient was negative for C difficile antigen and toxin. He tolerated FMT well but did not have any significant clinical improvement. He therefore increased his mesalamine and started taking prednisone; eventually he started methotrexate and folic acid. He developed C difficile at 3 months post-FMT. At 6-month follow-up telephone call, C difficile had been treated with vancomycin and he had cleared the infection. The second patient developed diarrhea and was diagnosed as having C difficile and Aeromonas after FMT. Timing of the dual infections was approximately 4 months after FMT. Donor workup had been negative for both of these infections.
To follow the patients with UC clinically, the PUCAI scoring was done at each follow-up visit. None of the patients clinically improved with FMT. Three individuals received additional standard medical therapies before the end of the study. Patient 1 began methotrexate (MTX) and prednisone at week 2. Patient 3 began MTX, mesalamine, and prednisone by week 2 follow-up. Patient 4 began MTX and prednisone by week 2 and infliximab by week 12, owing to ongoing symptoms. Patient 2 did not start additional therapy but began an elimination diet, removing foods to which he was allergic, before the 12-week visit. The PUCAI did not change significantly for any patient at the 2-week follow-up (Table 2), nor were there any significant changes in laboratory values, including C-reactive protein, albumin, and hematocrit after FMT. Stool calprotectin did not change significantly (Table 3).
The results of this prospective study of FMT via NG tube showed it to be safe in active pediatric UC, but had little effect on clinical disease activity or laboratory parameters. There were 2 patients diagnosed as having C difficile and 1 with Aeromonas during the 6-month follow-up. Although none of the infections were believed to be related to the FMT itself, given the timing of the infections and negative donor workup, the impact the FMT via NG tube had on the biodiversity of the individual microbiome is unclear, and how this delivery method could affect a recipient's susceptibility to infection requires more investigation.
In our study, it is possible that the effect of gastric acid and/or passage through the small intestine may moderate the viability of crucial microbiota and reduce efficacy of the procedure. We did not evaluate whether single FMT by NG tube in our pediatric patients with UC caused engraftment of donor microbiota or changed recipient intestinal microbiota diversity, as has been described previously with single-donor NG tube delivery of FMT for patients with recurrent C difficile infection (9). In our study, rifaximin administration within 24 hours of the FMT and bowel preparation could theoretically affect the successful renewal of microbiota diversity described by this group with single FMT by NG administration.
The published experience of FMT in UC, to which we can compare our experience, is limited. A number of case reports and case series exist, which give a mixed picture of efficacy. Kund et al (7) demonstrated the safety and tolerability of fecal transplantation in young adults and children with UC. In this article, 10 patients, ages 7 to 21 years, with PUCAI scores between 15 and 65, received daily fecal enemas for 5 days. Seven patients had clinical response defined as the PUCAI score decreasing 15 points after 1 week, and 3 achieved clinical remission after 1 week with a PUCAI <10. Other studies have not shown significant results. Kump et al also showed that a single administration of FMT via colonoscopy in adult patients with UC did not achieve remission within 90-day follow-up; however, all of the patients did report a temporary improvement within the 2 weeks after FMT, as noted by a decrease in stool frequency (8).
It is important to acknowledge our limited understanding of the gastrointestinal microbiota and its effect on overall health and disease. Emerging evidence suggests there is an association between intestinal microbiota and conditions such as obesity, diabetes, colorectal cancer, and irritable bowel syndrome (10). As we learn more about the impact of the gastrointestinal microbiome on disease, it will become even more important to find a way to successfully modify the microbiome to affect disease course.
To date, the research in FMT for IBD is still in its infancy. Not only are we unsure of its true efficacy but we also have yet to determine the ideal dosage, timing, and route of administration. With FMT for recurrent C difficile, studies have shown no significant difference in clinical outcomes between NG and colonoscopic administration of feces (9,11). There are practical and clinical ramifications of each route of delivery. NG delivery of FMT for UC avoids the need for invasive procedures and anesthesia, but in this study did not result in improvement by clinical or laboratory measures. Despite negative results from this study, there have been numerous case reports and series suggesting that FMT via enema may have clinical benefit. Further study is required to assess the efficacy of FMT in UC with a focus on alternative routes of administration, dosage, timing of the FMT in the disease course, and assessment of the effect of FMT on the donor's intestinal microbiota (12,13).
1. Rajilic-Stojanovic M, Shanahan F, Guarner F, et al. Phylogenetic analysis of dysbiosis in ulcerative colitis
during remission. Inflamm Bowel Dis
2. Nemoto H, Kataoka K, Ishikawa H, et al. Reduced diversity and imbalance of fecal microbiota in patients with ulcerative colitis
. Dig Dis Sci
3. Angelberger S, Reinisch W, Makristathis A, et al. Temporal bacterial community dynamics vary among ulcerative colitis
patients after fecal microbiota transplantation. Am J Gastroenterol
4. Eiseman B, Silen B, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery
5. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile
infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol
6. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis
7. Bauschlein M, Haas S, Hofer G, et al. Epilepsy. Kinderkrankenschwester
8. Kump PK, Grochenig HP, Lackner S, et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis
. Inflamm Bowel Dis
9. Youngster I, Sauk J, Pinder C, et al. Fecal microbiota transplant for relapsing Clostridium difficile
infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis
10. Walsh CJ, Guinane CM, O’Toole PW, et al. Beneficial modulation of the gut microbiota. FEBS Lett
11. Postigo R, Kim JH. Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile
infection: a review and pooled analysis. Infection
12. Bennet JD, Brinkman M. Treatment of ulcerative colitis
by implantation of normal colonic flora. Lancet
13. Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis
using fecal bacteriotherapy. J Clin Gastroenterol