Thomas J. Borody

Treating clostridium difficile infection with fecal microbiota transplantation

Clostridium difficile infection is increasing in incidence, severity, and mortality. Treatment options are limited and appear to be losing efficacy. Recurrent disease is especially challenging; extended treatment with oral vancomycin is becoming increasingly common but is expensive. Fecal microbiota transplantation is safe, inexpensive, and effective; according to case and small series reports, about 90% of patients are cured. We discuss the rationale, methods, and use of fecal microbiota transplantation.

Fecal microbiota transplantation and emerging applications

Fecal microbiota transplantation (FMT) has been utilized sporadically for over 50 years. In the past few years, Clostridium difficile infection (CDI) epidemics in the USA and Europe have resulted in the increased use of FMT, given its high efficacy in eradicating CDI and associated symptoms. As more patients request treatment and more clinics incorporate FMT into their treatment repertoire, reports of applications outside of CDI are emerging, paving the way for the use of FMT in several idiopathic conditions. Interest in this therapy has largely been driven by new research into the gut microbiota, which is now beginning to be appreciated as a microbial human organ with important roles in immunity and energy metabolism. This new paradigm raises the possibility that many diseases result, at least partially, from microbiota-related dysfunction. This understanding invites the investigation of FMT for several disorders, including IBD, IBS, the metabolic syndrome, neurodevelopmental disorders, autoimmune diseases and allergic diseases, among others. The field of microbiota-related disorders is currently in its infancy; it certainly is an exciting time in the burgeoning science of FMT and we expect to see new and previously unexpected applications in the near future. Well-designed and well-executed randomized trials are now needed to further define these microbiota-related conditions.

Human Interdigestive Motility: Variations in Patterns From Esophagus to Colon

In most fasting mammals, motility of the foregut and small intestine undergoes regular cycles of activity. Much of the expanding knowledge of this phenomenon comes from species other than humans; however, disorders of these patterns are proposed as being clinically important. We report studies in 16 healthy humans in whom motility was recorded from intraluminal pressure sensors, both when fasting and after a meal, for prolonged periods. The recording system spanned the area from stomach to proximal colon in all subjects and included the lower esophagus in 11 of the 16 studied. Half the interdigestive cycles involved the esophagus, approximately one-third began in the gastroduodenal region, and the remainder commenced more distally. Fewer than half the migrating motor complexes were recognizable beyond the midpoint of the small bowel, and less than 10% reached the distal ileum. The migrating motor complex was more prominent at night; and its progression through the jejunum was then slower. Small meals (345-395 kcal) interrupted fasting patterns for 90-240 min, but the amount of fat did not influence the duration of these disruptions. Motility varied widely between and within individuals, and differences between normal patterns in the jejunum and ileum were particularly striking. Thus, levels of recordings must be defined accurately if putative abnormalities, of possible clinical significance, are to be interpreted correctly. Relating local motor patterns to the maximal rate of rhythmic contractions, which reflects the frequency of slow waves and is a guide to the level of the small bowel, may be helpful in this regard.

Treatment of ulcerative colitis using fecal bacteriotherapy.

Background Although the etiology of idiopathic ulcerative colitis (UC) remains poorly understood, the intestinal flora is suspected to play an important role. Specific, consistent abnormalities in flora composition peculiar to UC have not yet been described, however Clostridium difficile colitis has been cured by the infusion of human fecal flora into the colon. This approach may also be applicable to the treatment of UC on the basis of restoration of flora imbalances. Goal To observe the clinical, colonoscopic and histologic effects of human probiotic infusions (HPI) in 6 selected patients with UC. Case Reports Six patients (3 men and 3 women aged 25–53 years) with UC for less than 5 years were treated with HPI. All patients had suffered severe, recurrent symptoms and UC had been confirmed on colonoscopy and histology. Fecal flora donors were healthy adults who were extensively screened for parasites and bacterial pathogens. Patients were prepared with antibiotics and oral polyethylene glycol lavage. Fecal suspensions were administered as retention enemas within 10 minutes of preparation and the process repeated daily for 5 days. By 1 week post-HPI some symptoms of UC had improved. Complete reversal of symptoms was achieved in all patients by 4 months post-HPI, by which time all other UC medications had been ceased. At 1 to 13 years post-HPI and without any UC medication, there was no clinical, colonoscopic, or histologic evidence of UC in any patient. Conclusions Colonic infusion of donor human intestinal flora can reverse UC in selected patients. These anecdotal results support the concept of abnormal bowel flora or even a specific, albeit unidentified, bacterial pathogen causing UC.

Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients

OBJECTIVES:Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients.METHODS:A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT.RESULTS:Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3–46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT.CONCLUSIONS:This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

Bacteriotherapy using fecal flora: Toying with human motions

The intestinal flora may play a key role in the pathogenesis of certain gastrointestinal (GI) diseases. Components of bowel flora such as Lactobacillus acidophilus and Bifidobacterium bifidus have long been used empirically as therapeutic agents for GI disorders. More complex combinations of probiotics for therapeutic bacteriotherapy have also recently become available, however the most elaborate mix of human-derived probiotic bacteria is, by definition, the entire fecal flora. Fecal bacteriotherapy uses the complete normal human flora as a therapeutic probiotic mixture of living organisms. This type of bacteriotherapy has a longstanding history in animal health and has been used sporadically against chronic infections of the bowel, especially as a treatment of last resort for patients with severe Clostridium difficile syndromes including recurrent diarrhea, colitis, and pseudomembranous colitis. Encouraging results have also been observed following infusions of human fecal flora in patients with inflammatory bowel disease, irritable bowel syndrome, and chronic constipation. The therapeutic use of fecal bacteriotherapy is reviewed here and possible mechanisms of action and potential applications explored. Published reports on fecal bacteriotherapy are few in number, and detail the results of small uncontrolled open studies and case reports. Nevertheless, given the promising clinical responses, formal research into fecal bacteriotherapy is now warranted.

Phagocyte‐specific S100 proteins are released from affected mucosa and promote immune responses during inflammatory bowel disease

Phagocyte‐derived S100 proteins are endogenous activators of innate immune responses. S100A12 binds to the receptor for advanced glycation end‐products, while complexes of S100A8/S100A9 (myeloid‐related proteins, MRP8/14; calprotectin) are ligands of toll‐like receptor 4. These S100 proteins can be detected in stool. In the present study we analyse the release of S100A12 and MRP8/14 from intestinal tissue. Specimens from patients with Crohns disease (CD; n = 30), ulcerative colitis (UC; n = 30), irritable bowel syndrome (IBS; n = 30) or without inflammation (n = 30) were obtained during endoscopy. After 24 h culture, S100A12 and MRP8/14 were analysed in supernatants. Endoscopic, histological, laboratory and clinical disease activity measures were documented. We found an increased spontaneous release of S100A12 from tissue in inflammatory bowel disease (IBD). The release of S100A12 into the supernatants was 28‐fold enhanced in inflamed tissue when compared to non‐inflamed tissue (mean 46.9 vs. 1.7 ng/ml, p < 0.0001). In active CD, release of S100A12 and MRP8/14 was strongly dependent on localization, with little release from sites of active ileal inflammation compared to colonic inflammation. This difference was more pronounced for S100A12 than for MRP8/14. S100A12 and MRP8/14 provoked up‐regulation of adhesion molecules and chemokines on human intestinal microvascular endothelial cells (HIMECs) isolated from normal colonic tissue. The direct release of phagocyte‐derived S100 proteins from inflamed tissues may reflect secretion from infiltrating neutrophils (S100A12) and also monocytes or epithelial cells (MRP8/14). Via activation of pattern recognition receptors, these proteins promote inflammation in intestinal tissue. The enhanced mucosal release can explain the correlation of fecal markers with disease activity in IBD. Copyright

Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial

BACKGROUND The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis. METHODS We conducted a multicentre, double-blind, randomised, placebo-controlled trial at three hospitals in Australia. We randomly allocated patients with active ulcerative colitis (Mayo score 4-10) in a 1:1 ratio, using a pre-established randomisation list, to either faecal microbiota transplantation or placebo colonoscopic infusion, followed by enemas 5 days per week for 8 weeks. Patients, treating clinicians, and other study staff were unaware of the assigned treatment. Faecal microbiota transplantation enemas were each derived from between three and seven unrelated donors. The primary outcome was steroid-free clinical remission with endoscopic remission or response (Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopy subscore) at week 8. Analysis was by modified intention-to-treat and included all patients receiving one study dose. We performed 16S rRNA stool analysis to assess associated microbial changes. This trial is registered with ClinicalTrials.gov, number NCT01896635. The trial has ended; this report presents the final analysis. FINDINGS From November, 2013, to May, 2015, 85 patients were enrolled to our trial, of whom 42 were randomly assigned faecal microbiota transplantation and 43 were allocated placebo. One patient assigned faecal microbiota transplantation and three allocated placebo did not receive study treatment and were excluded from the analysis. The primary outcome was achieved in 11 (27%) of 41 patients allocated faecal microbiota transplantation versus three (8%) of 40 who were assigned placebo (risk ratio 3·6, 95% CI 1·1-11·9; p=0·021). Adverse events were reported by 32 (78%) of 41 patients allocated faecal microbiota transplantation and 33 (83%) of 40 who were assigned placebo; most were self-limiting gastrointestinal complaints, with no significant difference in number or type of adverse events between treatment groups. Serious adverse events occurred in two patients assigned faecal microbiota transplantation and in one allocated placebo. Microbial diversity increased with and persisted after faecal microbiota transplantation. Several bacterial taxa were associated with clinical outcome; in particular, the presence of Fusobacterium spp was associated with lack of remission. INTERPRETATION Intensive-dosing, multidonor, faecal microbiota transplantation induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes that relate to outcome. Faecal microbiota transplantation is, thus, a promising new therapeutic option for ulcerative colitis. Future work should focus on precisely defining the optimum treatment intensity and the role of donor-recipient matching based on microbial profiles. FUNDING Broad Medical Research Program, Gastroenterological Society of Australia, Mount Sinai (New York) SUCCESS fund, University of New South Wales.

Cholelitholysis using methyl tertiary butyl ether.

We tested methyl tertiary butyl ether both in vitro and in vivo to evaluate its efficacy as a potential cholesterol gallstone solvent for direct instillation into the human gallbladder or bile duct. Like diethyl ether, methyl tertiary butyl ether is an aliphatic ether with an excellent cholesterol-solubilizing capacity. However, unlike diethyl ether which vaporizes at body temperature, methyl tertiary butyl ether remains a liquid having a boiling point of 55.2 degrees C. In vitro, methyl tertiary butyl ether dissolved human gallstones (40%-94% cholesterol) within 60-100 min. In contrast, monooctanoin, an established gallstone solvent, required greater than 50 h to dissolve similar stones. By direct catheter instillation in 6 dogs, methyl tertiary butyl ether required only 4-16 h to dissolve gallstones surgically implanted in the gallbladder. The dogs tolerated methyl tertiary butyl ether with only minor clinical, biochemical, or histologic effects. We conclude that further evaluation of methyl tertiary butyl ether for dissolution of human gallbladder and biliary duct cholesterol stones is warranted.

Fecal Microbiota Transplantation: Indications, Methods, Evidence, and Future Directions

Fecal microbiota transplantation (FMT) has attracted great interest in recent years, largely due to the global Clostridium difficile infection (CDI) epidemic and major advances in metagenomic sequencing of the gastrointestinal (GI) microbiota, with growing understanding of its structure and function. FMT is now recommended as the most effective therapy for relapsing CDI and, with further refinement, may even be used in “first-time” CDI. There is interest also in other conditions related to GI dysbiosis—for example, inflammatory bowel disease, irritable bowel syndrome, obesity, and diabetes mellitus—although quality evidence is at present lacking. A few trials are now underway in FMT for ulcerative colitis. Many unanswered questions remain, including FMT methodology—for example, optimal route of administration, what makes a “good donor,” safety issues, and long-term effects of FMT.