INTRODUCTION
Fecal microbiota transplantation (FMT), or infusion of a fecal suspension from a healthy individual into the gastrointestinal (GI) tract of another person to cure a specific disease, is best known as a treatment for recurrent Clostridium difficile infection (RCDI); FMT, however, also has been used successfully for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), idiopathic constipation and a variety of non-GI diseases. Recent studies have shown that the intestinal microbiota plays an important role in immunity and energy metabolism and that an imbalance in our commensal intestinal bacteria can predispose to disease development [1]. Re-establishment of the wide diversity of intestinal microbiota via infusion of donor feces into the colon is the proposed mechanism by which FMT results in clinical improvement in patients with RCDI.
FMT is by no means a new therapeutic modality, however, it did not receive public attention until recently, after several studies were published showing that stool is a biologically active, complex mixture of living organisms with great therapeutic potential for Clostridium difficile infection (CDI) [2–4] and perhaps other GI [5–8] and non-GI disorders [9,10]. The revelations about the human microbiome being published by the Human Microbiome Project consortium is bringing the strength of science to clinical observation, thereby enhancing our understanding of the complexities of our intestine and stool [11]. The administration of human fecal suspension by mouth for patients with food poisoning or severe diarrhea was first reported in fourth century China by Ge Hong [12]. In the 16th century, Li Shizhen described use of a variety of stool products for treatment of diarrhea, fever, pain, vomiting and constipation [12]. In the 17th century, FMT was used in veterinary medicine and later termed ‘transfaunation’ [5]. The first use of fecal enemas in humans for the treatment of pseudomembranous colitis was reported in 1958 by Eiseman et al.[13].
;)
Box 1: no caption available
FECAL MICROBIOTA TRANSPLANTATION METHODOLOGY: ROUTE OF ADMINISTRATION
Until 1989, retention enema was the most common technique for FMT [14▪▪], however, alternative methods have been used subsequently, including nasogastric tube (1991) [15], colonoscopy (2000), [16] and self-administered enemas (2010) [17]. To date, over 400 cases of FMT have been reported worldwide including approximately 75% by colonoscopy or retention enema, and 25% by nasogastric or nasoduodenal tube, or by EGD [18,19]. Although there is no consensus, the colonoscopic approach is favored over fecal enema for RCDI because enemas only reach the splenic flexure [16], whereas with colonoscopy, the entire colon and ileum can be inoculated and disease extent and severity can be elucidated [18].
FECAL MICROBIOTA TRANSPLANTATION METHODOLOGY: STOOL PREPARATION
Patients undergoing FMT for RCDI typically remain on their CDI antimicrobials until 2–3 days prior to FMT. A bowel preparation is administered to all patients the day before the procedure, regardless of route. Donor stool is most often used within 8 h of passage, however, frozen stool samples from standardized donors have been thawed and colonoscopically administered 1–8 weeks after passage for treatment of RCDI with similar success rates to fresh stool [19]. The patient's relationship to the donor does not appear to affect outcome [20▪▪,21▪]. The amount of stool used has varied, however, in a recent review, relapse was four-fold greater when less than 50 g of stool was used [20▪▪]. Stool is most commonly suspended in nonbacteriostatic saline, however, water and other diluents (e.g., yogurt and milk) have been used without consistent differences in resolution or relapse rates [20▪▪]. Donated stool is mixed with diluent to a consistency that can be injected via the biopsy channel of a colonoscope. Before aspiration into a syringe, the suspension is filtered through gauze pads or strainer to remove large particulate matter. The volume of stool suspension used for FMT has varied from 200 ml or less to 500 ml or more, and it appears there is a trend toward improved outcome with larger volumes [20▪▪].
FECAL MICROBIOTA TRANSPLANTATION METHODOLOGY: DONOR SCREENING
In general, donors are excluded if they have taken antibiotics within the preceding 3 months; are on immunosuppressive or chemotherapeutic agents; have known or recent exposure to HIV; hepatitis B or C; have a current communicable disease; are morbidly obese; have IBD, IBS, atopy, chronic diarrhea or constipation; GI malignancy or polyposis; participate in high-risk sexual behaviors; use illicit drugs; have a history of recent incarceration or travel to areas with endemic diarrhea. Donor blood testing should be performed for HIV, hepatitis A, B and C; donor stool testing includes culture, C. difficile toxin, ova and parasites, Giardia antigen, cryptosporidium antigen and Helicobacter pylori antigen if the oral route is to be used [14▪▪].
TREATMENT OF GASTROINTESTINAL DISEASES: CLOSTRIDIUM DIFFICILE INFECTION
The incidence of CDI has increased to epidemic proportion over the past 10–15 years. In the United States, from 1996 to 2003, CDI doubled from 98 000 to 178 000 cases and 31–61/100 000 hospital discharges [22], whereas the unadjusted case-fatality rate rose from 1.2% in 2000 to 2.3% in 2004 [23]. It is now estimated that between 500 000 and 700 000 cases of CDI occur annually in US hospitals and long-term care facilities with an estimated hospital excess cost of care of approximately 3.2 billion dollars [24].
Currently, first-line treatment for CDI includes cessation of the culprit antibiotic, if possible, and treatment with metronidazole or vancomycin (or fidaxomicin) depending on disease severity [25,26▪▪]. Most patients with CDI initially respond to this treatment, but recurrence rates are 15–30% [27]. Patients who have one recurrence have up to a 40% chance of a second recurrence, and after their second recurrence, up to 65% of patients will suffer a third [28]. Recurrences are usually treated with additional courses of metronidazole, oral vancomycin or prolonged vancomycin in pulsed-tapered regimens.
The high recurrence rates of CDI prompted the need for alternative therapies, for which FMT offers a rational and straightforward approach. It is now accepted that disruption of the normal balance of colonic microbiota from antibiotic use or other insult results in CDI. Patients with RCDI have decreased species richness and a reduction of Bacteroidetes and Firmicutes phyla in their stool as compared to patients with just one episode of CDI or antibiotic-associated diarrhea [4]. FMT likely provides therapeutic benefit by reintroducing a balanced microbiota via donor feces [29]. Studies using terminal restriction fragment length polymorphism analyses and gene sequencing techniques have shown that the bacteria of the recipient's stool closely resembles that of the donor about 2 weeks after FMT and is dominated by Bacteroides spp [2,3]; this alteration persists for more than 30 days after transplantation [2,3].
Current literature on FMT for RCDI is predominantly comprised of single center case series and case reports [30–41], a meta-analysis [42] and one systematic review [20▪▪]. In all, about 92% of patients were cured of their RCDI, with a range of 81–100% [20▪▪,30–42]. A multicenter long-term follow-up study of patients who underwent colonoscopic FMT for RCDI reported an astounding overall ultimate cure rate of 98% [21▪]. Patients in this study had symptoms for an average of 11 months before FMT and most (74%) reported resolution of diarrhea within 3 days [21▪]. Immediate symptom resolution and long disease-free intervals after FMT for RCDI also have been reported in other studies [5,20▪▪,31,32], and may result from the durable effect of FMT on re-populating the colon with normal commensal organisms [2,3].
A systematic review of FMT, including all methods of administration and comprising 317 patients from eight countries and 27 case series and reports, reported an overall cure rate for RCDI of 92% [20▪▪]. FMT via colonoscopy or enema has proved more successful for RCDI than the nasogastric route; the latter gives an overall resolution rate of 80% [20▪▪].
Perhaps surprisingly, FMT has been found to be quite acceptable to patients. In the recent multicenter study, 97% of patients with RCDI reported willingness to undergo another FMT if they were to have a repeat CDI episode, and 53% stated that they would choose FMT as first-line therapy before antibiotics [21▪].
TREATMENT OF GASTROINTESTINAL DISEASES: INFLAMMATORY BOWEL DISEASE
Specific infectious agents, such as Mycobacterium paratuberculosis and invasive E. coli, have been etiologically linked to Crohn's disease, however, isolation of a causative pathogen is awaited in ulcerative colitis [11]. An alternative hypothesis, now widely accepted, suggests that IBD results from continuous antigenic stimulation by nonpathogenic commensals, leading to an exaggerated sustained immune response in genetically predisposed hosts [11]. Dysbiosis, or dysregulation between protective and injurious commensals, is the mechanism by which intestinal flora are thought to lead to IBD [43]. First, patients with IBD have an abundance of Enterobacteriaceae and paucity of Faecalibacterium prausnitzii[11]. Second, IBD patients also have 30–50% reduction in the biodiversity of their intestinal microbiota, attributable to decreased Firmicutes (specifically Lachnospiraceae) and Bacteroidetes[43,44]. Third, patients with IBD are more likely to have been prescribed antibiotics in the 2–5 years preceding their diagnosis [45]. Finally, colitis is absent in germ-free, genetically susceptible mice but develops in the presence of intestinal microbiota [43]. Thus, it seems reasonable that restoration of a healthy balance of intestinal flora by FMT could be therapeutic for IBD.
FMT for refractory ulcerative colitis has been described in four publications, comprising nine patients [6–8,46], all of whom had severe, active longstanding ulcerative colitis (mean, 8.6 years) refractory to treatment with corticosteroids, 5-aminosalicylates and azathiaprine [5]. FMT was administered as retention enemas and resulted in the complete resolution of all symptoms with cessation of ulcerative colitis medications within 6 weeks without relapse [5]. Remission was maintained for up to 13 years and follow-up colonoscopy in eight of the nine patients showed no evidence of ulcerative colitis (n = 6) or only mild chronic inflammation (n = 2) [6–8]. Only one case report has been published on FMT for Crohn's disease, a patient who was refractory to prednisone and salazopyrin and responded to FMT within three days allowing discontinuation of medications [6]; disease relapsed within 18 months [5].
Use of colonoscopic FMT followed by self-administered fecal enemas in a tapered fashion and as maintenance therapy for ulcerative colitis has been described in an additional eight patients (Brandt and Aroniadis, ACG annual meeting, 2012). After FMT, seven of these eight (88%) patients reported improvement in stool frequency and abdominal pain, however, the degree of benefit varied widely and was maximal in those with concomitant CDI (n = 3), or newly diagnosed ulcerative colitis in the setting of antibiotic use (n = 1) and those who were able to effectively retain the enemas.
FMT may be efficacious in managing refractory ulcerative colitis, however, multiple infusions seem to be required to maintain remission. Additionally, FMT may provide greater therapeutic benefit in patients whose onset of ulcerative colitis was associated with an alteration in the fecal microbiota from antibiotic use or concomitant colonic infection. Experience with FMT for ulcerative colitis is just beginning and controlled trials are needed to establish its role, if any.
TREATMENT OF GASTROINTESTINAL DISEASES: IRRITABLE BOWEL SYNDROME AND CHRONIC CONSTIPATION
Postinfectious IBS has been reported in up to 30% of patients with acute gastroenteritis, suggesting that the pathogenesis of IBS may be intimately linked to an altered intestinal microbiota [47–49]. The composition of the intestinal microbiota in patients with IBS has not been extensively studied, however, patients with constipation-predominant IBS have been shown to increase population of sulphate-reducing bacteria compared with healthy controls [50]. Probiotics can restore the intestinal microbiota in patients with IBS [49,51] and result in improvement of postinfectious IBS in animal models [11]; FMT, however, may prove more beneficial, as donated feces, in a sense, are the ultimate human probiotic.
In a case series of 55 patients with IBS and IBD treated with FMT, cure was reported in 20 (36%), decreased symptoms in nine (16%) and no response in 26 (47%) patients [6]. In another series, 45 patients with chronic constipation were treated with colonoscopic FMT and subsequent fecal enema infusions, 89% of whom (40 of 45 patients) reported relief in defecation, bloating and abdominal pain immediately after the procedure [52]. Normal defecation, without laxative use, persisted in 18 of 30 patients (60%) contacted 9–19 months later [52].
TREATMENT OF NONGASTROINTESTINAL DISEASES
Studies in germ-free animals suggest that intestinal microbiota may contribute to pathogenesis of non-GI diseases. Germ-free animals exhibit dysregulation of their hypothalamic–pituitary–adrenal axis leading to an exaggerated stress response, impaired cardiac output, altered brain derived hormones (e.g., norepinephrine and tryptophan) and increased caloric intake to maintain body weight [11]. Moreover, the microbiota may play a role in pathogenesis of various neurologic disorders and data support the concept of the brain–gut–microbiota axis [53]. Introduction of pathogenic bacteria into the rodent colon results in activation of brain stem nuclei possibly via the afferent vagus nerve, which originates in the brainstem and innervates abdominal viscera [11].
TREATMENT OF NONGASTROINTESTINAL DISEASES: AUTOIMMUNE AND NEUROLOGIC DISORDERS
The beneficial effect of FMT on non-GI disorders was a serendipitous observation. In one patient with ulcerative colitis and idiopathic thrombocytopenic purpura (ITP), FMT not only resulted in remission of ulcerative colitis but also reversal of ITP with platelet counts that increased from a mean of 97 to 195 × 109 μl [54]. Normal defecation was achieved in three patients with multiple sclerosis, who underwent FMT for chronic constipation and who also noted improvement of motor symptoms and urinary function, resulting in a regained ability to walk and removal of indwelling catheters [55]. One report described the co-development of myoclonus dystonia and chronic diarrhea in a 6-year old child who had ongoing myoclonus dystonia symptoms for 22 years [56]. FMT resulted in 90% improvement of her myoclonus dystonia symptoms, allowing her to resume employment and execute fine motor tasks, such as drinking from a cup, fastening buttons, and dressing [56]. Neurologic improvement has also been reported in one patient with Parkinson's disease after FMT for chronic constipation [10].
TREATMENT OF NONGASTROINTESTINAL DISEASES: OBESITY
The intestinal microbiota metabolize ingested nutrients into energy-rich substrates for utilization by the host and commensal flora [11,57] and can adapt their metabolism based on nutrient availability [11]. Obese mice have an increased capacity to harvest energy from luminal nutrients compared with their lean counterparts, which is reflected by a higher Firmicutes to Bacteroidetes ratio [11,58]. In fact, a 60% increase in body fat and insulin resistance results when intestinal microbiota from conventionally raised mice are introduced into germ-free mice [59]. Furthermore, the obese (ob/ob) phenotype has been shown to be transmissible and is adopted in germ-free mice, infused with intestinal microbiota from conventionally raised, genetically obese mice [58]. Related data are sparse in humans. One double-blinded, controlled trial randomized 18 men with metabolic syndrome to FMT using their own feces or feces donated from lean men [9]. The nine men who received stool from lean donors developed markedly reduced fasting triglyceride levels and peripheral and hepatic insulin sensitivity after FMT compared with those who were transplanted with their own (placebo) stool [9].
TREATMENT OF NONGASTROINTESTINAL DISEASES: CHRONIC FATIGUE SYNDROME
Thirty-four patients with chronic fatigue syndrome (CFS) were treated with FMT and followed over 11–28 months: 14 (41%) reported persistent relief and 12 (35%) showed little or late relief of related symptoms [60].
TREATMENT OF NONGASTROINTESTINAL DISEASES: AUTISM
A role for microbiota in the pathogenesis of autism is supported by studies which show that the onset of autism is often accompanied by GI complaints and preceded by antibiotic use [11]. Additionally, oral vancomycin has been shown to improve symptoms [11]. In a single case series, the intestinal microbiota of 13 children with autism were analyzed and compared with nine children without the disease [61]. The autistic children were found to have greater numbers and different types of clostridial species when compared with controls [61]. There are published observations of improvement in autistic symptoms in two children after FMT and in five children who received daily cultured Bacteroidetes and Clostridia for several weeks (T. Borody, personal correspondence).
CONCLUSION
FMT re-establishes a balanced intestinal microbiota and results in impressive cure rates in patients with recurrent CDI. Standardization of FMT protocols and a randomized controlled trial are ongoing. The complexity of the fecal microbiota is actively being defined and recent studies have shown that the pathogenesis of many diseases, both GI and non-GI, result from microbiota-related dysregulation. FMT is likely to achieve widespread therapeutic benefit for a variety of diseases in the future.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 103).
REFERENCES
1. Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 2011; 9:88–96.
2. Grehan MJ, Borody TJ, Leis SM, et al. Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol 2010; 44:551–561.
3. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent
Clostridium difficile associated diarrhea. J Clin Gastroenterol 2010; 44:354–360.
4. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal microbiome in recurrent
Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197:435–438.
5. Borody TJ, Warren EF, Leis SM, et al. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol 2004; 38:475–483.
6. Borody TJ, George L, Andrews PJ, et al. Bowel flora alteration: a potential cure of inflammatory bowel disease and irritable bowel syndrome? Med J Aust 1989; 150:604.
7. Borody TJ, Leis S, McGrath K,
et al. Treatment of chronic constipation and colitis using human probiotic infusions: In: Probiotics, prebiotics and new foods conference, Universita Urbaniana, Rome, September 2–4, 2001.
8. Borody TJ, Warrne EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003; 37:42–47.
9. Vrieze A, van Nood E, Holleman F,
et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in subjects with metabolic syndrome. Gastroenterology 2012 [Epub ahead of print].
10. Anathaswamy A. Faecal transplant eases symptoms of Parkinson's. New Scientist 2011; 2796:8–9.
11. Sekirov I, Russell SL, Antunes CM, et al. Gut microbiomes in health and disease. Physiol Rev 2010; 90:859–904.
12. Zhang F, Luo W, Shi Y,
et al. Should we standardize the 1700-year-old fecal microbiota transplantation? Am J Gastroenterol 2012 (in press).
13. Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958; 44:854–859.
14▪▪. Bakken JS, Borody T, Brandt LJ, et al. Treating
Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol and Hepatol 2011; 9:1044–1049.
This excellent review summarizes the current protocol for stool preparation and presents summary data on routes of administration for FMT.
15. Aas J, Gessert CE, Bakken JS. Recurrent
Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003; 36:580–585.
16. Persky S, Brandt LJ. Treatment of recurrent
Clostridium difficile-associated diarrhea by administration of donated stool directly though a colonoscope. Am J Gastroenterol 2000; 95:3283–3285.
17. Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic
Clostridium difficile infection. Clin Gastroenterol Hepatol 2010; 8:471–473.
18. Brandt LJ, Reddy SS. Fecal microbiota transplantation for recurrent
Clostridium difficile infection. J Clin Gastroenterol 2011; 45:S159–S167.
19. Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107:761–767.
20▪▪. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent
Clostridium difficile infection. Clin Infect Dis 2011; 53:994–1002.
This systematic review summarizes data on CDI recurrence rates based on FMT route of administration and donor relationship.
21▪. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent
Clostridium difficile infection. Am J Gastroenterol 2012; 107:1079–1087.
This multicenter study is the only long-term follow-up study to date of patients who received FMT for RCDI.
22. McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals. Emerg Infect Dis 2006; 12:409–415.
23. Zilberberg M, Shorr AF, Kollef MH. Increase in adult
Clostridium difficile-related hospitalizations and case-fatality rate, United States, 2000–2005. Emerg Infect Dis 2008; 14:929–931.
24. O’Brien JA, Lahue BJ, Caro JJ 18. The emerging infectious challenge of Clostridium difficile infection in adults: 2010 update by the Society of Healthcare Epidemiologyof America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431–455.
25. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for
Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control and Hosp Epidemiol 2010; 31:431–455.
26▪▪. Surawicz CM, Brandt LJ, Binion DG,
et al. Guidelines in
Clostridium difficile infections. ACG Guidelines. 2012 (in press).
These are the most recent comprehensive guidelines that include recommendations for the treatment of mild, moderate, severe and complicated CDI.
27. Bakken JS. Fecal bacteriotherapy for recurrent
Clostridium difficile infection. Anaerobe 2009; 15:285–289.
28. Huebner ES, Surawicz CM. Treatment of recurrent
Clostrium difficile diarrrhea. Gastroenterol Hepatol 2006; 2:203–208.
29. Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin North Am 2001; 30:753–777.
30. Lund-Tonnesen S, Berstad A, Schreiner A, et al.
Clostridium difficile-associated diarrhea treated with homologous feces. Tidsskr Nor Laegeforen 1998; 118:1027–1030.
31. Yoon SS, Brandt LJ. Treatment of refractory/recurrent
C. difficile-associated disease by donated stool transplanted via colonoscopy. A case series of 12 patients. J Clin Gastroenterol 2010; 22:562–566.
32. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent
Clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010; 44:567–570.
33. MacConnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal transplant for recurrent
Clostridium difficile-associated diarrhea: a UK case series. Q J Med 2009; 102:781–784.
34. Rubin TA, Fessert CE, Aas J. Stool transplantation for older patients with
Clostridium difficile infection. JAGS 2009; 57:2386–2387.
35. Russell G, Kaplan J, Ferraro MJ, Michelow IC. Fecal bacteriotherapy for relapsing
Clostridium difficile infection in a child: a proposed treatment protocol. Paediatrics 2010; 126:e239–e242.
36. Schwan A, Sjolin S, Trottestam U. Relapsing
Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet 1983; 2:845.
37. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing
Clostridium difficile diarrhoea in six patients. Lancet 1989; 1:1156–1160.
38. Paterson DL, Iredell J, Whitby M. Putting back the bugs: bacterial treatment relieves chronic diarrhoea. Med J Aust 1994; 160:232–233.
39. You DM, Franzos MA. Successful treatment of fulminant
Clostridium difficile infection with fecal bacteriotherapy. Ann Intern Med 2008; 148:632–633.
40. Silverman MS, Davis I, Pillai D. Success of self-administered home fecal transplantation for chronic
Clostridium difficile infection. Clin Gastroenterol Hepatol 2010; 8:471–473.
41. Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplantation via retention enemas is effective for recurrent or refractory Clostridium difficile-associated diarrhea. Gastroenterology 2010; 138:S207–S208.
42. Sofi A, Nawras A, Sodeman T,
et al. Fecal bacteriotherapy works for
Clostridium difficile infection: a meta-analysis. Presented at the 2011 ACG Annual Meeting.
43. Sartor RB, Mazmanian SK. Intestinal microbes in inflammatory bowel disease. Am J Gastroenterol Suppl 2012; 1:15–21.
44. Frank DN, St Amand AL, Feldman RA, et al. Molecular-phylogenetic characterization of the microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA 2007; 104:13780–13785.
45. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn's disease and ulcerative colitis. Am J Gastroenterol 2011; 106:2133–2142.
46. Bennet JD, Brindkman M. Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet 1989; 1:164.
47. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterol 2003; 125:1651–1659.
48. Collins SM, Chang C, Mearin F. Postinfectious chronic gut dysfunction: from bench to bedside. Am J Gastroenterol Suppl 2012; 1:2–8.
49. Ringel Y, Quigley EMM, Lin H. Using probiotics in gastrointestinal disorders. Am J Gastroenterol Suppl 2012; 1:34–40.
50. Chassard C, Dapoingy M, Scott KP, et al. Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome. Aliment Pharmacol Ther 2012; 35:828–838.
51. Foxx-Orenstein AE, Chey W. Manipulation of the gut microbiota as a novel treatment strategy for gastrointestinal disorders. Am J Gastroenterol Suppl 2012; 1:41–46.
52. Andrews P, Borody TJ, Shortis NP, Thompson S. Bacteriotherapy for chronic constipation – long term follow-up. Gastroenterology 1995; 108:A563.
53. Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009; 136:2003–2014.
54. Borody TJ, Campbell J, Torres M 18. Reversal of idiopathic thrombocytopenic purpura (ITP) with fecal microbiota transplantation (FMT) [abstract]. Am J Gastroenterol 2011; 106:S352.
55. Borody TJ, Leis S, Campbell J, et al. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS)s. Am J Gastroenterol 2011; 106:S352.
56. Borody TJ, Rosen DM, Torres M, et al. Myoclonus-dystonia (M-D) mediated by GI microbiota diarrhoea treatment improves M-D symptoms. Am J Gastroenterol 2011; 106:S352.
57. DiBaise JK, Frank DN, Mathur R. Impact of the gut microbiota on the development of obesity: current concepts. Am J Gastroenterol Suppl 2012; 1:22–27.
58. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444:1027–1031.
59. Backhead F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat-storage. Proc Natl Acad Sci USA 2004; 101:15718–157123.
60. Borody TJ. Bacteriotherapy for chronic fatigue syndrome: a long-term follow-up study. Presented at the 1995 CFS National Consensus Conference.
61. Finegold SM, Molitors D, Song Y. Gastrointestinal micro flora studies in late-onset autism. Clin Infect Dis 2002; 35:S6–S16.
