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Lectura accesible en http://www.nature.com/ajg/journal/vaop/ncurrent/full/ajg2012450a.html

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Intestinal microbiota fecal trasplant Intestinal microbiota fecal trasplant Document Transcript

  • nature publishing group REVIEWS FROM THE ACG ANNUAL MEETING 1see related editorial on page xAmerican Journal of Gastroenterology Lecture: Intestinal REVIEWMicrobiota and the Role of Fecal Microbiota Transplant(FMT) in Treatment of C. difficile InfectionLawrence J. Brandt, MD, MACG1The vital roles that intestinal flora, now called microbiota, have in maintaining our health are being increasinglyappreciated. Starting with birth, exposure to the outside world begins the life-long intimate association our microbiotawill have with our diet and environment, and initiates determination of the post-natal structural and functionalmaturation of the gut. Moreover, vital interactions of the microbiota with our metabolic activities, as well as with theimmunological apparatus that constitutes our major defense system against foreign antigens continues throughoutlife. A perturbed intestinal microbiome has been associated with an increasing number of gastrointestinal andnon-gastrointestinal diseases including Clostridium difficile infection (CDI). It has become recognized that fecalmicrobiota transplantation (FMT) can correct the dysbiosis that characterizes chronic CDI, and effect a seeminglysafe, relatively inexpensive, and rapidly effective cure in the vast majority of patients so treated. In addition, FMT hasbeen used to treat an array of other gastrointestinal and non-gastrointestinal disorders, although experience in theseother non-CDI diseases is in its infancy. More work needs to be done with FMT to ensure its safety and optimal routeof administration. There is a conceptual sea change that is developing in our view of bacteria from their role only aspathogens to that of being critical to health maintenance in a changing world. Future studies are certain to narrow thespectrum of organisms that need to be given to patients to cure disease. FMT is but the first step in this journey.Am J Gastroenterol advance online publication, 15 January 2013; doi:10.1038/ajg.2012.450INTRODUCTION by the National Institutes of Health in 2007 along with relatedAlthough the concept that our intestinal microbiota has an ventures such as the MetaHit (Metagenomics of the Humanimportant role in maintaining our health is relatively new, the Intestinal tract) consortium, which involves 13 research centerssubject of fecal transplantation has been around for millennia. from 8 countries, are now beginning to be published and willIts first mention in the literature was during the 4th century, revolutionize knowledge of our microbes and our bodies (2).when Ge Hong described the use of human fecal suspension by For example, although we knew the human body is inhab-mouth for food poisoning or severe diarrhea (1). In the 16th ited by a vast number of microorganisms including bacteria,century, Li Shizhen detailed a variety of fecal preparations called archea (single-celled prokaryotic microorganisms separately“yellow soup” to be given for diarrhea, abdominal pain, vom- classified from bacteria), viruses, fungi, and even parasites, alliting, and constipation (1). I will discuss the modern history of which normally live in peaceful coexistence with us, theirof fecal transplantation later, but we can be sure that future hosts, we soon learned that only 5–20% of the intestinal micro-history will reveal high-quality scientific studies into the nature, biota can be cultured and that culture can reliably distinguishawesome complexity, and therapeutic powers of our intestinal among bacterial phylogenetic groups, but not down to species-microbiome. or strain-level (2,3). New approaches to study our microbiota were developed using culture-independent techniques includ-The intestinal microbiota ing bacterial 16S ribosomal RNA gene sequencing and DNAWe are witness to a paradigm shift in the way the microbial flora fingerprinting methods, such as terminal restriction fragmentthat dwell within our inner recesses are viewed. No longer is it length polymorphisms. A new vocabulary was even developedsimply that the host is “good” and the bacteria that live therein to help detail the “meta” family techniques used to evaluate“bad”, but the vital roles our intestinal flora, now called micro- the microbiomic functional capacity including metagenomicsbiota, have in maintaining health are being increasingly appre- (study of genes collected and sequenced from the environment),ciated. Results of the Human Microbiome Project launched metabolomics (study of metabolites that are end-products of1 Montefiore Medical Center, Bronx, New York, USA. Correspondence: Lawrence J. Brandt, MD, MACG, Montefiore Medical Center, 111 East 210th Street, Bronx,New York 10467, USA. E-mail: lbrandt@montefiore.orgReceived 29 August 2012; accepted 6 December 2012© 2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
  • 2 Brandt cellular processes), metaproteomics (study of all proteins in an eign antigens. (Figures 1 and 2). We know that reduced microbial environment), and metatranscriptomics (study of all RNA mole- stimulation during infancy results in slowed postnatal maturation cules produced in a population of cells). Microbial communi- of the immune system and delayed development of an optimalREVIEW ties differed remarkably at each of the 15 (male) to 18 (female) balance between TH1 and TH2-like immunity (9). During the first Human Microbiome Project-sampled body sites (nasal pas- year of life, the total number of IgA-, IgG- and IgM-secreting cells sages, oropharynx, skin, stool, and vagina) and the diversity of is lower in infants born by vaginal delivery than in those born by each habitat’s signature microbes varied widely among healthy cesarean section, possibly reflecting excessive antigen exposure individuals, with further variation not just dependent upon across the vulnerable intestine (7). ethnicity and host genetics, but also on one’s diet and environ- The numbers and types of our intestinal microbiota increase ment (2). Stool, representing the distal bowel, showed relatively over the first year of life to assume a relatively stable adult pattern high intra- and inter-subject diversity. The majority of our at the phylum level, but continue to evolve at the species level with microbiota is anaerobic, and although more than 50 bacterial subsequent dietary and environmental exposures, including anti- phyla have been described, only four constitute the majority of microbial therapies (3). In one study, diet inventories of 98 indi- mammalian intestinal microbiota (Bacteroidetes, Firmicutes, viduals were correlated with participants’ fecal enterotypes to show Actinobacteria, and Proteobacteria) and only two predominate that the Bacteroides enterotype was highly associated with animal in our intestinal tract: the Bacteroidetes and the Firmicutes; protein, a variety of amino acids, and saturated fats (western diet), most of the Firmicutes phyla are members of the Clostridia class whereas the Prevotella enterotype was associated with low values (4). It is estimated that about 4,000 bacterial species reside in for these groups but high values for carbohydrates and simple sug- our gastrointestinal tract, and that the human microbiota con- ars (agrarian diet). Moreover, microbiome composition changed tains as many as 1014 bacterial cells, a number that is 10 times within 24 h of dietary alteration (10). greater than the number of human cells in our body (5). Per Intestinal microbiota has important roles in the post-natal struc- gram of contents, there is a marked and progressive distal tural and functional maturation of the gut. Germ-free animals increase in the number of bacteria: 101 in the stomach, 103 in have, for example, enlarged ceca; increased enterochromaffin cell the duodenum, 104 in the jejunum, 107 in the ileum, and 1012 area; a reduced intestinal surface area with narrower villi resulting in the colon. This longitudinal heterogeneity of the microbiota from reduced cell regeneration and prolonged cell cycle time, and population has a predominance of Firmicutes and Proteobac- a smaller villous capillary network; hypotonic and hyporesponsive teria (notably Helicobacter pylori in the stomach), Firmicutes mesenteric vasculature; impaired lymphoid organs; impaired peri- and Actinobacteria in the small intestine and a prevalence of stalsis; and abnormal cholesterol and bile acid metabolism (3). It Bacteroidetes and the Lachnospirae family of Firmicutes in the has been shown, for example, that Bacteroides thetaiotaomicron colon; of note, bacteria account for 60% of the dry weight of can induce angiogenesis (11); influence enteric nerve function, feces. The microbiota within the intestinal lumen differs sig- and, therefore, possibly peristalsis (12); and also modulate intes- nificantly from that dwelling in close proximity to or within tinal glycocalyx structure (13). Various microbiota, including the intestinal epithelium (6). Therefore, fecal micro-organisms B.thetaiotaomicron and Lactobacilli, are also involved in maintain- cannot be used as a surrogate for all communities of the bowel ing intestinal barrier integrity through maintenance of cell-to-cell microflora. Moreover, luminal microbial communities and junctions and promotion of epithelial repair after injury (1). surface adherent/associated populations are distinct and fulfill The areas in which microbiota have a major influence are legion, different roles, only some of which I will mention briefly. growing, and far beyond the scope of this general overview. One Our intestine becomes colonized with micro-organisms during such area is mucosal immunity with influence on immunocytes, or shortly after birth and the intestinal microbiota of infants deliv- gut-associated lymphoid tissue, Peyer’s patches, IgA-producing ered by cesarean section differs from that of vaginally-delivered plasma cells, immunoglobulin secretion, and pattern recognition infants (7,8). The gastrointestinal tract of the newborn is still sterile receptors including toll-like and NOD-like receptors. As a specific after caesarian section and its microbiota is initiated with feeding; example, the deficiency of CD4 + T-cells in germ-free mice can in breast-fed infants Bifidobacteria predominate with minor rep- be completely reversed by mono-contamination with Bacteroides resentation from lactobacilli and streptococci, whereas in formula- fragilis or administration of its polysaccharide capsular antigen (14). fed infants, similar amounts of Bacteroides and Bifidobacteria are The gastrointestinal tract needs to coexist with the dense car- found with minor representation from Staphylococci, Escherichia pet of bacteria that overlies its mucosa without inducing exces- coli, and Clostridia (8). The first colonization of the intestine is a sive immune reaction, and the intestinal microbiota mediates profound immunological exposure and early maternal inocula- such antigenic tolerance. As examples, intestinal dendritic cells tion, as occurs with vaginal delivery, likely has an important role in are conditioned to a tolerogenic phenotype by intestinal epithe- subsequent immune reactions and our susceptibility or resistance lial cells that are stimulated by Lactobacillus spp and certain E. to certain diseases. Indeed, this initial exposure heralds the con- coli strains (15); B. thetaiotaomicron prevents activation of the tinuing intimate roles our microbiota will have with our diet and proinflammatory transcription factor NFkβ (16); and Aeromonas environment, and initiates the vital interactions of the microbiota or Pseudomonas promote intestinal alkaline phosphatase, which with our metabolic activities, as well as with the immunological dephosphorylates and inactivates the lipopolysaccharide found apparatus that constitutes our major defense system against for- in the outer membrane of Gram-negative bacteria thus protecting The American Journal of GASTROENTEROLOGY VOLUME 104 | XXX 2012 www.amjgastro.com
  • Intestinal Microbiota and Fecal Microbiota Transplant for C. difficile 3 Vitamin A 6 SFB REVIEW 1 Diet 2 Microbiota 3 Unmodified dietary components 5 Dietary components modified by 4 Microbial microbiota signals (acetate) (MAMPs) ? GPR43 Other Inflammasome TLRs metabolite ASC sensors? Pro- MyD88 IL-1β IL-1β NF-κB Metabolic signals Classical innate signals Immunologically Antigen-presenting cell active nutrients T cell and metabolites? T cell Antigen-presenting cell mTOR TLRs Promotes TH1, TH2, TH17 cell Inflammasomes differentiation; inhibits Treg cell mTOR differentiation Modulates DC function and RAR-RXR differentiation Promotes intestinal T-cell homing; RAR-RXR and VDR-RXR promotes TH2 and Treg cell differentiation AHR Modulates DC differentiation VDR-RXR Promotes Treg cell differentiation; PKR inhibits TH1 and TH17 cell Regulates inflammatory differentiation responses AHR GPR120 Promotes TH17 and Treg cell Inhibits inflammatory responses differentiation in macrophages LXR and PPAR Control T-cell differentinationFigure 1. Inter-relationships of nutrients, immune responses and the microbiome. Ingested nutrients (1) influence our microbiota (2) which, in turn,changes the nutritional value of the consumed food. (3) Absorbed dietary components interact with a variety of immune cells (e.g., omega 3-fatty acids).(4) Microbial signals in the form of Microbe Associated Molecular Patterns (MAMPs) also modify local mucosal immune responses through innatesignaling pathways, e.g., the inflammasome or Toll-like receptors (TLRs). (5) Additionally, microbe-modified dietary components (e.g., acetate producedfrom fermentation of polysaccharides) provide signals by which the immune system can monitor the metabolic activities of the microbiota. (6) An exampleof micronutrients directly modifying intestinal microbial ecology is vitamin A, which can modify the representation of segmented filamentous bacterium(SFB) in the mouse gut microbiota; SFB induce differentiation of Th17 cells. From Kau et al. (54).against septic shock (17). Our commensal bacteria, their structural vates defensins. Even the mere presence of microbiota in the gastroin-components and their metabolic products can induce expression and testinal tract, especially Gram-positive anaerobes, serves as a deterrentactivation of antimicrobial proteins to protect against pathogens and to pathogen colonization; as an example, Lactobacilli and Bifidobacte-to prevent overgrowth of the commensals themselves (3). For example, ria prevent Listeria infection of cultured epithelial cells (18).B. thetaiotaomicron colonization of germ-free mice induces As mentioned above, our intestinal microbiota is related toPaneth cells to express matrilysin, a matrix metalloproteinase that acti- the type of food we eat, but it also is very much involved with© 2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
  • 4 Brandt Bifidobacterium spp. Clostridium spp.REVIEW Bacteroidetes Gm-PG SCFA Conjugation of SCFAs B. fragilis (PSA) Gm-LPS metabolism linoleic acid Cellular immunity Xenobiotics metabolism Oxalate AMPs IgA Nutrition Lymphoid organogenesis Drug disposition excretion Mucosal immunity Immunocompetence Lap Lipid Behavior O. fomigenes Tolerance activation metabolism NFKB Normalization of DC tolerization inactivation HPA stress response Lactobacillus spp. E. coli B. thetaiotaomicron B. infantis Peristalsis Angiogenesis Glycosylation Barrier GIT surface maturation maintenance GIT functional maturation Figure 2. Some examples of the effects of intestinal microbiota and host physiology. The intestinal microbiota can affect many aspects of normal host development and function. Members of the microbiota, with their various components or products of metabolism are shown in red. Microbial effects on the host are shown in green. Affected host phenotypes are shown in blue. AMP, antimicrobial peptides; DC, dendritic cells; Gm, Gram negative; HPA, hypothalamus-pituitary adrenal; Iap, intestinal alkaline phosphatase; PG, peptidoglycan; PSA, polysaccharide. From Sekirov et al. (3). appetite regulation, energy utilization, digestion and absorption microbiota transplantation (FMT). Fecal microbiota transplant is of ingested nutrients, and drug metabolism. Bacterial metabo- the term used when stool is taken from a healthy individual and lism of dietary fiber to short chain fatty acids, and conversion of instilled into a sick person to cure a certain disease. As the exact indigestible polysaccharides to absorbable monosaccharides are agent or agents that effect cure is currently unknown, the term well known examples of such interaction. B. thetaiotaomicron, as fecal microbiota transplant (FMT) presently is preferred to fecal another example, has been shown to upregulate expression of pan- bacterial transplantation, or fecal bacteriotherapy; stool trans- creatic co-lipase and an intestinal Na + /glucose co-transporter (12). plant is an accurate but unaesthetic term (21). Awareness of the interplay between these complex metabolic func- I’ve already reviewed the very early history of FMT, but FMT tions and the intestinal microbiome sets the stage to study whether also has been used for centuries in veterinary medicine per rectum manipulation of the microbiome can be used to understand and to treat horses with diarrhea or per os as rumen transfaunation to treat conditions of obesity and underweight (19). Inter-individual treat a variety of illness in cattle. Its first clinical use in the English and inter-population differences in intestinal microbiomes with language dates back to a 1958 case series of four patients with their attendant varied metabolic profiles may explain the differ- pseudomembranous enterocolitis, three of whom were critically ent toxicities of commonly used therapeutics in varied geographic/ ill. C. difficile had not yet been recognized as a cause of pseu- cultural populations and set the stage for the development of domembranous colitis and Micrococcus pyogenes (hemolytic, personalized medicine-based on one’s intestinal microbiome coagulase-positive Staphylococcus aureus) was cultured from each profile (20). patient’s stool. Fecal enemas were administered as an adjunct to antibiotic treatment and all four patients had “dramatic” reso- Clostridium difficile infection and fecal microbiota lution of symptoms within 24–48 h of FMT (22); the first use transplantation (FMT): introduction of FMT for confirmed recurrent CDI was reported in 1983 by A perturbed intestinal microbiome has been associated with an Schwan et al. (23), in a 65-year-old woman who thereafter had increasing number of gastrointestinal and non-gastrointestinal “prompt and complete normalization of bowel function”. Up until diseases which brings us to C. difficile infection (CDI) and fecal 1989, retention enemas had been the most common technique The American Journal of GASTROENTEROLOGY VOLUME 104 | XXX 2012 www.amjgastro.com
  • Intestinal Microbiota and Fecal Microbiota Transplant for C. difficile 5for FMT, however, alternative methods of fecal infusion subse- C. difficile excretion and that upon cessation of treatment relapsequently were developed including nasogastric duodenal tube in occurred, just as in the human who has recurrent CDI. FMT1991 (24), colonoscopy in 2000 (25), and self-administered ene- using homogenized feces from a healthy mouse and given by REVIEWmas in 2010 (26). In 2011, a review was reported of 325 cases of oral gavage, suppressed C. difficile shedding for months. Finally,FMT performed worldwide, ~75% of which had been adminis- these authors reasoned that introduction of a phylogeneticallytered by colonoscopy or retention enema, and 25% by nasogastric diverse but limited bacterial mixture might trigger recovery ofor nasoduodenal tube, or by EGD (27,28). Worldwide mean cure the intestinal ecosystem and disrupt the stability of the micro-rates to date are consistently around 91% (28) and FMT is effec- biota of the mice with chronic CDI. Ultimately they fashionedtive even in patients with the C. difficile NAP1/BI/027 strain (29). a mixture of six physiologically diverse species including bothRoute does seem to influence results, however, and when FMT obligate and facultative anaerobes that resolved the CDI. Thisis done via upper tract endoscopy, nasogastric, or nasoduodenal series of experiments addresses the major concepts involved intube, resolution rates are in the range of 76–79% (28,30). Regard- trying to understand the pathophysiology of the effectiveness ofless of route, FMT appears to be safe, with no adverse effects or FMT in treating patients afflicted with chronic, recurrent CDI.complications directly attributed to the procedure yet published (Figure 3): (1) perturbation of the intestinal microbiota, (2)(21,31). colonization and establishment of C. difficile, which allows (3) persistence of a disturbed intestinal microbiota with (4) alteredCDI and FMT: pathophysiology and rationale intestinal fermentation, and (5) loss of nutrients to the bowel; (6)The rationale for FMT in patients with recurrent CDI lies in FMT induces re-establishment of microbiota diversity and (7)the belief that CDI results when the community of organisms termination or suppression of C. difficile colonization. It is likelyresiding in the gastrointestinal tract is perturbed and that per- that the colitis seen with chronic CDI is also associated withsisting imbalance, or dysbiosis, explains the high CDI recur- increased colonic permeability that is worsened by the reduc-rence rates of 10–20% after initial antibiotic therapy and up to tion in butyrate and acetate and which then facilitates colonic40–65% in patients who are retreated for a second episode (32). protein loss with hypoalbuminemia, and bacterial translocationIt is believed that reintroduction of normal flora via donor feces with sepsis, especially in cases of severe CDI.corrects the imbalance, restores both phylogenetic richness andcolonization resistance, and thereby enables recovery of normal CDI and FMT: how to do itbowel function; this contrasts with the chronic use of antibiotics, The potential for transmission of infectious agents is a majorwhich, in a sense, perpetuates the very condition that lead to the concern, however, and rigorous screening tests are recom-initial episode of CDI, namely an altered intestinal microbiome. mended to reduce such risk (21). As an integral part of our pro-In an elegant series of experiments, Lawley et al. (33) treated tocol for a double-blind randomized controlled trial of FMT formice with clindamycin for 7 days and then infected them with recurrent CDI (see below), the NIH required that donor stool beC. difficile (genotype 027/BI) isolated from hospitalized patients. tested for C. difficile toxin, enteric bacterial pathogens (includ-They showed that the mice went on to develop highly conta- ing specifically Listeria monocytogenes, Vibrio cholera and Vibriogious, chronic disease with persistent dysbiosis characterized by: parahemolyticus), parasites such as Giardia (Giardia antigen test)(1) a simplified microbiota with reduced phylotypic diversity; Cryptosporidium (Cryptosporidium antigen test), and Isospora(2) opportunistic pathogens (e.g., Klebsiella pneumonia, E. coli, (acid-fast stain), and Rotavirus; donor blood must be screenedProteus mirabilis, Parabacteroides distasonis, and Enterococcus for hepatitis A (IgM), B (HBsAg, anti-HBc (IgG and IgM), andfaecalis— all of which have been identified in the microbiota of anti-HBsAg) and C (HCV antibody) viruses, human immunode-humans with chronic CDI (34); (3) upregulated pro-inflamma- ficiency virus (HIV) types 1 and 2, and syphilis. Screening for H.tory genes—particularly those known to promote neutrophil pylori is also prudent regardless whether FMT is performed viainfiltration; (4) and altered metabolite production, similar the upper or lower route. Recipients are tested for HIV 1 and 2,to that which occurs in the human immune response to CDI. Hepatitis A, C, and syphilis. This testing is much more rigorousSpecifically, they demonstrated a disturbance in fecal short- chain and extensive than that performed in the community, where mostfatty acids, which are the end-products of intestinal bacterial practitioners just have donor stool screened for enteric patho-metabolism of ingested complex carbohydrates. This disturbance gens, ova and parasites, and C. difficile toxin. Of course, becauseincluded a reduction in butyrate and acetate, which are the main of the ready availability of stool, patients may accept offers ofnutrient sources for the colon and an increase in succinate levels; unscreened stool from well-meaning friends and relatives whoof note, there was an increase in P. disasonis, which is a succinate are aware of FMT. I have had several patients who wanted me toproducer. Acetate and butyrate influence a wealth of functions perform FMT on them after self-administration of unscreenedin the colon; acetate: crypt cell proliferation, motility, blood donor stool had failed. This practice of using unscreened stoolflow, adipogenesis, and cellular immunity; butyrate: colonocyte is to be eschewed, except perhaps for emergent FMT, when tim-health, inflammation, intestinal permeability, inflammation, ing may be more critical than long-term safety outcome. As theapoptosis, cell growth and differentiation, and barrier function, perturbing effect of antibiotics on the intestinal microflora canto name but a few (35). Lawley et al. (33) then demonstrated that persist for 3 months or more, donors are excluded if they havevancomycin administration was associated with suppression of had antibiotics within this time; high-risk sexual behaviors, a© 2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
  • 6 Brandt (a) HomeostasisREVIEW (d) Expansion of commensals (b) Antibiotic perturbation (c) Transient dysbiosis (h) C.difficile clearance (e) C.difficile exposure (g) Disrupting dysbiosis (f) Persistent dysbiosis Bacteriotherapy or FMT Figure 3. Role of antibiotics and C. difficile in perturbing Intestinal homeostasis and the corrective effect of fecal microbiota transplantation (FMT). Intestinal homeostasis (a) is characterized by a diverse, stable microbiota. Antibiotic perturbation (b–c) kills susceptible bacteria resulting in a less diverse community structure with loss of colonization resistance. In the absence of opportunistic infection, the microbiota usually recovers its diversity (d) to re-establish homeostasis and colonization resistance (a). Exposure to C. difficile (e) after antibiotic perturbation (b), however, can lead to persistent dysbiosis (f). Bacteriotherapy or FMT can disrupt the dysbiosis (g) allowing clearance of C. difficile (h) and re-establishment of intestinal homeostasis (a). Modified from Lawley et al. (33). body piercing or tattoo in the previous 3 months or recent incar- blender is to be used for several patients, its parts would have to ceration are also exclusions. A history of diarrhea, constipation, be sterilized before the next procedure. Some authors use milk inflammatory bowel disease, colorectal polyps or cancer, irri- as the suspending fluid, others water; saline and milk may give table bowel syndrome, immunocompromise, morbid obesity, slightly lower resolution (86.2 and 88.6%, respectively) and recur- metabolic syndrome, atopy, and chronic fatigue syndrome are rence (3.0 and 3.2%, respectively) rates, while water may give additional donor exclusions because they conceivably may be higher resolution (98.5%) and recurrence (7.8%) rates (28). The transmittable by inoculation with intestinal microbiota. amount of stool to use has not been standardized, although those One systematic review provided data to suggest that FMT given to weighing and measuring rather than just “eyeballing” the using stool from a related donor (spouse, or intimate partner), product’s appearance favor 50 g in 250 cc of diluent. It seems as yields a somewhat higher rate (93.3%) of CDI resolution than if more is better and most “FMTers” are now using about 300 cc when stool from an unrelated donor (84%) was used (28). More for colonic FMT and 60 cc for upper tract FMT. An administered recent experience with frozen/thawed or fresh fecal preparations volume of < 200 ml gave a resolution rate of 80% and a relapse obtained from “standard” or “universal” donors, however, gave rate of 6.2%, whereas a volume of > 500 ml gave a resolution rate excellent results (90–92% resolution, 9% recurrence) exceeding of 97.3% and a relapse rate of 4.7%. Use of < 50 g of stool was those obtained with patient-selected donors (70% resolution, associated with resolution and relapse rates of 8.2% and 3.8%, 30% recurrence), and casting doubt on preference for related or respectively, whereas > 50 g of stool had resolution and relapse intimate contacts (36). rates of 86.2% and 1.0%, respectively (28). I like to use donor stool So what are the “nuts and bolts” of FMT? The donor has a rela- within 8 h of passage although this time limit has never been stud- tively simple job: to provide the stool in a timely fashion. This, I ied rigorously. Stool should not be frozen and need not, but may, have seen, may cause a level of “performance anxiety” in some be refrigerated for travel. After adding my beverage of choice to donors. To facilitate passage and to enable me to work with a the stool and getting it to the proper consistency, I filter the mix- soft stool, I have the donor take a double dose of milk of mag- ture through gauze pads to remove large particulate matter that nesia before bedtime the night before the procedure. A soft stool may obstruct the colonoscope’s channel and then draw the elixir is passed into a clean plastic container. I add non-bacteriostatic into 60 cc catheter-tipped syringes. It is recommended that stool saline to the stool, stir it, shake it, and mix it thoroughly. Oth- preparation be performed under a hood, because stool is rated as ers have opted for the blender method and some practitioners a Level 2 biohazard, although this recommendation is not practi- have even had patients bring their own blender. Obviously, if a cal and this is the safest stool we, as gastroenterologists, will ever The American Journal of GASTROENTEROLOGY VOLUME 104 | XXX 2012 www.amjgastro.com
  • Intestinal Microbiota and Fecal Microbiota Transplant for C. difficile 7encounter. Recipients should take a large volume colon lavage study, principal investigators of which are Dr Colleen Kellybefore the procedure, regardless of which route is chosen. In cases and I, will evaluate FMT in 80 patients with at least three boutsof recurrent CDI, I have the patients stop their vancomycin and of CDI, and compare results of blinded FMT, using either donor REVIEWother antibiotics 3 days before the procedure if possible; this too or recipient stool for the transplant.has not been studied against continuing the antibiotics up until or The use of stool for such transplants is but the first step in aeven after the procedure. I also have the recipient take two lopera- long journey. Stool is the ultimate probiotic but greater knowl-mide tablets before they leave home or about an hour before the edge of the intestinal microbiota and its functions will certainlyprocedure to help them hold the administered stool for at least enable us to administer one or more intestinal micro-organisms4 h, and preferably 6 h, after FMT. To actually do the transplant,I perform a colonoscopy and upon reaching the cecum, I removethe accessory channel cap of the colonoscope, connect a piece ofsuction tubing to it, and then administer one syringe-full of stool Table 1. Disorders associated with an altered intestinalsuspension after another into the cecum/ascending colon or into microbiomethe ileum until the desired amount has been given. I have on many Gastrointestinaloccasions taken random colon biopsy specimens during insertion Cholelithiasisto ascertain histology without adverse effect. After infusion of the Colorectal cancerdonor stool, I withdraw swiftly, aspirating air only from the distalleft colon, sigmoid and rectum for patient comfort. Hepatic encephalopathy Idiopathic constipationaCDI and FMT: long-term follow-up and safety issues IBSaIn the only long-term follow-up of FMT to date, a five- IBDamedical center cross-country joint effort, 77 patients who had Familial Mediterranean Feverhad FMT and were followed for more than 3 months experi-enced a 91% primary cure rate and a 98% secondary cure rate, Gastric carcinoma and lymphomathe latter defined as cure enabled by use of antibiotics to which Recurrent Clostridium difficile infectionathe patient hadn’t responded to before the FMT or by a second Non-gastrointestinalFMT (37). It is interesting that 97% of these patients stated they Arthritiswould have another FMT were they to develop CDI again and58% said they would choose to have FMT rather than antibiotics. AsthmaIt is not unusual for patients to develop some gastrointestinal Atopycomplaints or altered bowel habit for several days after FMT, Autismaincluding absence of bowel movement, abdominal cramping, Autoimmune disordersgurgling bowel sounds, or increased feelings of gaseousness. Chronic fatigue syndromeaOf the 77 subjects in this study, four developed an autoimmunedisease (rheumatoid arthritis, Sjogren syndrome, idiopathic Diabetes mellitus and insulin resistanceathrombocytopenic purpura, and peripheral neuropathy) at some Eczematime after the FMT, although a clear relationship between the Fatty livernew disease and FMT was not evident. Safety of FMT in immu- Fibromyalgiaanosuppressed patients needs to be established, although limitedexperience to date would suggest immune-compromise is not Hay feverof concern. I personally have performed FMT in many patients Hypercholesterolemiawho were either on glucocorticoids, immunosuppressive Idiopathic thrombocytopenic purpuraa(6-mercaptopurine, azathioprine), or biological agents (inflixi- Ischemic heart diseasemab, adalimumab), or who had diseases or therapies charac- Metabolic syndromeaterized by immunocompromise (kidney transplant, chroniclymphocytic leukemia, lymphoma, primary immune deficiency, Mood disordersSchwachman–Diamond syndrome) without ill effect. Nonethe- Multiple sclerosisaless, safety remains the prime consideration and larger numbers Myoclonus dystoniaaof observations in controlled circumstances are needed. Con- Obesitytrolled trials also are necessary to prove the efficacy of FMT,and to determine the optimal route of administration among Oxalic acid kidney stonesother variables. Two such randomized, controlled trials are Parkinson’s diseaseapending; one that compares conventional vancomycin therapy IBD, inflammatory bowel disease; IBS, irritable bowel syndrome.alone and with bowel lavage, or with bowel lavage plus FMT a Indicates some reports on transient or long-term improvement or cure with fecal microbiota transplant.is currently in progress (38). A recently approved NIH-funded© 2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
  • 8 Brandt or genetically refined products derived from stool rather children; and autistic symptoms have sometimes been reduced by than stool itself to treat CDI. The next step in this journey oral vancomycin treatment (3). Although at first glance it appears has already been taken with the development of a standard- as if there is no connection with neuropsychiatric disease andREVIEW ized filtered, frozen preparation of stool for FMT and use of a intestinal flora, studies now have expanded the original concept “universal donor” (36). of the brain-gut axis and recognize the brain-gut-microbiota axis (51). Moreover, the increasing recognition of the role that micro- When should FMT be done? biota have in affecting mood and thought is actively being worked When should FMT be done for CDI? The clearest indication, on (52,53). as discussed above, is recurrent or refractory disease, but even this is not universally accepted and awaits the results of rand- omized controlled trials; to quote a reviewer of our NIH grant, CONCLUSION however, “…we all know it works”. I believe it also has a role as I believe that the intestinal microbiota will be shown to have first-line treatment for patients with CDI rather than antibiot- important roles in maintaining our health and modulating energy ics because of its rapid effect, minimal risk, relatively low cost expenditure, inflammation, and resistance or susceptibility to var- and reestablishment of a “balanced” colonic microbiota (39). I, ious disease, some gastrointestinal and some not. Bacteria should and others, also have used FMT to treat patients with severe CDI no longer be regarded as just “bad” guys and we have come a long manifest by toxic megacolon or ileus and have seen the patient’s, way since Hippocrates said,” All disease begins in the gut”; today family’s, gastroenterologist’s, and even surgeon’s relief as the he might instead say “Our health is determined by the micro- patient’s abdominal distention, fever, and white blood cell count biota in our gut”. We are witnessing a paradigm shift in the way decreased, occasionally within hours of the procedure; in none we understand health and treat disease and in its center is our of these cases was the patient’s condition or course of disease microbiota. worsened by FMT. FMT also has been used to treat a variety of other gastro- CONFLICT OF INTEREST intestinal disorders including ulcerative colitis, Crohn’s disease, Guarantor of the article: Lawrence J. Brandt, MD, MACG. irritable bowel syndrome, and constipation and there is a grow- Financial support: None. ing literature on an altered intestinal microbiome in these disor- Potential competing interests: Dr Brandt is on the ‘Speaker’s ders (40–42) (See Table 1). I now have personal experience with Bureau of Optimer Pharmaceuticals, Inc. and has received a research FMT in 20 patients with UC, 4 with Crohn’s disease and 20 with grant from Optimer Pharmaceuticals, Inc. IBS; and in all groups, I have noted remarkable symptomatic improvement in some individuals. Rigorous studies of FMT in REFERENCES these areas are also needed to determine who is the optimal candi- 1. Zhang F, Luo W, Shi Y et al. Should we standardize the 1700-year-old date, and via what route and how often FMT should be delivered, fecal microbiota transplantation? Am J Gastroenterol 2012; 107:1755. 2. The Human Microbiome Project Consortium.. 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