Intern Emerg Med DOI 10.1007/s11739-014-1069-4
IM - REVIEW
Gut microbiota modulation: probiotics, antibiotics or fecal microbiota transplantation? Giovanni Cammarota • Gianluca Ianiro Stefano Bibbo` • Antonio Gasbarrini
•
Received: 25 February 2014 / Accepted: 10 March 2014 Ó SIMI 2014
Abstract Gut microbiota is known to have a relevant role in our health, and is also related to both gastrointestinal and extradigestive diseases. Therefore, restoring the alteration of gut microbiota represents an outstanding clinical target for the treatment of gut microbiota-related diseases. The modulation of gut microbiota is perhaps an ancestral, innate concept for human beings. At this time, the restoration of gut microbiota impairment is a well-established concept in mainstream medicine, and several therapeutic approaches have been developed in this regard. Antibiotics, prebiotics and probiotics are the best known and commercially available options to overcome gastrointestinal dysbiosis. Fecal microbiota transplantation is an old procedure that has recently become popular again. It has shown a clear effectiveness in the treatment of C. difficile infection, and now represents a cutting-edge option for the restoration of gut microbiota. Nevertheless, such weapons should be used with caution. Antibiotics can indeed harm and alter gut microbiota composition. Probiotics, instead, are not at all the same thing, and thinking in terms of different strains is probably the only way to improve clinical outcomes.
G. Cammarota G. Ianiro S. Bibbo` A. Gasbarrini School of Medicine and Surgery, Catholic University, Rome, Italy G. Cammarota G. Ianiro S. Bibbo` A. Gasbarrini Division of Internal Medicine and Gastroenterology, Department of Medical Sciences, A. Gemelli University Hospital, Rome, Italy G. Cammarota (&) A. Gemelli University Hospital, Largo A. Gemelli 8, 00168 Rome, Italy e-mail: [email protected]
Moreover, fecal microbiota transplantation has shown promising results, but stronger proofs are needed. Considerable efforts are needed to increase our knowledge in the field of gut microbiota, especially with regard to the future use in its modulation for therapeutic purposes. Keywords Gut microbiota Gut microbiota modulation Antibiotics Probiotics Fecal microbiota transplantation
Gut microbiota in health and disease An enormous number of microbes colonize our body, both inside and out. They number from 10 trillion to 100 trillion cells, outnumbering human eukaryotic cells at least by tenfold. Most of them reside in our intestine, forming the so-called ‘‘human gut microbiota’’ [1]. Gut microbiota and its whole genome (called microbiome) provides humans with genetic and metabolic features that they did not develop by themselves. Gut microbiota and host act, therefore, in a symbiotic manner, constituting essentially a complex ‘‘super-organism’’ [2]. Most microbes, especially anaerobes, cannot be cultured through standard microbiological tools. Such technical limitations have encumbered our understanding of gut microbiota. The development of new, culture-independent techniques for the study of intestinal microbes, such as high-throughput DNA sequencing and other metagenomics technologies, has enhanced our knowledge in the field of gut microbiota [3]. Many initiatives have been established, and are still ongoing, both in the United States (Human Microbiome Project) [2] and in Europe (MetaHIT Consortium) [4], which attempt to characterize microbes of our body and their genomes, and to assess their role in human health and disease.
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Nevertheless, gut microbiota composition is not yet completely defined. Bacteria are certainly the most represented micro-organisms, reaching more than 1 kg of weight and more than 1,100 species. Bacteroidetes and Firmicutes usually are the predominant phyla in adult people, whereas Actinobacteria, or Proteobacteria are less common [4, 5]. The human microbiota also contains archaea, viruses (mainly bacteriophage), fungi and other Eukarya (as Blastocystis and Amoebozoa), [5]. Three main enterotypes, with different metabolic traits, have been recently identified [6]. They are distinguished by their relative abundance of one of the following three genera: Bacteroides (prevalent in enterotype 1); Prevotella (more represented in enterotype 2); Ruminococcus (more abundant in enterotype 3). The presence of a specific enterotype may depend on a particular long-term dietary pattern: animal-based diets, rich in fat and protein, support the development of enterotypes 1 and 3, while a high carbohydrate diet favors the growth of enterotype 2 [7]. Moreover, short-term dietary modifications have been proven to alter the human gut microbiota [8]. The rapidity of our microbiota in switching between different functional profiles may be an evolutionary trick that humans have acquired over time. At birth, the human gut is sterile, and is rapidly colonized by the maternal microbiota; both route of delivery and type of feeding influencing its composition [9]. Both environmental and genetic factors [10] contribute to the development of a ‘‘core native microbiome,’’ which achieves stability during early life, and is maintained over time in the absence of major alterations [11]. In health, gut microbiota plays a relevant role within our body, being involved in many functional processes essential for our homeostasis, such as the control of several metabolic pathways, the metabolism of nutrients, and is also xenobiotic, the production of vitamins and micronutrients, the development and maturation of mucosal and systemic immunity, the regulation of gastrointestinal motility, and the maintenance of intestinal epithelium barrier integrity [12]. Qualitative or quantitative impairment of gut microbiota composition causes the loss of such a homeostasis, leading to the development of a disease state. Several illnesses are known to be influenced by the imbalance of gut microbiota. They include: inflammatory bowel disease (IBD,) [13], irritable bowel syndrome (IBS,) and other functional diseases of the gastrointestinal tract [14], gastroenteric infections [15], colorectal cancer [16], liver diseases [17, 18], and also non gastrointestinal diseases such as obesity and the metabolic syndrome [19, 20], autism [21], and allergic diseases [22]. However, just as the impairment of gut microbiota can lead to a pathological condition, so its manipulation can restore the prior state of
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homeostasis. Healing the alteration of gut microbiota, therefore, represents an outstanding clinical target for the treatment of gut microbiota-related diseases.
Available possibility to modulate gut microbiota The modulation of gut microbiota is perhaps an ancestral, innate concept for human individuals. As recently described by Leach [23], the Hadzabe people, a hunter-gatherer tribe of Tanzania, often eat the raw intestines of hunted preys, and also use the animal’s stomach, full of its microbial matter, as hand cleanser; such a behavior helps to increase the diversity of gut microbes among tribe members. Since a decreased bacterial diversity has been found in several diseases, including IBD [24], IBS [25], obesity and metabolic diseases [26, 27] and asthma [28], such a custom by the Hadzabe tribe can be considered a primitive kind of therapeutic modulation of gut microbiota. Antibiotics Antibiotics are the cornerstone of the treatment of infectious disease [29]. However, bacterial resistance to antibiotics has increased over time, and keeps on rising [30]. The quintessence of this phenomenon is represented by the growing difficulty in eradicating H. pylori infection [31] because of the rise in antibiotic resistance. The improvement in our knowledge of gut microbiota reveals that antibiotics behave in a two-edged manner toward our intestinal microbes [32]; simultaneously, antibiotics demolish both pathogenic bacteria and healthy ones. Moreover, absorbable antibiotics, even if administered for an extra-intestinal disease, attack the microbial flora anyway, because of their widespread, systemic diffusion within our body. Such a phenomenon leads to the impairment of gut microbiota with a consequent increase in susceptibility to its associated diseases. This pathophysiological mechanism is well recognized as being the trigger for C. difficile infection [33], but is also involved in the pathogenesis of other enteric infections [34] or in the intestinal outgrowth of fungi. [35] Moreover, it appears to also influence the development of other diseases, such as obesity [36]. In addition, gut microbiota disruption caused by antibiotic therapy may lead to the development of antibiotic resistance [37]. Antibiotics have indeed been shown to provoke the enrichment of phage-encoded genes that confer resistance via disparate mechanisms both to the administered antimicrobial, as well as to other unrelated antibiotics [38]. Therefore, the relationship between antibiotics and gut microbiota is truly complex, and should be investigated carefully to identify the correct application of
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antibiotics for gut microbiota-related diseases, and to improve disease outcomes. Probiotics and prebiotics According to the 2001 FAO/WHO definition, probiotics are ‘‘live micro-organisms, which when administered in adequate amounts confer a health benefit on the host’’ [39]. The rationale for the use of probiotics for the treatment of gut microbiota-related disease is the restoration of intestinal homeostasis by beneficial microbes. Most probiotics consist of Lactobacilli and Bifidobacteria, but also yeasts such as Saccharomyces boulardii have been used with good outcomes [40]. Suggested mechanisms of action include the inhibition of microbial adherence and translocation, the establishment of a restrictive luminal environment (e.g., through, modification of the luminal pH), the production of peptides with antibacterial properties (such as bacteriocins), or the induction of an host immune response (such as expression of human defensins) [41]. In clinical practice, probiotics have been used for the treatment of many diseases, even without solid evidence. [42]. Assessing the effectiveness of probiotics in a specific disease can be difficult, mainly because of the large heterogeneity among different studies in terms of administered strains, dosage, length of treatment, and administration methods [43]. In addition, considering all probiotics the same thing, without taking into account strain specificity, impairs an adequate understanding of their real therapeutic potential. Several lines of evidence, both in vitro models as well as in vivo human studies, support the variability in actions and outcomes among different strains [44, 45]. Further trials should, therefore, involve probiotics not as such, but with a strain-specific approach [46]. Prebiotics were defined for the first time in 1995 by Gibson and Roberfroid [47] as ‘‘non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of one of a limited number of bacterial species already present in the colon, thus improving host health.’’ To include other fields that may profit by prebiotic action [48], this definition has been renewed by Roberfroid in 2007: ‘‘A prebiotic is a selectively fermented ingredient that allows specific changes, both in the composition or activity in the gastrointestinal microflora that confer benefits upon host well-being and health’’ [49, 50]. To be classified as a prebiotic, a food ingredient needs to fulfill the following criteria: resistance to gastric acid secretion and to hydrolysis by digestive enzymes; absorption in the upper gastrointestinal tract and fermentation by the intestinal gut microbiota; and stimulation of the growth or activity of beneficial microbes. At present, only inulin and trans-galacto-oligosaccharides
completely meet such a definition [48]. Two bacterial genera, respectively, Lactobacilli and Bifidobacteria, are the main target of prebiotics [50], even if other strains have also been proven to benefit of prebiotic properties [51]. Proposed mechanisms of the action of prebiotics include an increase in the production of short-chain fatty acids (SCFA) or a decrease of intestinal pH [52]. To date, definite evidence of the effectiveness of prebiotics for the treatment of gut microbiota-related diseases is lacking, and adequate trials have not yet been performed. Fecal microbiota transplantation (FMT) FMT, also known as ‘‘fecal infusion’’ or ‘‘fecal bacteriotherapy’’, refers to the introduction of a liquid filtrate of stools from a healthy donor into the gastrointestinal tract of a patient for the treatment of specific diseases. The administration of feces for therapeutic purposes was first described more than 1,500 years ago by Ge Hong [53]. Afterward, in the sixteenth century, Li Shizhen treated several gastrointestinal symptoms, such as diarrhea, constipation, vomiting or pain, by fecal products. The transplantation of enteric bacteria (later called transfaunation) was applied also in veterinary science, for the cure of animals unable to ruminate, as described by the Italian anatomist Fabricius Acquapendente in the seventeenth century [54]. The consumption of camel stools has been described both by German soldiers during World War II, as well as by Bedouins as a treatment for dysentery [55]. FMT came to the attention of mainstream medical science only in the late 50’s: in 1958, Eiseman, a surgeon from Colorado, successfully treated four patients with pseudomembranous colitis using fecal enemas [56]. The efficacy of FMT against C. difficile infection was later also confirmed. Early attempts, however, even if almost always successful, were described in occasional case series and anecdotally carried out in a totally empirical way. Both the rising epidemic of C. difficile infection and the growing scientific interest toward the gut microbiota have recently led to the renewal of FMT. Recently, a profound change in the epidemiology of C. difficile infection has occurred, with a rise in its frequency, severity, and mortality [57]. Both the refractoriness of the infection to standard therapy as well as its probability of recurrence have also increased [58], representing an important clinical issue. Positive results shown by FMT in the eradication of recurrent C. difficile infections have encouraged the use of this procedure worldwide, especially in Western Countries. Well-designed studies, both large case series [59] and randomized controlled trials [60], have been conducted to assess its effectiveness. In addition, the recent advancement in our understanding of gut microbiota has given a solid pathophysiological
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background to FMT. Accounting our microbial flora as a bodily organ [61] let the interpretation of FMT change from being considered a mere injection of feces to becoming a true organ transplantation. Such a conceptual transition has led FMT to being used in the treatment of several diseases associated with the disruption of gut microbiota, such as inflammatory bowel disease (IBD) [62] and the metabolic syndrome [63]. FMT may be more effective than probiotics in the restoration of altered gut microbiota, since a fecal infusion overcomes the intrinsic quantitative gap of probiotics (oral probiotic doses are usually more than three orders of magnitude lower than the 100 trillion native micro-organisms of the large bowel). In addition, the administration of fecal flora establishes a durable alteration of the recipient’s gut microbiota [64], while probiotics are able to colonize the gut lumen only for a temporary period [65]. FMT can be performed through various routes: nasogastric or nasojejunal tube, upper endoscopy, retention enema, as well as colonoscopy [66]. In early usage, retention enemas were the preferred mode of delivery [67]. In a recent systematic review of studies using FMT for the treatment of recurrente C. difficile infection, Cammarota et al. [68] report that the lower gastrointestinal route (colonoscopy, enema) leads to the achievement of higher eradication rates than upper delivery (gastroscopy, nasogastric or nasojejunal tube) (81–86 versus 84–93 %, respectively). In theory, among different lower gastrointestinal routes, colonoscopy appears to be a more reliable route than retention enemata for the treatment of C. difficile infection, since it can reach the whole colon (while enemas only ascend to the left colon), and colonoscopy can also assess the features of the disease: such as its extent and severity [69, 70]. Nevertheless, low invasiveness and costs of the retention enema approach and its proven efficacy even when selfadministered, [71] make it extremely competitive for a routine use. Probably the optimal route of administration does not exist absolutely, and any of the therapeutic routes should be chosen depending on the features and the location of the disease, as shown by the successful results obtained in the treatment of metabolic diseases by duodenal administration of feces [62]. Further discoveries of the therapeutic chances of FMT, and its systematic application to several gut microbiotaassociated diseases will make the specific administration route an important issue. The growth of many beneficial bacteria is indeed influenced by their specific transfer through the gastrointestinal tract. Many spore-forming Firmicutes require transit through the upper gastrointestinal tract to work effectively. Bacteroidetes can be injured by
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gastric acid secretion, and a lower route may be preferable [72, 73]. A combined approach of delivery has not yet been attempted [74], and may perhaps become an option in the future. Donor selection is certainly easier for FMT than for other organ transplants, since there is no need of immunological matching of donor and recipient. Nevertheless, an accurate evaluation is necessary to avoid disease transmission to the recipient, and unfortunately, the transfer of unknown pathogens is not completely avoidable [75]. Usually, to overcome the repulsion of the patient toward receiving an infusion of feces (the so-called yuck factor,) donors are usually friends or family members, both related and unrelated. The administration of feces derived from related donors appears to achieve slightly higher resolution rates than stools from unrelated ones (respectively, 93 versus 84 % resolution rates) for the treatment of C. difficile infection, as observed through systematic review by Gough et al.. Donor gender, instead, does not influence eradication rates [76]. Initially, the medical history of potential donors is collected, usually by clinical questionnaire. The following clinical characteristics have been proposed: [67] as absolute contraindications to the donation of feces for the treatment of C. difficile infection: known human immunodeficiency virus (HIV), hepatitis B or C infections; known exposure to HIV or viral hepatitis (within the previous 12 months); high-risk sexual behaviors; use of illicit drugs; tattoos or body piercing performed within 6 months; incarceration or history of incarceration; known current communicable disease (e.g., upper respiratory tract infection); risk factors for variant Creutzfeldt–Jakob disease; travel (within the last 6 months) to areas of the world where diarrheal illnesses are endemic or with high risk of traveler’s diarrhea; history of IBD, IBS and other functional diseases; history of gastrointestinal malignancy or known polyposis; use of antibiotics within the preceding 3 months, immunosuppressant, chemotherapeutic drugs; and recent consumption of a potential allergen for the recipient. The following features are deemed as relative contraindications: history of major gastrointestinal surgery; the metabolic syndrome, autoimmune diseases, atopic diseases, and chronic pain syndromes [67]. After completion of the questionnaire, potential donors undergo serum and stool testing. Donor serum testing includes screening for HIV, Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus and syphilis, while donor stool testing consists of stool culture for common enteric pathogens, C. difficile toxin, Giardia antigens, Cryptosporidium antigens, Helicobacter pylori antigens, helminths, ova and parasites. This protocol has been applied with success for donor selection in the management of C. difficile infection by
Intern Emerg Med Table 1 Fully published reports on FMT treatment First author
Year
Indication
Study design
No. of patients
Eiseman
1958
Pseudomembranous colitis
Case series
4
Cutolo
1959
Pseudomembranous colitis
Case report
1
Collins
1960
Pseudomembranous colitis
Case series
4
Fenton
1974
Pseudomembranous colitis
Case report
1
Bowden
1981
Pseudomembranous colitis
Case series
16 1
Schwan
1984
C. difficile infection
Case report
Tvede
1989
C. difficile infection
Case series
6
Bennet
1989
IBD
Case report
1
Borody
1989
IBS and IBD
Case series
55
Flotterod
1991
C. difficile infection
Case report
1
Andrews Paterson
1992 1994
Chronic constipation C. difficile infection
Case report Case series
1 7
Harkonen
1996
Pseudomembranous colitis
Case report
1
Lund- Tønnesen
1998
C. difficile infection
Case series
18
Gustafsson
1998
C. difficile infection
Case series
9
Persky
2000
C. difficile infection
Case report
1
Aas
2003
C. difficile infectiona
Case series
18
Borody
2003
IBD
Case series
6
Jorup-Ronstrom
2006
C. difficile infection
Case series
5
Nieuwdrop
2008
C. difficile infection
Case series
7
You
2008
C. difficile infection
Case report
1
Hellermans
2009
C. difficile infection
Case report
1
MacConnachie
2009
C. difficile infection
Case series
15
Garborg
2010
C. difficile infection
Case series
40
Grehan
2010
C. difficile infectiona
Open-label trial
10
Khoruts
2010
C. difficile infection
Case report
1
Rohlke Russell
2010 2010
C. difficile infection C. difficile infection
Case series Case report
19 1
Silverman
2010
C. difficile infection
Case series
7
Yoon
2010
C. difficile infection
Case series
12
Kelly
2011
C. difficile infection
Case series
26
Polak
2011
C. difficile infection
Case series
15
Brandt
2012
C. difficile infection
Multicenter long-term follow-up study
77
Hamilton
2012
C. difficile infection
Open-label trial
43
Jorup-Ronstrom
2012
C. difficile infection
Case series
32
Kahn
2012
C. difficile infection
Case report
1
Mattila
2012
C. difficile infection
Case series
70
Nagy
2012
C. difficile infection
Case report
1
Neeman
2012
C. difficile infection
Case report
1
Rubin
2012
C. difficile infection
Case series
74
Trubiano
2012
C. difficile infection
Case report
1
Vrieze Zainah
2012 2012
Metabolic syndrome C. difficile infectiona
Case report
Angelberger
2013
IBD
Open-label trial
5
Broecker
2013
C. difficile infection
Case report
1
De Leon
2013
C. difficile infectiona
Case report
1
Emanuelsson
2013
C. difficile infection
Case series
31
Kleger
2013
C. difficile infection
Case report
1
Randomized controlled trial
18 1
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Intern Emerg Med Table 1 continued First author
Year
Indication
Study design
No. of patients
Kump
2013
IBD
Open-label trial
6
Kunde
2013
IBD
Open-label trial
10
Gutman Lofland
2013 2013
C. difficile infection C. difficile infection
Case series Case report
2 1
Quera
2013
C. difficile infectiona
Case report
1
Schwartz
2013
C. difficile infection
Case series
Song
2013
C. difficile infection
Open-label trial
14
van Nood
2013
C. difficile infection
Randomized controlled trial
42
Weingarden
2013
C. difficile infection
Open-label trial
16
Weingarden
2013
C. difficile infection
Case series
4
Zhang
2013
IBD
Case report
1
2
IBD inflammatory bowel disease, IBS irritable bowel syndrome a
Including also patients with IBD and C. difficile superinfection
FMT [77]. However, such an approach seems to be inadequate when dealing with other gut microbiota-related diseases, such as IBD, where the composition of the donor’s gut microbiota may influence clinical outcomes [74]. New tools for the investigation of gut microbiota composition, such as metagenomics and target gene sequencing will probably aid in our understanding in this field, and their application for the selection of donors is an interesting future prospect. After donation, stools are processed for being infused. Most data about the stool preparation protocol comes from studies applying FMT for the treatment of recurrent C. difficile infection, as reviewed by Gough and colleagues [76]. Even if there is no standardization about the required amount of feces, using less than 50 g has been correlated with C. difficile relapse rates [76]. Feces are then suspended in a diluent, generally saline or water; the use of water appears to get higher eradication rates than saline (98.5 versus 86 %), but also higher relapse rates. Other diluents, including milk or yoghurt, achieve resolution rates of 94 %. The suspension is then passed through gauzes or sieve, to eliminate gross materials. The filtrate volume is largely heterogeneous among studies, ranging between 200 ml or less and 500 ml or more. The use of larger volumes ([500 ml) is positively associated (although in a nonsignificant manner) with higher resolution rates [76]. In most cases, the transplantation is performed within 6–8 h after the donation [78, 79]. Frozen stools have, however, shown a comparable efficacy to fresh ones for the treatment of recurrent C. difficile infection [80]. Usually, patients undergo a bowel preparation the day before the infusion. Many physicians advocate using a PPI if the upper route is chosen [74]. In trials dealing with C. difficile infection, a single infusion of feces has usually been administered, with
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excellent results [68]. Nevertheless, the future application of FMT to chronic diseases (such as IBD, IBS, obesity) may perhaps require several infusions to achieve success. FMT is a theoretically promising option for several diseases, differing from each other by pathophysiology and clinical features. Probably, a unique protocol of stool preparation is, therefore, an outdated idea, and in the future every clinical indication will correspond to a different protocol. An up-to-date overview of fully published reports on FMT treatment for both gastrointestinal and extraintestinal diseases is described in Table 1.
Conclusions The role of gut microbiota in health and disease was first hypothesized in 1907 by Metchnikoff and Mitchell [81]. More than one century after, our knowledge of gut microbiota has enormously grown, and our consideration of gut microbiota has changed from an amalgam of microbes to another organ of our body, forming a ‘‘super-organism’’ with us. Moreover, we have discovered a deep relationship between gut microbiota and both gastrointestinal and extradigestive diseases. New technologies such as metagenomics have increased our understanding of gut microbiota composition in health and disease. Such gain in knowledge can potentially change our therapeutic perspectives: gut modulation can become a therapeutic option. Some tools, such as antibiotics or probiotics, are well known, and other, such as FMT, represent an intriguing, cutting-edge weapon. However, in the recent past scientific community learned that ‘‘all that glitters is no gold.’’ Antibiotics can indeed harm and alter gut microbiota composition. Probiotics, instead, are not all the same, and thinking in terms of different strains is probably
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the only way to improve clinical outcomes. Finally, FMT, although promising, is not yet a standardized procedure. Considerable efforts are needed to increase our knowledge in the field of gut microbiota, especially in regard to future modulations for therapeutic purposes. Conflict of interest
None.
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IM - REVIEW
Gut microbiota modulation: probiotics, antibiotics or fecal microbiota transplantation? Giovanni Cammarota • Gianluca Ianiro Stefano Bibbo` • Antonio Gasbarrini
•
Received: 25 February 2014 / Accepted: 10 March 2014 Ó SIMI 2014
Abstract Gut microbiota is known to have a relevant role in our health, and is also related to both gastrointestinal and extradigestive diseases. Therefore, restoring the alteration of gut microbiota represents an outstanding clinical target for the treatment of gut microbiota-related diseases. The modulation of gut microbiota is perhaps an ancestral, innate concept for human beings. At this time, the restoration of gut microbiota impairment is a well-established concept in mainstream medicine, and several therapeutic approaches have been developed in this regard. Antibiotics, prebiotics and probiotics are the best known and commercially available options to overcome gastrointestinal dysbiosis. Fecal microbiota transplantation is an old procedure that has recently become popular again. It has shown a clear effectiveness in the treatment of C. difficile infection, and now represents a cutting-edge option for the restoration of gut microbiota. Nevertheless, such weapons should be used with caution. Antibiotics can indeed harm and alter gut microbiota composition. Probiotics, instead, are not at all the same thing, and thinking in terms of different strains is probably the only way to improve clinical outcomes.
G. Cammarota G. Ianiro S. Bibbo` A. Gasbarrini School of Medicine and Surgery, Catholic University, Rome, Italy G. Cammarota G. Ianiro S. Bibbo` A. Gasbarrini Division of Internal Medicine and Gastroenterology, Department of Medical Sciences, A. Gemelli University Hospital, Rome, Italy G. Cammarota (&) A. Gemelli University Hospital, Largo A. Gemelli 8, 00168 Rome, Italy e-mail: [email protected]
Moreover, fecal microbiota transplantation has shown promising results, but stronger proofs are needed. Considerable efforts are needed to increase our knowledge in the field of gut microbiota, especially with regard to the future use in its modulation for therapeutic purposes. Keywords Gut microbiota Gut microbiota modulation Antibiotics Probiotics Fecal microbiota transplantation
Gut microbiota in health and disease An enormous number of microbes colonize our body, both inside and out. They number from 10 trillion to 100 trillion cells, outnumbering human eukaryotic cells at least by tenfold. Most of them reside in our intestine, forming the so-called ‘‘human gut microbiota’’ [1]. Gut microbiota and its whole genome (called microbiome) provides humans with genetic and metabolic features that they did not develop by themselves. Gut microbiota and host act, therefore, in a symbiotic manner, constituting essentially a complex ‘‘super-organism’’ [2]. Most microbes, especially anaerobes, cannot be cultured through standard microbiological tools. Such technical limitations have encumbered our understanding of gut microbiota. The development of new, culture-independent techniques for the study of intestinal microbes, such as high-throughput DNA sequencing and other metagenomics technologies, has enhanced our knowledge in the field of gut microbiota [3]. Many initiatives have been established, and are still ongoing, both in the United States (Human Microbiome Project) [2] and in Europe (MetaHIT Consortium) [4], which attempt to characterize microbes of our body and their genomes, and to assess their role in human health and disease.
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Nevertheless, gut microbiota composition is not yet completely defined. Bacteria are certainly the most represented micro-organisms, reaching more than 1 kg of weight and more than 1,100 species. Bacteroidetes and Firmicutes usually are the predominant phyla in adult people, whereas Actinobacteria, or Proteobacteria are less common [4, 5]. The human microbiota also contains archaea, viruses (mainly bacteriophage), fungi and other Eukarya (as Blastocystis and Amoebozoa), [5]. Three main enterotypes, with different metabolic traits, have been recently identified [6]. They are distinguished by their relative abundance of one of the following three genera: Bacteroides (prevalent in enterotype 1); Prevotella (more represented in enterotype 2); Ruminococcus (more abundant in enterotype 3). The presence of a specific enterotype may depend on a particular long-term dietary pattern: animal-based diets, rich in fat and protein, support the development of enterotypes 1 and 3, while a high carbohydrate diet favors the growth of enterotype 2 [7]. Moreover, short-term dietary modifications have been proven to alter the human gut microbiota [8]. The rapidity of our microbiota in switching between different functional profiles may be an evolutionary trick that humans have acquired over time. At birth, the human gut is sterile, and is rapidly colonized by the maternal microbiota; both route of delivery and type of feeding influencing its composition [9]. Both environmental and genetic factors [10] contribute to the development of a ‘‘core native microbiome,’’ which achieves stability during early life, and is maintained over time in the absence of major alterations [11]. In health, gut microbiota plays a relevant role within our body, being involved in many functional processes essential for our homeostasis, such as the control of several metabolic pathways, the metabolism of nutrients, and is also xenobiotic, the production of vitamins and micronutrients, the development and maturation of mucosal and systemic immunity, the regulation of gastrointestinal motility, and the maintenance of intestinal epithelium barrier integrity [12]. Qualitative or quantitative impairment of gut microbiota composition causes the loss of such a homeostasis, leading to the development of a disease state. Several illnesses are known to be influenced by the imbalance of gut microbiota. They include: inflammatory bowel disease (IBD,) [13], irritable bowel syndrome (IBS,) and other functional diseases of the gastrointestinal tract [14], gastroenteric infections [15], colorectal cancer [16], liver diseases [17, 18], and also non gastrointestinal diseases such as obesity and the metabolic syndrome [19, 20], autism [21], and allergic diseases [22]. However, just as the impairment of gut microbiota can lead to a pathological condition, so its manipulation can restore the prior state of
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homeostasis. Healing the alteration of gut microbiota, therefore, represents an outstanding clinical target for the treatment of gut microbiota-related diseases.
Available possibility to modulate gut microbiota The modulation of gut microbiota is perhaps an ancestral, innate concept for human individuals. As recently described by Leach [23], the Hadzabe people, a hunter-gatherer tribe of Tanzania, often eat the raw intestines of hunted preys, and also use the animal’s stomach, full of its microbial matter, as hand cleanser; such a behavior helps to increase the diversity of gut microbes among tribe members. Since a decreased bacterial diversity has been found in several diseases, including IBD [24], IBS [25], obesity and metabolic diseases [26, 27] and asthma [28], such a custom by the Hadzabe tribe can be considered a primitive kind of therapeutic modulation of gut microbiota. Antibiotics Antibiotics are the cornerstone of the treatment of infectious disease [29]. However, bacterial resistance to antibiotics has increased over time, and keeps on rising [30]. The quintessence of this phenomenon is represented by the growing difficulty in eradicating H. pylori infection [31] because of the rise in antibiotic resistance. The improvement in our knowledge of gut microbiota reveals that antibiotics behave in a two-edged manner toward our intestinal microbes [32]; simultaneously, antibiotics demolish both pathogenic bacteria and healthy ones. Moreover, absorbable antibiotics, even if administered for an extra-intestinal disease, attack the microbial flora anyway, because of their widespread, systemic diffusion within our body. Such a phenomenon leads to the impairment of gut microbiota with a consequent increase in susceptibility to its associated diseases. This pathophysiological mechanism is well recognized as being the trigger for C. difficile infection [33], but is also involved in the pathogenesis of other enteric infections [34] or in the intestinal outgrowth of fungi. [35] Moreover, it appears to also influence the development of other diseases, such as obesity [36]. In addition, gut microbiota disruption caused by antibiotic therapy may lead to the development of antibiotic resistance [37]. Antibiotics have indeed been shown to provoke the enrichment of phage-encoded genes that confer resistance via disparate mechanisms both to the administered antimicrobial, as well as to other unrelated antibiotics [38]. Therefore, the relationship between antibiotics and gut microbiota is truly complex, and should be investigated carefully to identify the correct application of
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antibiotics for gut microbiota-related diseases, and to improve disease outcomes. Probiotics and prebiotics According to the 2001 FAO/WHO definition, probiotics are ‘‘live micro-organisms, which when administered in adequate amounts confer a health benefit on the host’’ [39]. The rationale for the use of probiotics for the treatment of gut microbiota-related disease is the restoration of intestinal homeostasis by beneficial microbes. Most probiotics consist of Lactobacilli and Bifidobacteria, but also yeasts such as Saccharomyces boulardii have been used with good outcomes [40]. Suggested mechanisms of action include the inhibition of microbial adherence and translocation, the establishment of a restrictive luminal environment (e.g., through, modification of the luminal pH), the production of peptides with antibacterial properties (such as bacteriocins), or the induction of an host immune response (such as expression of human defensins) [41]. In clinical practice, probiotics have been used for the treatment of many diseases, even without solid evidence. [42]. Assessing the effectiveness of probiotics in a specific disease can be difficult, mainly because of the large heterogeneity among different studies in terms of administered strains, dosage, length of treatment, and administration methods [43]. In addition, considering all probiotics the same thing, without taking into account strain specificity, impairs an adequate understanding of their real therapeutic potential. Several lines of evidence, both in vitro models as well as in vivo human studies, support the variability in actions and outcomes among different strains [44, 45]. Further trials should, therefore, involve probiotics not as such, but with a strain-specific approach [46]. Prebiotics were defined for the first time in 1995 by Gibson and Roberfroid [47] as ‘‘non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of one of a limited number of bacterial species already present in the colon, thus improving host health.’’ To include other fields that may profit by prebiotic action [48], this definition has been renewed by Roberfroid in 2007: ‘‘A prebiotic is a selectively fermented ingredient that allows specific changes, both in the composition or activity in the gastrointestinal microflora that confer benefits upon host well-being and health’’ [49, 50]. To be classified as a prebiotic, a food ingredient needs to fulfill the following criteria: resistance to gastric acid secretion and to hydrolysis by digestive enzymes; absorption in the upper gastrointestinal tract and fermentation by the intestinal gut microbiota; and stimulation of the growth or activity of beneficial microbes. At present, only inulin and trans-galacto-oligosaccharides
completely meet such a definition [48]. Two bacterial genera, respectively, Lactobacilli and Bifidobacteria, are the main target of prebiotics [50], even if other strains have also been proven to benefit of prebiotic properties [51]. Proposed mechanisms of the action of prebiotics include an increase in the production of short-chain fatty acids (SCFA) or a decrease of intestinal pH [52]. To date, definite evidence of the effectiveness of prebiotics for the treatment of gut microbiota-related diseases is lacking, and adequate trials have not yet been performed. Fecal microbiota transplantation (FMT) FMT, also known as ‘‘fecal infusion’’ or ‘‘fecal bacteriotherapy’’, refers to the introduction of a liquid filtrate of stools from a healthy donor into the gastrointestinal tract of a patient for the treatment of specific diseases. The administration of feces for therapeutic purposes was first described more than 1,500 years ago by Ge Hong [53]. Afterward, in the sixteenth century, Li Shizhen treated several gastrointestinal symptoms, such as diarrhea, constipation, vomiting or pain, by fecal products. The transplantation of enteric bacteria (later called transfaunation) was applied also in veterinary science, for the cure of animals unable to ruminate, as described by the Italian anatomist Fabricius Acquapendente in the seventeenth century [54]. The consumption of camel stools has been described both by German soldiers during World War II, as well as by Bedouins as a treatment for dysentery [55]. FMT came to the attention of mainstream medical science only in the late 50’s: in 1958, Eiseman, a surgeon from Colorado, successfully treated four patients with pseudomembranous colitis using fecal enemas [56]. The efficacy of FMT against C. difficile infection was later also confirmed. Early attempts, however, even if almost always successful, were described in occasional case series and anecdotally carried out in a totally empirical way. Both the rising epidemic of C. difficile infection and the growing scientific interest toward the gut microbiota have recently led to the renewal of FMT. Recently, a profound change in the epidemiology of C. difficile infection has occurred, with a rise in its frequency, severity, and mortality [57]. Both the refractoriness of the infection to standard therapy as well as its probability of recurrence have also increased [58], representing an important clinical issue. Positive results shown by FMT in the eradication of recurrent C. difficile infections have encouraged the use of this procedure worldwide, especially in Western Countries. Well-designed studies, both large case series [59] and randomized controlled trials [60], have been conducted to assess its effectiveness. In addition, the recent advancement in our understanding of gut microbiota has given a solid pathophysiological
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background to FMT. Accounting our microbial flora as a bodily organ [61] let the interpretation of FMT change from being considered a mere injection of feces to becoming a true organ transplantation. Such a conceptual transition has led FMT to being used in the treatment of several diseases associated with the disruption of gut microbiota, such as inflammatory bowel disease (IBD) [62] and the metabolic syndrome [63]. FMT may be more effective than probiotics in the restoration of altered gut microbiota, since a fecal infusion overcomes the intrinsic quantitative gap of probiotics (oral probiotic doses are usually more than three orders of magnitude lower than the 100 trillion native micro-organisms of the large bowel). In addition, the administration of fecal flora establishes a durable alteration of the recipient’s gut microbiota [64], while probiotics are able to colonize the gut lumen only for a temporary period [65]. FMT can be performed through various routes: nasogastric or nasojejunal tube, upper endoscopy, retention enema, as well as colonoscopy [66]. In early usage, retention enemas were the preferred mode of delivery [67]. In a recent systematic review of studies using FMT for the treatment of recurrente C. difficile infection, Cammarota et al. [68] report that the lower gastrointestinal route (colonoscopy, enema) leads to the achievement of higher eradication rates than upper delivery (gastroscopy, nasogastric or nasojejunal tube) (81–86 versus 84–93 %, respectively). In theory, among different lower gastrointestinal routes, colonoscopy appears to be a more reliable route than retention enemata for the treatment of C. difficile infection, since it can reach the whole colon (while enemas only ascend to the left colon), and colonoscopy can also assess the features of the disease: such as its extent and severity [69, 70]. Nevertheless, low invasiveness and costs of the retention enema approach and its proven efficacy even when selfadministered, [71] make it extremely competitive for a routine use. Probably the optimal route of administration does not exist absolutely, and any of the therapeutic routes should be chosen depending on the features and the location of the disease, as shown by the successful results obtained in the treatment of metabolic diseases by duodenal administration of feces [62]. Further discoveries of the therapeutic chances of FMT, and its systematic application to several gut microbiotaassociated diseases will make the specific administration route an important issue. The growth of many beneficial bacteria is indeed influenced by their specific transfer through the gastrointestinal tract. Many spore-forming Firmicutes require transit through the upper gastrointestinal tract to work effectively. Bacteroidetes can be injured by
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gastric acid secretion, and a lower route may be preferable [72, 73]. A combined approach of delivery has not yet been attempted [74], and may perhaps become an option in the future. Donor selection is certainly easier for FMT than for other organ transplants, since there is no need of immunological matching of donor and recipient. Nevertheless, an accurate evaluation is necessary to avoid disease transmission to the recipient, and unfortunately, the transfer of unknown pathogens is not completely avoidable [75]. Usually, to overcome the repulsion of the patient toward receiving an infusion of feces (the so-called yuck factor,) donors are usually friends or family members, both related and unrelated. The administration of feces derived from related donors appears to achieve slightly higher resolution rates than stools from unrelated ones (respectively, 93 versus 84 % resolution rates) for the treatment of C. difficile infection, as observed through systematic review by Gough et al.. Donor gender, instead, does not influence eradication rates [76]. Initially, the medical history of potential donors is collected, usually by clinical questionnaire. The following clinical characteristics have been proposed: [67] as absolute contraindications to the donation of feces for the treatment of C. difficile infection: known human immunodeficiency virus (HIV), hepatitis B or C infections; known exposure to HIV or viral hepatitis (within the previous 12 months); high-risk sexual behaviors; use of illicit drugs; tattoos or body piercing performed within 6 months; incarceration or history of incarceration; known current communicable disease (e.g., upper respiratory tract infection); risk factors for variant Creutzfeldt–Jakob disease; travel (within the last 6 months) to areas of the world where diarrheal illnesses are endemic or with high risk of traveler’s diarrhea; history of IBD, IBS and other functional diseases; history of gastrointestinal malignancy or known polyposis; use of antibiotics within the preceding 3 months, immunosuppressant, chemotherapeutic drugs; and recent consumption of a potential allergen for the recipient. The following features are deemed as relative contraindications: history of major gastrointestinal surgery; the metabolic syndrome, autoimmune diseases, atopic diseases, and chronic pain syndromes [67]. After completion of the questionnaire, potential donors undergo serum and stool testing. Donor serum testing includes screening for HIV, Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus and syphilis, while donor stool testing consists of stool culture for common enteric pathogens, C. difficile toxin, Giardia antigens, Cryptosporidium antigens, Helicobacter pylori antigens, helminths, ova and parasites. This protocol has been applied with success for donor selection in the management of C. difficile infection by
Intern Emerg Med Table 1 Fully published reports on FMT treatment First author
Year
Indication
Study design
No. of patients
Eiseman
1958
Pseudomembranous colitis
Case series
4
Cutolo
1959
Pseudomembranous colitis
Case report
1
Collins
1960
Pseudomembranous colitis
Case series
4
Fenton
1974
Pseudomembranous colitis
Case report
1
Bowden
1981
Pseudomembranous colitis
Case series
16 1
Schwan
1984
C. difficile infection
Case report
Tvede
1989
C. difficile infection
Case series
6
Bennet
1989
IBD
Case report
1
Borody
1989
IBS and IBD
Case series
55
Flotterod
1991
C. difficile infection
Case report
1
Andrews Paterson
1992 1994
Chronic constipation C. difficile infection
Case report Case series
1 7
Harkonen
1996
Pseudomembranous colitis
Case report
1
Lund- Tønnesen
1998
C. difficile infection
Case series
18
Gustafsson
1998
C. difficile infection
Case series
9
Persky
2000
C. difficile infection
Case report
1
Aas
2003
C. difficile infectiona
Case series
18
Borody
2003
IBD
Case series
6
Jorup-Ronstrom
2006
C. difficile infection
Case series
5
Nieuwdrop
2008
C. difficile infection
Case series
7
You
2008
C. difficile infection
Case report
1
Hellermans
2009
C. difficile infection
Case report
1
MacConnachie
2009
C. difficile infection
Case series
15
Garborg
2010
C. difficile infection
Case series
40
Grehan
2010
C. difficile infectiona
Open-label trial
10
Khoruts
2010
C. difficile infection
Case report
1
Rohlke Russell
2010 2010
C. difficile infection C. difficile infection
Case series Case report
19 1
Silverman
2010
C. difficile infection
Case series
7
Yoon
2010
C. difficile infection
Case series
12
Kelly
2011
C. difficile infection
Case series
26
Polak
2011
C. difficile infection
Case series
15
Brandt
2012
C. difficile infection
Multicenter long-term follow-up study
77
Hamilton
2012
C. difficile infection
Open-label trial
43
Jorup-Ronstrom
2012
C. difficile infection
Case series
32
Kahn
2012
C. difficile infection
Case report
1
Mattila
2012
C. difficile infection
Case series
70
Nagy
2012
C. difficile infection
Case report
1
Neeman
2012
C. difficile infection
Case report
1
Rubin
2012
C. difficile infection
Case series
74
Trubiano
2012
C. difficile infection
Case report
1
Vrieze Zainah
2012 2012
Metabolic syndrome C. difficile infectiona
Case report
Angelberger
2013
IBD
Open-label trial
5
Broecker
2013
C. difficile infection
Case report
1
De Leon
2013
C. difficile infectiona
Case report
1
Emanuelsson
2013
C. difficile infection
Case series
31
Kleger
2013
C. difficile infection
Case report
1
Randomized controlled trial
18 1
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Intern Emerg Med Table 1 continued First author
Year
Indication
Study design
No. of patients
Kump
2013
IBD
Open-label trial
6
Kunde
2013
IBD
Open-label trial
10
Gutman Lofland
2013 2013
C. difficile infection C. difficile infection
Case series Case report
2 1
Quera
2013
C. difficile infectiona
Case report
1
Schwartz
2013
C. difficile infection
Case series
Song
2013
C. difficile infection
Open-label trial
14
van Nood
2013
C. difficile infection
Randomized controlled trial
42
Weingarden
2013
C. difficile infection
Open-label trial
16
Weingarden
2013
C. difficile infection
Case series
4
Zhang
2013
IBD
Case report
1
2
IBD inflammatory bowel disease, IBS irritable bowel syndrome a
Including also patients with IBD and C. difficile superinfection
FMT [77]. However, such an approach seems to be inadequate when dealing with other gut microbiota-related diseases, such as IBD, where the composition of the donor’s gut microbiota may influence clinical outcomes [74]. New tools for the investigation of gut microbiota composition, such as metagenomics and target gene sequencing will probably aid in our understanding in this field, and their application for the selection of donors is an interesting future prospect. After donation, stools are processed for being infused. Most data about the stool preparation protocol comes from studies applying FMT for the treatment of recurrent C. difficile infection, as reviewed by Gough and colleagues [76]. Even if there is no standardization about the required amount of feces, using less than 50 g has been correlated with C. difficile relapse rates [76]. Feces are then suspended in a diluent, generally saline or water; the use of water appears to get higher eradication rates than saline (98.5 versus 86 %), but also higher relapse rates. Other diluents, including milk or yoghurt, achieve resolution rates of 94 %. The suspension is then passed through gauzes or sieve, to eliminate gross materials. The filtrate volume is largely heterogeneous among studies, ranging between 200 ml or less and 500 ml or more. The use of larger volumes ([500 ml) is positively associated (although in a nonsignificant manner) with higher resolution rates [76]. In most cases, the transplantation is performed within 6–8 h after the donation [78, 79]. Frozen stools have, however, shown a comparable efficacy to fresh ones for the treatment of recurrent C. difficile infection [80]. Usually, patients undergo a bowel preparation the day before the infusion. Many physicians advocate using a PPI if the upper route is chosen [74]. In trials dealing with C. difficile infection, a single infusion of feces has usually been administered, with
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excellent results [68]. Nevertheless, the future application of FMT to chronic diseases (such as IBD, IBS, obesity) may perhaps require several infusions to achieve success. FMT is a theoretically promising option for several diseases, differing from each other by pathophysiology and clinical features. Probably, a unique protocol of stool preparation is, therefore, an outdated idea, and in the future every clinical indication will correspond to a different protocol. An up-to-date overview of fully published reports on FMT treatment for both gastrointestinal and extraintestinal diseases is described in Table 1.
Conclusions The role of gut microbiota in health and disease was first hypothesized in 1907 by Metchnikoff and Mitchell [81]. More than one century after, our knowledge of gut microbiota has enormously grown, and our consideration of gut microbiota has changed from an amalgam of microbes to another organ of our body, forming a ‘‘super-organism’’ with us. Moreover, we have discovered a deep relationship between gut microbiota and both gastrointestinal and extradigestive diseases. New technologies such as metagenomics have increased our understanding of gut microbiota composition in health and disease. Such gain in knowledge can potentially change our therapeutic perspectives: gut modulation can become a therapeutic option. Some tools, such as antibiotics or probiotics, are well known, and other, such as FMT, represent an intriguing, cutting-edge weapon. However, in the recent past scientific community learned that ‘‘all that glitters is no gold.’’ Antibiotics can indeed harm and alter gut microbiota composition. Probiotics, instead, are not all the same, and thinking in terms of different strains is probably
Intern Emerg Med
the only way to improve clinical outcomes. Finally, FMT, although promising, is not yet a standardized procedure. Considerable efforts are needed to increase our knowledge in the field of gut microbiota, especially in regard to future modulations for therapeutic purposes. Conflict of interest
None.
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52. 53.
54.
55. 56.
57.
58.
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