Faecal Microbiota Transplantation as Emerging Treatment in European Countries

  • Marcello Maida
  • James Mcilroy
  • Gianluca Ianiro
  • Giovanni Cammarota
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1050)

Abstract

Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections in the world and is a leading cause of morbidity and mortality in hospitalized patients.

Although several antibiotics effectively treat CDI, some individuals do not respond to these drugs and may be cured by transplanting stool from healthy donors. This procedure, termed Faecal Microbiota Transplantation (FMT), has demonstrated remarkable efficacy as a treatment for recurrent CDI.

FMT has also been investigated in other diseases and disorders where perturbations to the gut microbiota have been theorized to play a causative role in pathogenesis and severity, such as inflammatory bowel disease (IBD). Although FMT is currently not recommended to cure IBD patients in clinical practice, several studies have recently been carried out with promising results. The aim of future research is therefore to standardize protocols and develop FMT as a therapeutic option for these patients.

This review summarizes data on the use of FMT as a treatment for CDI and IBD, with special attention given to studies conducted in European countries.

Keywords

Clostridium difficile European Faecal microbiota transplantation Fecal Inflammatory bowel disease 

1 Introduction

Gut microbiota is critical to health and functions and therefore emerges as a “virtual” organ with a level of complexity comparable to that of any other organ system. Fecal microbiota transplantation (FMT) is a medical treatment that aims to restore the normal gut microbiota in diseases or infections associated with bacterial imbalances. FMT has the potential to compete with powerful antibiotics as a treatment strategy in several gastrointestinal disorders. Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections in the world and is a leading cause of morbidity and mortality in hospitalized patients. Although several antibiotics effectively treat CDI, some individuals do not respond to these drugs and may be cured by FMT, which has demonstrated extraordinary efficacy for the cure of recurrent CDI (rCDI). FMT has also been investigated in other diseases and disorders where perturbations to the gut microbiota have been theorized to play a causative role in pathogenesis and severity, such as inflammatory bowel disease (IBD) (Ianiro et al. 2014; Cammarota et al. 2015a). The current therapeutic options for IBD have limitations with regards to cost, safety profile and the onset of drug resistance and dependence. There is therefore a need to develop novel therapeutic avenues that are both safe and effective to control the disease. Although FMT is currently not recommended to cure IBD patients in clinical practice (Cammarota et al. 2017), several studies have recently been carried out with promising results. The aim of future research is therefore to standardize protocols and develop FMT as a therapeutic option for these patients. This review summarizes data on the use of FMT for the treatment of both CDI and IBD, with special attention given to studies carried out in European countries.

2 Faecal Microbiota Transplantation for Clostridium difficile Infection

2.1 The Burden of C. difficile

CDI is the most common cause of hospital associated diarrhoea in the western world and is one of the leading causes of morbidity and mortality in hospitalized patients globally (Bagdasarian et al. 2015). CDI is highly prevalent in North America and Europe. A population-based study performed in the United States reported that there were 453,000 incidences of CDI in 2011 (Lessa et al. 2015) CDIs, 83,000 cases of first recurrences and an estimated number of deaths of 29,300 only in 2011 (Lessa et al. 2015). In Europe the extent of CDI is less clear. The burden of healthcare-associated CDIs in acute care hospitals has been estimated at 123,997 cases annually with a mortality of 3700 per year (European Surveillance of CDI 2015). A prospective study conducted in 2005 in 38 hospitals in 14 different European countries reported a mean incidence of nosocomial CDI of 2.45 per 10,000 patient-days (range 0.1–7.1) (Barbut et al. 2007). Beside this, a more recent and larger hospital-based survey performed through a network of 97 hospitals from 34 European countries, reported a higher CDI incidence of 4.1 per 10,000 patient days (Bauer et al. 2011).

Similar epidemiological data are observed in the eastern countries. A meta-analysis of 51 studies, showed similar rates of CDI in Asia compared to Europe and North America (Borren et al. 2017).

Beside this, epidemiological trends show that the incidence of CD has increased over recent decades. In the United States, reported cases of CDI doubled from 2000 to 2010 and are expected to increase further (Lessa et al. 2015). A recent retrospective cohort study that analysed more than 38 billion commercially insured patients in the United States showed that between the years of 2001 and 2012, the annual incidence of CDI and multiply recurrent CDI (mrCDI) per 1000 person-years increased by 42.7% (from 0.4408 to 0.6289 case) and 188.8% (from 0.0107 to 0.0309 case) respectively (Ma et al. 2017). However, it should be noted that these results may be biased by the selection of the only insured patients.

This raising in incidence and virulence of CD can been explained, at least in part, by inappropriate antibiotic usage, outbreaks of CDI in healthcare facilities, and the diffusion of fluoroquinolone-resistant strains belonging to the PCR-ribotype 027 (Warny et al. 2005; McDonald et al. 2005).

CDI infection is also palaces a significant economic burden on the health services. A recent analysis of health-care associated infections in the United States ranked CDI fourth in terms of attributable costs and length of hospital stay (Zimlichman et al. 2013).

The bacterium Clostridium difficile (CD) is spread via the faecal-oral route. CDI generally requires two things: the presence (endogenous infection) or acquisition (exogenous infection) of CD and an altered composition of gut microbiota. Risk factors facilitating infection are older age, hospitalization, recent use of antibiotics, long-term therapy with proton pump inhibitors and chronic kidney disease (Asha et al. 2006; Mullane et al. 2013; Stevens et al. 2011).

Once the bacterium is present in the large intestine it proliferates, taking advantage of an impaired gut microbiota. The production of toxins create its main virulence factors. Toxin A (TcdA) and B (TcdB) induce mucosal inflammation, disruption of colonic epithelium with pseudomembrane formation resulting in lower abdominal pain, fever and diarrhea. Clinical pictures of CDI are variable and range widely from mild colitis to fulminant disease with associated toxic megacolon and death.

Diagnosis of CDI is established by the presence of (1) diarrhoea (≥3 loose stools in 24 h), (2) ileus or toxic megacolon (3) confirmation of infection thought a stool test positive for CD or for A and B toxins, and/or endoscopic or histopathological picture of pseudomembranous colitis (Bagdasarian et al. 2015).

According to current guidelines (Surawicz et al. 2013; Debast et al. 2014), first line treatment of CDI includes rehydration and removing the inciting antibiotic. Following this, therapy with metronidazole, vancomycin or fidaxomycin should be considered. Unfortunately, despite administration of antibiotics, up to 60% of patients experience a recurrence (Cohen et al. 2010). A recently published study by Ma et al. (2017) has demonstrated the increasing incidence of multiply rCDI in the United States.

2.2 Faecal Microbiota Transplantation and C. difficile

In recent decades, FMT has been trialed as a treatment for rCDI and, over the years, a considerable body of evidence has emerged in support of its effectiveness. Consequently, FMT is recommended as a treatment option for rCDI in guidelines produced by the European Society for Microbiology and Infectious Disease and the American College of Gastroenterology (Surawicz et al. 2013; Debast et al. 2014). Furthermore, a recent European consensus conference on FMT was held with the aim of standardizing FMT guidance across Europe. According to the statements of the conference, FMT is recommended as treatment option for both mild and severe rCDI (Cammarota et al. 2017).

Three randomized controlled trials (RCTs) have been performed, to date, with the aim to assess the effectiveness of FMT compared to conventional therapy, two of the RCT’s were conducted in European countries and one in Canada (Table 1). The first RCT was conducted in the Netherlands by van Nood et al. (2013). The group randomised 43 patients with rCDI to receive one of the following therapies: (1) vancomycin (500 mg orally four times per day for 4 days), followed by bowel lavage and subsequent FMT through a nasoduodenal tube; (2) vancomycin regimen with bowel lavage; (3) vancomycin regimen alone. The study was interrupted after the interim analysis. Among the first group 15/16 patients (94.1%) had a resolution of CDI, 13 patients after one infusion and 2 patients after multiple infusions. In contrast, resolution of CDI occurred in 4/13 patients (31%) receiving vancomycin alone and in 3/13 patients (23%) receiving vancomycin with bowel lavage (p < 0.001). There were no differences in adverse events among the three study groups.
Table 1

Characteristics of main studies assessing FMT for C. difficile infection in European and extra European countries

Author

Study level

Single/multiple center study

Area

Sample

Age (mean or median)

Route of delivery

Frozen/fresh material

Fecal dosage (g/ml)

Follow-up (weeks)

Overall resolution rate after minimum follow-up

Studies from European countries

MacConnachie et al. (2009)

RCS

Single

UK

15

81.5 (68–95)

Nasogastric tube

Fresh

30 g/150 ml

16

11/15

Garborg et al. (2010)

RCS

Single

Norway

40

75 (53–94)

Gastroscopy and colonoscopy

Fresh

50–100 g/250 ml

11

33/40

Polak et al. (2011)

PCS

Single

Czech Republic

15

82 (NR)

Nasojejunal tube

Fresh

20–30/NR

12

13/15

Mattila et al. (2012)

RCS

Single

Finland

70

73 (22–90)

Colonoscopy

Fresh

20–30 ml feces/100–200 ml water

12

66/70

Jorup-Ronstrom et al. (2012)

RCS

Single

Sweden

32

75 (27–94)

Colonoscopy and enema

Fresh

NR/30 ml

104

22/32

van Nood et al. (2013)

RCT

Single

Netherlands

16

73 (60–86)

Nasojejunal tube

Fresh

≥150/500 ml

10

15/16

Cammarota et al. (2015c)

RCT

Single

Italy

20

73 (29–89)

Colonoscopy

Fresh

152 ± 32 g/500 ml

10

18/20

Satokari et al. (2015)

RCS

Single

Finland

49

56.8 (20–88)

Colonoscopy or enema

Fresh and frozen

30 g/150 mL

12

47/49

Hagel et al. (2016)

RCS

Multiple

Germany

92

75 (59–81)

Gastroscopy, duodenal route, colonoscopy, capsule

Fresh, frozen (no separated efficacy data available)

NR

20

79/92

Ianiro et al. (2017)

PCS

Single

Italy

64

74 (29–94)

Colonoscopy

Fresh, frozen

120–180 g for fresh feces, 50 g for frozen feces/500 ml

8

62/64

Studies from extra European countries

Hamilton et al. (2012)

PCS

Single

USA

43

58 (39–68)

Colonoscopy

Frozen

50 g/250 cc

8

41/43

Kassam et al. (2012)

RCS

Single

Canada

27

69.4 (26–87)

Enema

Fresh

150 g/300 cc

61

24/26

Brandt et al. (2012)

RCS

Single

USA

77

65 (22–87)

Colonoscopy

Fresh

300–700 mL

17

66/77

Kelly et al. (2014)

RCS

Multiple

USA

80

50 (6–88)

Upper and lower route (no data)

NR

NR

12

70/80

Khan et al. (2014)

RCS

Single

USA

20

66 (50–86)

Colonoscopy

Fresh

50 g/200 cc

24

20/20

Lee et al. (2014)

RCS

Single

Canada

94

72 (24–95)

Enema

Fresh

150 g/300 ml

24–96

81/94

Youngster et al. (2014b)

RCT

Single

USA

20

54.5 ± 24.2

Nasogastric tube and colonoscopy

Frozen

NR

8

18/20

Dutta et al. (2014)

PCS

Single

USA

27

64.5 (18–89)

Enteroscopy and colonoscopy

Fresh

25–30 g/180 mL 20.6 (enteroscopy) or 270 mL (colonoscopy)

80

27/27

Zainah et al. (2014)

RCS

Single

USA

14

73.4 (52–92)

Nasogastric tube and colonoscopy

Fresh

30–50 g stool. Total: 20–180 mL (NGT), 300–500 mL (colonoscopy)

14

11/14

Costello et al. (2015)

PCS

Single

Australia

20

64 (31–90)

Colonoscopy and push enteroscopy

Frozen

50 g/150 ml

12

20/20

Hirsch et al. (2015)

RCS

Single

USA

19

61 (26–92)

Capsule

Frozen

18–27 g/350 ml/8–12 capsules

12

17/19

Lee et al. (2016)

RCT

Multiple

Canada

178

72 (56–88)

Enema

Fresh, frozen

100 g/300 ml

13

171/178

Mandalia et al. (2016)

RCS

Single

USA

95

NR

Upper GI route, colonoscopy

NR

NR

12

93/95

Meighani et al. (2016)

RCS

Single

USA

201

67 (49–85)

Nasogastric, enema, colonoscopy

NR

NR

12

176/201

Millan et al. (2016)

PCS

Single

Canada

20

68 (35–85)

Colonoscopy

Fresh, frozen (no separated efficacy data available)

NR

12 weeks

20/20

Tauxe et al. (2016)

RCS

Single

USA

28

77 (65–96)

Colonoscopy, nasogastric, nasoduodenal and nasojejunal tube, PEG

NR

NR

8–96 (mean 36)

27/28

Youngster et al. (2016)

PCS

Single

USA

180

64 (7–95)

Capsule

Frozen

48 g/30 capsules

8–24

168/180

Hota et al. (2017)

RCT

Single

Canada

30

75.7 ± 14.5

Enema

Fresh

50 g/500 ml

17

7/12

Staley et al. (2017)

RCS

Single

USA

49

62.3 ± 17.1

Capsules

Freeze-dried

~1 × 1011 cells/capsule

8

43/49

RCT randomized controlled trial, PCS prospective case series, RCS retrospective case series, NR not reported

In a second open-label RCT conducted in Italy, Cammarota et al. (2015c) randomised 39 patients to (1) FMT (short regimen of vancomycin, 125 mg four times a day for 3 days, followed by one or more infusions of feces via colonoscopy) or (2) vancomycin (vancomycin 125 mg four times daily for 10 days, followed by 125–500 mg/day every 2–3 days for at least 3 weeks). As with Van Nood et al. this study was stopped at 1-year after interim analysis. The authors reported CDI resolution in 90% (18/20) of patients in the FMT arm compared to 26% (5/9) of patients in the vancomycin arm (p < 0.0001). There were no serious adverse events reported.

These RCTs show that FMT is safe, well tolerated and overperforms conventional antibiotic therapy. However, there are limitations to these studies that should be considered. These include small sample sizes and the early interruption of both the trials after interim analysis. In this regard, it is well known that RCTs stopped early for benefit can overestimate the magnitude of the treatment effect and underestimate the incidence of adverse events (Bassler et al. 2010).

The third RCT was conducted on a sample of 30 patients with rCDI that were randomly assigned in a 1:1 ratio to (1) a 14 day course of oral vancomycin followed by an FMT enema or (2) a 6-week oral vancomycin therapy. Resolution of infection within 120 days was reported in 7/16 (43.8%) patients receiving FMT and 7/12 (58.3%) receiving vancomycin, without significant differences in adverse events. The study was interrupted due to a futility analysis. In contrast to Van Nood et al. and Cammarota et al., a single FMT delivered by enema was not more efficacious than oral vancomycin as a treatment for rCDI (Hota et al. 2017). Weakness of this study include a small sample size and early interruption because of a futility analysis. In addition, the protocol did not include retreatment in the case of failure after first infusion, and this represents a limitation in assessing the overall effectiveness of FMT.

Finally, one of the most important issues to be raised is that all three studies evaluated FMT through three different routes of delivery (nasojejunal tube, colonoscopy and enema). This makes the studies challenging to compare and may explain, at least in part, the variability of results, since the route of administration may affect the treatment outcome.

To assimilate these data, a recent meta-analysis of 18 observational studies assessing FMT for CDI on a total sample of 611 patients, reported a primary cure rate of 91.2% (95% CI 86.7–94.8%), and an overall recurrence rate of 5.5% (95% CI 2.2–10.3%). Interestingly, a sub-analysis comparing the efficacy of lower vs. upper gastrointestinal delivery showed a greater primary cure rate for lower (93.2–95% CI, 88.7–96.7%) compared to upper gastrointestinal delivery (81.8–95% CI, 71.9–90.0%) (p = 0.015) (Li et al. 2016).

In line with this, a long-term retrospective multicenter observational study by the ‘German Clinical Microbiome Study Group’ (GCMSG), has been performed on a large sample of 133 rCDI with the aim to assess effectiveness of FMT performed trough different routes of delivery in Germany (Hagel et al. 2016). Patients receiving FMT by application into the rectum/colon/terminal ileum experienced a primary response of 89.6% on day 30 (n = 43/48) and 83.3% (n = 25/30) on day 90. For patients receiving FMT by application through gastroscopy, nasojejunal tube or capsule, the cure rates were 81% (n = 60/74) and 76.5% (n = 49/64) respectively. Despite inherent limitation deriving from the retrospective design, this study confirmed a trend towards higher response rates with FMT through the lower GI administrations.

Between lower routes, colonoscopy appears to be the most effective route of administration. Hamilton et al. (2012) reported a prospective analysis of 43 consecutive patients with rCDI, treated with frozen FMT by colonoscopy, showing an overall resolution rate of 95% (41/43 patients) after one or more infusions. Interesting, 30% of patients had underlying inflammatory bowel disease and FMT was equally effective in both groups.

A similar single-center prospective study performed by Cammarota et al. on a sample of 64 patients with rCDI reported that FMT delivered by colonoscopy was effective in 97% (62/64) of patients after one or more infusion. The authors reported that only 30% of patients were cured after a single infusion, which highlights the importance of repeating infusions in the case of failure after first treatment. Multivariate analysis revealed that severe CDI (OR 24.66; 95% CI 4.44–242.08; p 0.001) and inadequate bowel preparation (OR 11.53; 95% CI 1.71–115.51; p 0.019) were found to be independent predictors of failure after single infusion (Ianiro et al. 2017).

Moreover, a retrospective analysis by Khan et al. (2014) reported a cure rate of 100% on a group of 20 patients with community and hospital-acquired relapsing and refractory CDI treated with FMT administered via colonoscopy. Finally, a retrospective analysis showed that the frequency of surgery in patients with CDI decreased after implementing FMT through colonoscopy for treatment of severe CDI (Cammarota et al. 2015b). Taken together, these studies support colonoscopy as an effective route of delivery for FMT without reporting any adverse events secondary to endoscopic technique or transplantation itself.

FMT can also be administered by enema, although this route appears to be inferior when compared to colonoscopy, especially if FMT is administered as a single infusion.

A retrospective study assessing 94 patients with recurrent or refractory CDI treated with FMT via enema reported that the primary resolution after a single infusion was 47.9% (45/94 patients) and 86.2% (81/94 patients) after multiple infusions (Lee et al. 2014). Similarly, another retrospective study of 26 cases of refractory CDI showed that 81% of patients (21/26) cleared the infection after first infusion and 92% (24/26) after multiple infusions (Kassam et al. 2012).

Despite the literature suggesting that lower GI administration may be superior, upper GI delivery of FMT is common worldwide. In a retrospective analysis of 40 patients with rCDI mainly treated with FMT administered by gastroscopy, by Garborg et al. (2010) reported a resolution rate of 82.5% (33/40 patients) within 80 days after the procedure. FMT by nasoduodenal tube has been tested in the previously cited RCT by van Nood et al. (2013), showing a resolution rate of rCDI in 94.1% of cases (16/17 patients). Furthermore, a randomized, open-label, 20 patient pilot study in patients with relapsing/refractory CDI, reported primary resolution of 60% (6/10 patients) by nasoduodenal tube and of 80% (8/10 patients) by colonoscopy after a single infusion, with an overall resolution rate after retreatment of 80% and 100%, respectively (Youngster et al. 2014b).

These data support the effectiveness of FMT. The observed variability of efficacy may be due to, at least in part, the methodical differences between studies (Table 1). Despite promising results, these routes of administration are still burdened by procedure-related risks and their invasive nature.

One innovative and non-invasive method of administration is through orally delivered FMT capsules. A retrospective analysis by Hirsch et al. (2015) assessed effectiveness of FMT by capsule on a sample of 19 patients with rCDI. Thirteen patients (68%) had resolution after a single instance of FMT treatment. Of six patients that did not respond to the initial treatment, four achieved cure after a subsequent infusion, resulting in a cumulative resolution rate of 89%. These results are similar to those reported from invasive transplantation procedures.

Similarly, an open-label, single-arm preliminary feasibility study (n = 20) was performed in order to evaluate the effectiveness and safety of frozen FMT capsules for the treatment of relapsing or rCDI. Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at −80 °C. Patients received 15 capsules on two consecutive days, resulting in a overall 90% (95% CI, 68–98%) rate of clinical resolution after a 6 months follow-up, with no reported serious adverse events (Youngster et al. 2016a).

Similar results have been reached with encapsulated FMT using a freeze-dried preparation of microbiota resistant to a wide range of temperatures. Staley et al. (2017) tested this new delivery system on a group of 49 patients with rCDI showing a resolution rate of 88% (43/49 patients) after a 2 month follow-up. These lyophilized preparations confer additional advantages over the standard encapsulated FMT. Namely, the preservation of viability and diversity of the taxonomic spectrum of microbiota and physicochemical properties that enable consistent encapsulation.

Taken collectively, these studies suggest that capsule delivered FMT is a non-invasive, safe and effective. However, larger prospective studies are needed to confirm these data.

A further point of consideration is how donations are prepared. Most of FMT’s are performed with fresh stool, but there are logistical challenges associated with this method. On the contrary, frozen preparations offer several advantages, such as the immediate availability of FMT, the possibility of administering FMT at centers that cannot collect and process samples, a reduction in number and frequency of donor screenings and reductions in cost.

In previous years, some studies supported the use of frozen FMT for rCDI. However, no study included a direct comparison of frozen vs. fresh transplantation (Hamilton et al. 2012; Youngster et al. 2014a; Satokari et al. 2015) (Table 1).

To solve this problem, a recent RCT by Lee et al. (2016) was conducted with the aim of comparing frozen vs. fresh FMT. A large cohort of 232 adults with recurrent or refractory CDI was randomly assigned to receive frozen (n = 114) or fresh (n = 118) FMT by enema. The proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group by per-protocol analysis, (difference, −1.6% [95% CI, −10.5% to ∞]; p = 0.01 for non-inferiority). In the intention-to-treat analysis, the clinical resolution rate was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, −5.2% to ∞]; P < 0.001 for non-inferiority). There was no statistically significant differences in adverse events. This study confirms the non-inferiority of frozen as opposite to fresh FMT in terms of efficacy and safety.

In addition to these data, a recent meta-analysis of six studies showed that frozen FMT was as effective as fresh FMT, both after single infusion (65.0–95% CI 57.0%, 73.0% vs. 65.0–95% CI 57.0%, 73.0%, p = 0.962) and after multiple infusions (95.0–95% CI 91.0%, 99.0% vs. 95.0–95% CI 92.0%, 99.0%, p = 0.880) (Tang et al. 2017).

Based on these data, it appears that frozen and fresh FMT are equally effective and when considering the potential logistical and economic advantages, frozen FMT appears to be preferable.

In conclusion, faecal microbiota transplantation is a highly efficacious treatment for rCDI and is increasingly being used in Europe in accordance with recommendations from international practice guidelines (Surawicz et al. 2013; Debast et al. 2014).

Although a deal of evidence supports its effectiveness and safety, current FMT protocols differ in several aspects, including route of delivery, timing and number of infusions, dosage and methods of preparation (fresh or frozen) (Table 1). To date, no clear evidence supports the superiority of any individual protocol for the treatment of rCDI.

Latest literature suggests that lower administration via colonoscopy outperforms upper delivery routes. However, the recent introduction of FMT by oral capsules have proven to be effective and non-invasive. Capsules may expand the access to FMT in the future. As with routes of delivery, the method of preparation should be considered. Based on available evidence, the efficacy of frozen and fresh FMT is equivocal. However, in consideration of the potential logistical and economic advantages, frozen FMT is preferable.

Despite a wide availability of data from prospective and retrospective studies, future RCTs should compare the effectiveness of different routes of delivery and fresh vs. frozen FMT.

Moreover, it must be pointed out that many of the studies performed in the field of FMT suffer from methodological gaps. A systematic review of 85 studies assessing FMT showed that key components of FMT interventional studies, which are necessary to replicate and understand efficacy and safety results, are often poorly reported (Bafeta et al. 2017). For example, 47% of studies did not report eligibility criteria for donors, 96% omitted materials and methods for the collection of stools, 76% did not clearly indicate methods used for the preparation and storage of stools, and 67% of studies did not specify the weight of stools used. These methodological gaps affect the interpretation and reproducibility of results.

Notwithstanding the above, a recent consensus conference standardised the modalities of FMT across European countries (Cammarota et al. 2017). This consensus report provides guidance on technical, regulatory, administrative and laboratory requirements for FMT. Nevertheless, future research must focus on the standardization of donor screening, processing and delivery techniques. This, coupled with strict monitoring by regulatory authorities, will be critical in improving efficacy and safety of FMT in Europe and beyond.

3 Faecal Microbiota Transplantation for Inflammatory Bowel Disease

The first reported use of FMT as a treatment intervention for inflammatory bowel disease (IBD) was published in 1989 by Bennet and Brinkman (1989). Bennet, who was both a patient and a clinician, reported clinical resolution of symptoms after a week of self-administered enemas. Despite these encouraging results, research into FMT and IBD was sparse for over two decades, with only scattered case reports and case series being published in the literature (Borody et al. 1989, 2001, 2003, 2011a, b). These studies were limited by small numbers of patients, vague methods of FMT preparation and poorly defined and inconsistent outcomes. Indeed, a systematic review of the available evidence published in 2012 consisted of only nine retrospective reports, which was deemed by the authors to be insufficient to perform a meta-analysis (Anderson et al. 2012). However, the landmark paper published by Van Nood et al. (2013) reporting FMT’s efficacy in recurrent CDI galvanised the scientific and medical community to evaluate FMT’s therapeutic potential in several other diseases and disorders associated with imbalances of bacteria within the intestinal tract, such as IBD, where the prospect of modulating the microbiota is supported by logical scientific reasoning and is conceptually appealing for patients seeking alternatives to immunomodulatory and immunosuppressive drugs.

There is now a large body of controlled and non-controlled evidence on the role of FMT in the IBD subtypes of Crohn’s disease (CD) and Ulcerative Colitis (UC) and pouchitis. In comparison to the available data for CD and UC, the evidence for pouchitis is meagre and consists of two case reports (Fang et al. 2016; Schmid et al. 2017) that describe conflicting outcomes and two uncontrolled cohort studies (Landy et al. 2015; Stallmach et al. 2016) Each of the cohort studies have differing methodologies, endpoints and outcomes, which make the results challenging to integrate into the pouchitis treatment paradigm. Notably, in the only study that allowed for multiple FMT infusions, five out of five patients achieved a clinical response and four out of five achieved clinical remission (Stallmach et al. 2016). This suggests that more frequent dosing may be required to achieve the desired endpoint in pouchitis.

In Crohn’s disease (CD), the quality of the available evidence is low, with the available literature consisting of case reports (Borody et al. 1989; Swaminath 2014; Gordon and Harbord 2014; Kao et al. 2014; Bak et al. 2017), or small cohort studies (Kahn et al. 2014; Cui et al. 2015a; Suskind et al. 2015; Vermeire et al. 2016; Wei et al. 2015; Vaughn et al. 2016; Goyal et al. 2016). Nevertheless, a recent systematic review and meta-analysis conducted by Paramsothy et al. (2017b) reported that 52% of the pooled proportion of CD patients achieved clinical remission during follow-up, which is in keeping with results published in a previous meta-analysis by Colman and Rubin (2014). Taken together, these results suggest that FMT could benefit patients suffering from CD. However, limited sample sizes and significant differences in methodology between studies may have inflated the pooled effect size in the meta-analysis and therefore these results should be interpreted with caution.

The strongest evidence for FMT in IBD comes from four randomised controlled trials (RCTs) and a significant body of controlled and non-controlled cohort studies in patients (Table 2). The first cohort studies took place in Austria led by Angelberger et al. (2013) and Kump et al. (2013). The only European RCT was conducted in the Netherlands by Rossen et al. (2015), who randomised 50 adult patients suffering from active UC to undergo FMT from either a healthy donor or a patient’s own stool (autologous FMT) as a placebo. The primary endpoint was clinical remission (simple clinical colitis activity index scores ≤2) combined with ≥1-point decrease in the Mayo endoscopic score at week 12. FMT was administered once through nasoduodenal tube at baseline and week 3. The authors reported that there was no statistically significant difference in clinical and endoscopic remission between the treatment arm and the autologous placebo arm of the study.
Table 2

Characteristics of main studies assessing FMT for IBD

Study type

Author

FMT route

Sample

Frequency

Control/comparison

Frozen/vs. fresh

Definition of clinical remission or primary end point (RCT)

Clinical remission

Definition of clinical response or primary end point (RCT)

Clinical response

Cohort

Kunde et al. (2013)

Enema

10 (paediatric)

Once a day for 5 days

N/A

Fresh

PUCAI <10

3/9 (33%) at 1 week

PUCAI decrease of >15

7/9 (78%) at 1 week

Cohort

Cui et al. (2015b)

Endoscope to distal duodenum

15

1–2

N/A

Frozen

Montreal score 0

4/14 (29%)

Montreal improvement ≥1 and discontinuation of steroids

8/14 (57%)

Cohort

Kump et al. (2015)

Colonoscopy

17 (10 controls)

Once every 2 weeks for 5 weeks

Triple antibiotic therapy for 10 days

NR

Mayo ≤2

4/17 (24%)

Mayo drop ≥3

10/17 (59%)

Cohort

Wei et al. (2015)

Colonoscopy

11

1

N/A

Fresh

IBDQ >170, Mayo <2

6/11 (55%)

IBDQ increase >16, decrease in Mayo by >1

11/11 (100%)

Cohort

Karakan et al. (2016)

Colonoscopy

14

1–6

N/A

NR

NR

6/14 (43%)

NR

11/14 (78.5%)

Cohort

Zhang et al. (2016)

Endoscope

19

1

N/A

Fresh

Mayo ≤2 with no individual sub score ≥1

2/19 (11%)

Mayo drop ≥3 or ≥30% along with drop in bleeding sub score ≥1 or bleeding subscore ≤1

11/19 (58%)

Cohort

Wei et al. (2016)

Colonoscopy

20

1

FMT + oral pectin (5 days)

Fresh

Mayo ≤2

3/10 (33%) FMT, 4/10 FMT + Pectin 2

Reduction in the total Mayo score of >30% from baseline, a 1-point improvement in tarry stools, or an increase of >16 points in IBDQ criteria at week 12

7/10 (70%) FMT, 6/10 FMT + Pectin

Cohort

Ishikawa et al. (2017)

Colonoscopy

17

Single

19 FMT + triple antibiotic therapy

Fresh

Reduction in CAI ≥3 and CAI <10

14/19 (74%)

CAI < +3

6/19 (32%)

Cohort

Jacob et al. (2016)

Colonoscopy

20

12 (bi weekly for 6 weeks)

N/A

Frozen

Mayo ≤2 with no individual sub score >1

3/20 (15%)

Mayo drop ≥3 and a bleeding sub score of ≤1

7/20 (35%)

Cohort

Nishida et al. (2017)

Colonoscopy

41

1

N/A

Fresh

Mayo ≤2 with no individual sub score of 1 point or more

0/41 (0%)

Mayo </= 2

11/41 (27%)

Reduction in Mayo ≥3 or reduction of Mayo ≥2 decrease in recal bleeding subscore of 1

RCT

Rossen et al. (2015)

Nasoduodenal

23 (25 placebo)

One at baseline one at week 3

Autologous FMT

Fresh

Clinical remission and endoscopic improvement SCCAI ≤2 in combination with ≥1 point drop in combined Mayo endoscopic score

7/23 FMT (30%) vs. 5/25 (20%) placebo

≥1.5 point reduction in SCCAI

11/23 (48%) FMT vs. 13/25 (52%) placebo

RCT

Moayyedi et al. (2015)

Enema

 

Six enemas over 6 weeks

Saline

Frozen

Clinical and endoscopic remission Mayo <3 with endoscopic Mayo 0

9/38 (24%) FMT vs. 2/37 (5%) placebo

≥3 point reduction in Mayo score

15/38 FMT (39%) vs. 9/37 (24%)

RCT

Paramsothy et al. (2017a)

Colonscopy at baseline followed by enemas

41 (40 placebo)

Colonscopy at baseline followed by self administered enemas for 8 weeks (n = 40)

Discoloured and odoured water

Frozen

Total Mayo score ≤2, with all subscores ≤1, and ≥1 point reduction from baseline in endoscopy subscore

11/41 (27%) FMT vs. 3/40 (8%) placebo

Steroid- free drop in combined Mayo subscore for bleeding and stool frequency of ≥3

22/41 (54%)

FMT vs. 9/40 (23%)Placebo

RCT

Costello et al. (2017b)

Colonscopy at baseline followed by enemas

38 (35 placebo)

Colonscopy at baseline followed by one enema a week for 2 weeks

Autologous

Frozen

Total Mayo ≤2 with subscores of ≤1 for rectal bleeding, stool frequency and endoscopic appearance; and a ≥ 1 point reduction in endoscopic subscore

11/41 (27%) vs. 3/40 (8%) P = 0.02

≥3 point reduction in Mayo score or ≥50% reduction from baseline in combined rectal bleeding plus stool frequency sub-scores

22/41 (54%) vs. 9/40 (23%) P < 0.01

RCT randomized controlled trial, PCS prospective case series, RCS retrospective case series, NR not reported

Moayyedi et al. (2015) randomised 75 adult patients suffering from active UC to receive weekly FMT or water enemas for 6 weeks and evaluated responses at week 7. The primary endpoint of the study was clinical remission, defined as Mayo Score of ≤2 with an endoscopic Mayo score of 0 at week 7. In contrast to Rossen et al. the faecal microbiota was frozen before use. FMT was found to induce remission in a statistically greater percentage of patients than placebo (24% vs. 5%; p = 0.03). Interestingly, the authors reported that stool from one donor (donor B) induced remission in 39% of patients, which was remarkably higher than that of the other donors (10%). This suggests that donor characteristics may influence the efficacy of FMT in UC, which gives rise to the alluring prospect of matching donors to recipients.

In the largest RCT to date, Paramsothy et al. (2017a) allocated 81 adult patients with active UC to receive to FMT or isotonic saline with added brown food colourant and odorant placebo. Study participants initially received a colonoscopic infusion as baseline followed by self-administered enemas five times per week for 8 week (a total of 40 FMTs). The primary end point of steroid-free clinical remission together with endoscopic remission (total Mayo score ≤2 points) was met in 11 of 41 (27%) of patients receiving FMT vs. 3 of 40 (8%) of patients receiving placebo (p = 0.02). In contrast to the previous two RCTs, each FMT was prepared using a mixture of faecal microbiota from three to seven unrelated donors. The authors noted that this approach was implemented in an attempt to maximise the microbial diversity of each FMT and the validity of this approach was confirmed using 16S rRNA phylogenetic analyses. However, in implementing this approach, practitioners increase the risk of infection transmission between donors and patients. Furthermore, combining donor samples masks any donor patient compatibility effect, and increases the complexity of tracking microbial colonisation post FMT.

Costello et al. (2017b) and colleagues allocated 73 adult patients with active UC to receive FMT prepared from a mixture of faecal microbiota from three to four healthy donors or autologous FMT (placebo). FMT was administered by colonoscopy at baseline followed by two enemas by day 7. The primary endpoint was steroid-free remission of UC as defined by a total Mayo score of ≤2 with an endoscopic Mayo score of ≤1 at week 8. In the intention to treat (ITT) analysis, 12/38 (32%) patients who received pooled donor FMT achieved the primary end point of steroid-free remission, as compared to 3/35 (9%) who received autologous FMT (p = 0.02). In contrast to the previous studies, the faecal microbiota was prepared in anaerobic conditions. Further research is required to establish if this is the optimal method of preparation for FMT in IBD. However, as the majority of the human gut microbiota are known to be strict anaerobes that die in the presence of oxygen, anaerobic methods of production may positivity influence bacterial viability (Chu et al. 2017). Seminal work published by Sokol et al. demonstrated that administering the anti-inflammatory commensal bacterium Faecalibacterium prausnitzii attenuates colitis in animal models (Sokol et al. 2008). Faecalibacterium prausnitzii is known to be highly oxygen sensitive. Therefore, it can be hypothesised that maintaining the viability of anaerobic bacteria during sample preparation may positivity influence the efficacy of FMT in IBD.

To integrate these data, Costello et al. (2017a) undertook a systematic review and meta-analysis of the four published RCT’s. The authors reported that overall, remission was achieved in 39/140 patients (28%) in donor FMT recipients compared with 13/137 (9%) in placebo groups (OR: 3.67 95% CI: 1.82–7.39; P < 0.01). Interestingly, despite fundamental differences in the design of each trial, a robust microbial trend appears to emerge in responders. All authors report that faecal microbiota rich in butyrate-producing species from Clostridium cluster XIVa is associated with clinical remission.

Paramsothy et al. (2017b) performed a comprehensive systematic review assessing the efficacy and safety of FMT in IBD. The authors found that overall, FMT is a safe intervention in the short term, with the majority of adverse events being mild self-limiting gastrointestinal complaints. However, serious adverse events such as disease flares and C. difficile infection requiring colectomy have been reported (Cui et al. 2015a, b; Scaldaferri et al. 2015; Costello et al. 2017a, b). A case of aspiration pneumonia in a patient that received FMT through the nasogastric route was reported in one study (Vermeire et al. 2016). Mortality due to toxic megacolon and sepsis has also been reported (Grewal et al. 2016).

It is clear that FMT is effective at inducing remission in patients with active UC with few serious adverse events. There is however, currently insufficient data on long-term risks and efficacy. Each trial has several methodical differences that make the results challenging to integrate into clinical practice. Further research is required to optimise and standardised protocols. Furthermore, as FMT’s mechanism of action in IBD has yet to be elucidated, it is incumbent on researchers to investigate the mechanistic underpinnings of this procedure through microbial analysis of donors and patients. The evidence for FMT in CD and pouchitis is less convincing and further research through RCTs is required to draw definitive conclusions. As of July 2017, there are active clinical trials of FMT in IBD ongoing in Finland, Czech Republic, France, Italy, Poland and Spain. These trials will play an integral role in shaping clinical guidelines and policy in Europe for this highly promising yet relatively unrefined medical treatment.

Notes

Conflict-of-Interest Statement

James McIlroy has received personal fees from EnteroBiotix during the conduct of this manuscript.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Marcello Maida
    • 1
  • James Mcilroy
    • 2
  • Gianluca Ianiro
    • 3
  • Giovanni Cammarota
    • 3
  1. 1.Section of GastroenterologyS.Elia – Raimondi HospitalCaltanissettaItaly
  2. 2.School of Medicine, Medical Sciences and NutritionUniversity of AberdeenAberdeenUK
  3. 3.Gastroenterological AreaFondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro CuoreRomeItaly

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