Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review

Table 1 Quality assessment of selected case series according to the Chambers criteria

Indication for FMT	Author	Year	Publication type (J, CA)	1	2	3	4	5	6	7	8	Case series quality rating
CDI	Aas	2003	J	+	+	+	+	+	-	-	-	Poor
	Arkkila	2010	J	-	+	+	+	+	+	-	-	Poor
	Aroniadis	2013	J	+	-	+	+	+	-	-	-	Poor
	Bansal	2013	J	-	+	-	-	?	-	-	-	Poor
	Bobo	2013	CA	+	-	+	+	+	+	-	-	Poor
	Borody	2013	CA	-	+	+	-	?	-	-	-	Poor
	Bowden	1981	J	-	-	+	+	+	-	-	-	Poor
	Brandt	2012	J	+	+	+	+	+	-	-	-	Poor
	Byrne	2008	CA	+	+	-	-	+	+	-	-	Poor
	Eisman	1958	J	-	-	-	-	-	-	-	-	Poor
	Elopre	2013	J	-	-	-	-	+	-	-	-	Poor
	Fischer	2013	CA	-	-	+	+	+	-	-	+	Poor
	Garborg	2010	J	+	+	-	+	+	-	-	-	Poor
	Hamilton	2012	J	+	+	+	+	+	+	+	+	Good
	Ihunnah	2013	CA	-	-	+	+	-	-	-	-	Poor
	Jorup-Rönström	2012	J	+	+	+	+	+	-	-	-	Poor
	Kassam	2010	CA	-	+	+	+	+	+	+	-	Satisfactory
	Kelly	2012	J	-	+	+	+	+	-	-	-	Poor
	Khanna	2013	CA	+	+	+	-	+	+	-	-	Poor
	Louie	2013	CA	+	-	-	-	-	-	-	-	Poor
	MacConnachie	2009	J	+	+	-	-	+	-	-	-	Poor
	Mattila	2012	J	+	+	+	+	+	-	-	+	Poor
	Mellow	2010	J	-	+	+	+	+	-	-	-	Poor
	Miller	2010	J	-	+	-	-	+	-	-	-	Poor
	Neelakanta	2011	J	-	-	-	+	+	-	-	-	Poor
	Newton	2013	CA	-	-	-	-	-	-	+	-	Poor
	Potakamuri	2013	CA	-	+	+	-	?	-	-	-	Poor
	Rohlke	2010	J	-	+	-	+	+	-	-	-	Poor
	Rubin	2013	J	+	+	+	+	+	-	-	-	Poor
	Shiekh Sroujieh	2012	CA	+	+	+	+	+	+	-	-	Poor
	Silverman	2010	J	-	+	-	-	+	-	-	-	Poor
	Yoon	2010	J	+	+	+	+	+	-	-	-	Poor
	Youngster	2013	CA	+	+	-	+	+	+	-	-	Poor
IBD	Angelberger	2012	J	-	+	-	+	+	+	-	-	Poor
	Borody	2012	CA	-	+	+	+2	+2	-	-	-	Poor
	Greenberg	2013	CA	-	+	+	-1	-1	-	-	+	Poor
	Kump	2013	CA	-	+	-	+	+	+	-	-	Poor
	Kump	2013	J	+	+	+	+	+	+	-	+	Poor
	Kunde	2013	J	+	+	+	+	+	+	-	+/-	Poor
	Vermeire	2012	CA	-	+	+	+	+	+	-	-	Poor
IBS	Pinn	2013	CA	-	-	+	-	+	-	-	-	Poor
Pouchitis	Landy	2013	CA	+	-	+	+	+	+	-	-	Poor
Constipation	Borody	2001	J	-	-	-	-	+	+	-	-	Poor

¹Sixteen out of 21 treated patients were successfully contacted for FU;

²62 patients with FU results were included. Chambers criteria: (1) were selection/eligibility criteria adequately reported? (2) was the selected population representative of that seen in normal practice? (3) was an appropriate measure of variability reported? (4) was loss to follow-up reported or explained? (5) were at least 90% of those included at baseline followed up? (6) were patients recruited prospectively? (7) were patients recruited consecutively? and (8) did the study report relevant prognostic factors? J: Journal article; CA: Conference abstract. ?: Unknown; CDI: Clostridium difficile-infection; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome.

Table 2 Methodological quality of included randomised trials

Ref.	Random sequence generation	Allocation concealment	Blinding	Incomplete outcome data	Selective reporting
Vrieze et al[10]	Low1	Unclear2	Low3	Low4	Low
van Nood et al[18]	Low1	Unclear2	High3	Low	Low

¹Automated biased coin minimization, computer generated randomisation not in the paper but verified by the first author;

²Not described; rated as unclear for this item;

³Patients were randomised to either allogenic or autologous feces a, open label design;

⁴All patients completed the study; two subjects were excluded from analyses because of antibiotic use during the trial unrelated to the microbial infusion, all except one patient (due to a clinically driven protocol deviation) were taken into the intention to treat analyses.

Table 3 Treatment information on fecal microbiota transplantation, summarised for all studies

Indication	First author	Year	Pre-treatment with bowel lavage? (Y/N)	Route of administration1	Number of transplantations (n)	Amount of fresh stool per treatment (mL/g/tablespoons)	Suspension infused(cc or mL)	Donor2	ae (n)	Withdrawal due to ae (n)	Ae potentially associated with fmt3 (n)	Sae (n)
CDI	Aas	2003	NM	U	1	30 g	NM	G and O	0	0	0	24
	Arkkila	2010	Y	C	1-2	20-30 mL	NM	G or H? and O	NM	NM	0	14
	Aroniadis	2013	NM	NM	1-2	NM	NM	NM	NM	NM	0	14
	Bansal	2013	NM	U and C	NM	NM	NM	G or H? and O	NM	NM	NM	NM
	Bobo	2013	NM	U and Ce	1-2	NM	NM	NM	NM	NM	NM	NM
	Borody	2013	NM	NM	1-42	NM	NM	NM	0	0	0	0
	Bowden	1981	N	Ce and U	1	NM	NM	H and O	0	0	0	34
	Brandt	2012	NM	C	1	NM	300-700 cc infused	G and H and O	0	0	0	0
	Byrne	2008	N	Ce	1-3	300-500 g	NM	G and H and O	4	0	0	0
	Eisman	1958	N	Ce	4	NM	NM	O	0	0	0	0
	Elopre	2013	NM	U	1	NM	NM	G	0	0	0	0
	Fischer	2013	Y	C	1-2	NM	NM	O	0	0	0	0
	Garborg	2010	N	U or C	1	50-100 g	NM	G and H and O	0	0	0	54
	Hamilton	2012	Y	C	1-2	50 g	NM	G and H and O	155	0	0	0
	Ihunnah	2013	NM	NM	1-2	NM	NM	NM	5	NM	0	24 , 86
	Jorup-Rönström	2012	NM	Ce	1-3	30 cc suspension	30 cc suspension	O	0	0	0	0
	Kassam	2010	N	Ce	1-2	NM	NM	NM	0	0	0	0
	Kelly	2012	Y	C	1	6-8 tablespoons	NM	R	0	0	0	0
	Khanna	2013	NM	C	1	50 g	NM	NM	0	0	0	0
	Louie	2013	Y	U	24-34 caps	50 g	NM	R	NM	NM	NM	NM
	MacConnachie	2009	N	U	1	30 g	NM	O	0	0	0	NM
	Mattila	2012	Y	C	1	20-30 mL	100 mL suspension	G and H and O	0	0	0	144
	Mellow	2010	NM	C	1	NM	NM	NM	0	0	0	34
	Miller	2010	NM	C	1	NM	NM	G and H	NM	0	NM	NM
	Neelakanta	2011	NM	C	1	pt 1: 250 g, pt2: NM	NM	G or H	NM	NM	NM	NM
	Newton	2013	NM	NM	NM	NM	NM	NM	NM	NM	NM	34
	Potakamuri	2013	NM	NM	1-5	NM	NM	NM	NM	NM	NM	2 (14, 16)
	Rohlke	2010	Y	C	1	NM	200-350 mL infused	G and H and O	NM	NM	NM	NM
	Rubin	2013	N	U	1	25 mL	NM	O	0	0	0	0
	Shiekh Sroujieh	2012	NM	U or C	1	30-50 g	NM	NM	0	0	0	0
	Silverman	2010	N	Ce	1-2	50 mL	NM	G and H	47	0	0	0
CDI	Van Nood	2013	Y	U	1-2	> 50 g	NM	G and H and O	15'	0	158	16
	Yoon	2010	NM	C	1	NM	NM	G and H	0	0	0	0
	Youngster	2013	NM	U or C	1-2	NM	NM	NM	0	NM	0	NM
IBD	Angelberger	2013	Y	U and Ce	3	NM	23.8 g (16.7-25)U, 20 g (6-21.7)C	O	5	0	29	0
	Greenberg	2013	NM	U or C + Ce	> 1	NM	NM	NM	3	0	0	0
	Borody	2012	NM	NM	NM	NM	NM	NM	NM	NM	NM	0
	Kump	2013	NM	C	2-5	NM	NM	O	NM	0	NM	0
	Kump	2013	Y	C	1	100-150 g	NM	O	1	0	110	0
	Kunde	2013	N	Ce	511	90 g (70-113)	NM	G and O	9	112	210	0
	Vermeire	2012	Y	U	3	200 g	NM	NM	3	0	310	0
IBS	Pinn	2013	NM	NM	1-3	NM	NM	NM	NM	NM	NM	NM
Pouchitis	Landy	2013	N	U	1	30 g	NM	NM	NM	NM	NM	NM
Constipation	Borody	2001	Y	Ce	5-14	NM	NM	NM	NM	NM	NM	NM
Metabolic syndrome	Vrieze	2012	Y	U	1	NM	NM	O	NM	NM	NM	NM

¹Route of administration: Upper GI tract (U), colon (C) or colon per enema (Ce);

²Genetic related (G), sharing the same household (H) or other (O);

³Perforation, post-transplant spesis/ bacteriemia/ transmission of communicable diseases;

⁴Death, both unrelated and related;

⁵Some irregularity of bowel movements and excessive flatulence during the first couple of weeks following the procedure;

⁶Hospitalised;

⁷Post infectious IBS (1). antibiotic treatment for urinary tract infections (2). Antibiotics for perioperative prophylaxis of a hip replacement (1). None of these 3 patients relapsed with CDI despite the antibiotic therapy;

⁸(94%) had diarrhea, cramping (31%) and belching (19%): symptoms resolved within 3 h. During FU 3 patients who were treated with donor feces (19%) had constipation; ⁹Fever: blood cultures were taken, but no bacterial pathogen was detectable (2);

¹⁰Fever;

¹¹Intolerance with immediate leaking of enemas for 3 consecutive days;

¹²Daily for 5 d. NM: Not mentioned; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome.

Table 4 Donor screening for fecal microbiota transplantation

Screening questionnaire1

A questionnaire addressing risk factors for potentially transmissible diseases

Fecal test

Parasites, including Blastocystis hominis and Dientamoeba fragilis

Clostridium difficile, and enteropathogenic bacteria

Serology

Antibodies to HIV, human T-cell lymphotropic virus types 1 and 2, hepatitis A, B, and C, Cytomegalovirus, Epstein-Barr virus

Treponema pallidum, Strongyloides stercoralis, and Entamoeba histolytica

¹Screening according to van Nood et al[18] and Vrieze et al[10].

Table 5 Studies on fecal microbiota transplantation in Clostridium difficile-infection, outcome data

First author	Year	Patients enrolled (n)	Age (mean ± SD or median, range/IQR)	Male sex (n)	FU	Primary endpoint	Resolution of diarrhea	Resolution of diarrhea + free from relapse during FU
Aas	2003	181	73 ± 9	5	3 mo	90 d	94%	\
Arkkila	2010	37	69 (24-90)		12 mo		92%	86%
Aroniadis	2013	132	70 (38-89)	3	15 mo (1-42)	1-7 d	84%, 92%3	50%
Bansal	2013	12	70 (31-96)	4	3 mo	> 90 d	92%	\
Bobo	2013	214	70.9 ± 11.9	10	1 mo	30 d	95%	\
Borody	2013	285	F:36 ± 18.1 M: 31 ± 16	17			86%
Bowden	1981	16	56 (14-85)	7	12 d	12 d	81%	\
Brandt	2012	77	65 ± 17	21	17 mo (3-68)	90 d	91%	81%
Byrne	2008	45	62 (30-91)	12	12 mo		96%
Eisman	1958	4	45-68	3	< 10 d	24-48 h	100%	100%
Elopre	2013	26	48, 48	1	5 yr and 6 wk	1 d	100%	100%
Fischer	2013	127	46 ± 17	7	30 d	7 d	75%/, 92%/3	75%
Garborg	2010	39	75 (53-94)	18	3 mo	80 d	73%, 83%3	\
Hamilton	2012	435	69 ± 21	12	2 mo	1-2 mo	86%, 95%3
Ihunnah	2013	668			12 mo (3-51)		78%, 89%3	78% after 12 wk
Jorup-Rönström	2012	32	75 (27–94)	12	26 mo (1-68)		69%
Kassam	2010	141	65.3 (26-87)	7	7 mo	24 h	100%
Kelly	2012	26	59 (19-86)	2	11 mo (2-30)	post FMT	92%	85%
Khanna	2013	135	27 (21-48)	8		1-14 d	50%
Louie	2013	259			6 mo		100%	100%
MacConnachie	2009	151	81.5 (68-95)	14	4 mo (1-6)	5-24 wk	73%, 80%3	67%
Mattila	2012	701	70 (22-90)	28	12 mo	12 wk	94%	89%
Mellow	2010	131	67 (32-87)	7	5 mo (1-10)	30 d	92%	85%
Miller	2010	2	34-50	0	9 mo, 1 mo	9 mo, 1 mo	100%	\
Neelakanta	2011	25	27-39	1	12 mo, 5 mo	2 wk, post FMT	50%	50%
Newton	2013	176			90 d	post FMT	94%	76%
Potakamuri	2013	13	73.8 ± 18.8	2	5 wk- 18 mo	> 1 mo	92%	46%
Rohlke	2010	19	49 (29-82)	2	27.2 yr (6-65)	6 mo	95%, 100%3	79%
Rubin	2013	7418	63 (6-94)	26	2 mo	60 d	79%	58%
Shiekh Sroujieh	2012	68	66 (16-93)		100 d	1-4 d	100%	100%
Silverman	2010	7	72 (30-88)	4	4- 14 mo	post FMT	100%	100%
Van Nood	2013	16110	73 ± 13	8	2.5- 5 mo	10 wk	81%, 94%3	81%
Yoon	2010	12	66 (30-86)	3	3 wk- 8 yr	3-5 d	100%	100%
Youngster	2013	12			2 mo	8 wk	92%	\

¹Recurrent/refractory CDI. Aas et al (18), Kassam et al (7), MacConnachie et al (15), Mattila et al (70), Mellow et al (13), Rubin et al (74), van Nood et al (16);

²Severe CDI 84%, complicated CDI 92%;

³Resolution of diarrhea (% of the patients) after 2 FMT's;

⁴All patients were hospitalised at inclusion;

⁵IBD. Hamilt et al (14): CD (6), UC (4), lymphocytic colitis (4). Neelak et al (1 UC, 1 CD). Khanna et al CD (7), UC (6). Borody et al CD (14), UC (14);

⁶Patients were immunocompromised: upon review of their medical history, Newton et al (7) based on HIV Elopre et al (2);

⁷Other diagnoses (12): UC (3), UC and livertransplant for PSC (1), CD(3), multivisceral transplant (2), multiple myeloma (1), lung transplant (1), renal transplant (1);

⁸Cases included 5 pediatric (Ihunnah et al) and 2 pediatric patients (Rubin et al);

⁹> 3 episodes (25);

¹⁰Amount of patients randomised to intervention (FMT) arm. /: Outcome defined as negative stool test (PCR) after FMT only; \: No further follow up after archivieving the primary endpoint. FMT: Fecal microbiota transplantation; FU: Follow-up.

Table 6 Studies on fecal microbiota transplantation in inflammatory bowel disease, treatment and outcome data

Author	Publication year	Patients enrolled (n)	Diagnose, disease activity	Age (mean ± SD or median,range/ IQR)	Male sex (n)	FU (mo)	Medication use during study (n)	Timepoint primary endpoint (mo)	Clinical improvement	Clinical remission	Cessation of medication during FU (n/total number of patients on the drug)
Angelberger	2013	5	Refractory UC	27 (22-51)	3	7	5-asa (3), Immunosuppressive therapy stopped prior to FMT	3	20%		0
Borody	2012	62	Active UC	M: 42.3 ± 11.5 F: 48.45 ± 16.49	40	1-1981		NM	92%	68%
Greenberg	2013	16	Refractory CD (2)/UC (14)2	39 (20-75)	9	4.5-30	Steroids (10), antitnf (4), 6MP (1)	After FMT	63%		Steroids: stopped (4/10), decreased dose (3/10). anti-TNF stopped (1/4)
Kump	2013	9	Refractory UC	NM	NM	3		3	56%
Kump	2013	6	Refractory UC	36 (17-52)	3	12		3	33%	0%
Kunde	2013	103	Active UC4	(7-20)	6	3	5-asa (7), 6MP (4), steroids (3)	0.25	70%	30%	0
Vermeire	2012	4	Refractory CD	37.5 (29-50)	1	2		2	0%	0%

¹Endoscopic follow-up (n = 21);

²Concomitant CDI was present in 4 UC patients;

³Ref Kunde: 1 subject did not tollerate treatment, this subject was considered to be a treatment failure. Endpoint data of the study was adjusted in this table;

⁴Active disease diagnosed by colonoscopy < 6 mo before the enrollment. UC: Ulcerative colitis; FMT: Fecal microbiota transplantation; CD: Crohn’s disease; FU: Follow-up; NM: Not mentioned.