Pre-, Pro-, and Synbiotics: Do They Have a Role in Reducing Uremic Toxins? A Systematic Review and Meta-Analysis

Table 1

Published studies on the effectiveness of prebiotics on reducing indoxyl sulphate and p-cresyl sulphate.

Author; (year)	Study; design	Patients	Supplement total dose/day (CFU or g) number of doses/day	Duration	Analysis; method	Main results (preintervention and postintervention (mean difference (SD)))	Comments	Grade benefit
Cloetens et al., (2010); [18]	Randomised-placebo-controlled crossover trial	𝑛=20 healthy (6 male)	Prebiotic: AXOS degree of polymerization = 6; 10 g administered in orange juice; Placebo: maltodextrin 10 g; 2 dose/day	3 wks in; each arm	Heat and acid deproteinisation,; GC, MS	Δ  Urinary PC (mg/24 h) ^∧; (within group, 0–2 wks); Tx grp: 32.1–14.9 (−17.2 ) (0.011); Placebo: 32.9–27.3 (−5.6 ) (ns); (within group, 0–3 wks); Tx grp: 32.1–27.2 (−4.9) (ns); Placebo: 28.2–25.2 (−3.0) (ns)	(i) 4-week washout period between each arm; (ii) Analysis 0–2 weeks 𝑛=10 only in both groups; (iii) Analysis at week 3 was taken the day after prebiotic was ceased; (iv) Increased bifidobacterium levels at 2 weeks, 𝑃=0.025; compared to placebo, this was lost at week 3; (v) Correlation pre- and postintervention bifidobacterium levels 𝑟 = −0.51 𝑃=0.022; (vi) Usual diet, asked to have a regular eating pattern (3 meals/day), and foods containing prebiotics were limited to 1/week	Moderate; PC +; (0–2 wks)
De Preter et al., (2008)[19]	Case series; (2 independent studies—S1 and S2)	𝑛=48 healthy; S1, 𝑛=29; (14 male); S2,𝑛=19  (9 male)	S1: lactulose 20 g; S2: OF-IN (Orafti Synergy1); (i) Oligofructose degree of polymerization = 4, 10 g; (ii) Raftiline HP degree of polymerization = 25, 𝛽(2,1) linkage, 10 g; 2 dose/day	0–4 wks	Heat and acid deproteinisation, GCMS	Δ  Urinary PC (mg/24 h)(wk 0–4); S1: 20.7–12.7 (−8) (0.001); S2: 27.7–17.8 (−9.9) (0.005)	(i) Both studies increased in bifidobacterium levels S1: 𝑃=0.017, S2: 𝑃<0.001, and no difference between studies; (ii) Correlation between baseline PC levels and effect of prebiotic intervention (𝑟 = −0.64) (S1), 𝑟 = −0.74 (S2) 𝑃<0.001); (iii) No runout period; (iv) Usual diet, advised to keep stable. Avoid fermented milk products and foods containing fermentable carbohydrates	Low; PC +
Ito et al., (1993a); [20]	Case series	𝑛=12 healthy (all male)	TD (including GOS) 15 g administered in iced tea; 1 dose/day	0–6 days	Heat and acid deproteinisation GC, FID	Δ  Fecal (ug/g wet wt)(day 0–6); PC 9.8–3.3 (−6.5) (<0.05); Indole 10.5–7.4 (−3) (<0.01)	(i) Post was measured on the 6th day of ingestion; (ii) Increased bifidobacterium levels and lactobacillus 𝑃<0.01 and 𝑃<0.05, respectively. Decrease in; bacteroidaceae 𝑃 < 0.05; (iii) 6 day runout levels PC, indole returned towards baseline; (iv) Usual diet with no lactose containing foods or fermentation products	Low; PC+; IS+
Ito et al., (1993b); [21]	Case series	𝑛=12 healthy (all male)	GOS (Oligomate 50) 2.5 g administrated in apple juice which included; 1 dose/day	0–3 wks	Heat and acid deproteinisation; GC, FID	Δ  Fecal (mg/L); (wk 0–3); Indole 50.4–31.6 (−18.8) (<0.05); PC 48.7–41.1 (−7.6) (ns)	(i) Post was measured on 6th day of week 3; (ii) Participants were selected out of a group of 28 on the basis of the lowest bifidobacterium levels; (iii) Increased bifidobacterium levels 𝑃 < 0.05; (iv) 6 day runout levels indole decreased further 23.4 mg/L; (v) Usual diet with no lactose containing foods or fermentation products	Low; IS+; PC−
Terada et al., (1992); [22]	Case series	𝑛=8 healthy (𝑛=5 male)	Lactulose; 3 g administered in a drink; 1 dose/day	0–2 wks	Heat and acid deproteinisation GC, FID	Δ  Fecal (mg/d); (wk 0-1); Indole 6.3–2.4 (−3.9) (<0.05); PC (not reported); (wk 0–2); Indole 6.3–0.9 (−5.4) (<0.05); PC (not reported) (ns)	(i) Increased bifidobacterium levels and lactobacillus 𝑃 < 0.001 and 𝑃 < 0.05, respectively. Decrease in bacteroidaceae 𝑃 < 0.05; (ii) Usual diet. Avoided food with abundant viable cultures; (iii) 1 week runout period levels returned to preintervention levels*	Low; IS+; PC−
Geboes et al., (2006); [23]	Case series	𝑛=7 healthy (𝑛=2 male)	Inulin degree of polymerization = 12, 𝛽(2,1) linkage 15 g; 3 dose/day	0–4 wks	Heat and acid deproteinisation, GCMS	Δ  Urinary PC (mg/24 hr) ^∧; (wk 0–4); Total: 32.3–22.3 (−10) (ns); Percentage of isotope ([2H4]p-cresol): 0.81–0.51 (−0.3 ) (ns)	(i) Low overall recovery of the label; (ii) 1 week runout urinary PC and urinary percentage of isotope increased towards baseline. Fecal PC exceeded baseline, 13.33 mg/72 hrs, and fecal percentage of isotope decreased further to 0.44%	Very low; PC−
					Outcome markers-total PC and stable isotopes [2]p-cresol given as [2]tyrosine in test meal	Δ  Fecal PC (mg/72 hr) ^∧; (wk 0–4); Total: 9.7–9.3 (−0.4) (ns); Percentage of isotope ([2H4]p-cresol): 0.78–0.71 (−0.07) (ns)	(iii) Usual diet, advised to keep constant macronutrient composition. Diet records kept at intervals throughout the study to allow for qualitative comparison—results not reported
Alles et al., (1999); [24]	Placebo controlled nonrandomised experimental trial	𝑛=39 healthy; High dose = 14 (8 male); Low dose = 13 (7 male)	TOS degree of; polymerization = 2, Elix' or; high dose group = 15 g	0–3 wk standardise run in diet	Freeze-thaw deproteinisation,; HPLC, UV	Δ  Fecal indole (ug/g wet wt) (mean difference (95% CI))   (between placebo and intervention wk 3–7)	(i) Intervention and placebo increased in bifidobacterium levels.	Low
		Placebo = 12; (7 male)	Low dose group = 7.5 g; Administered in juice	3–7 wk intervention		High dose group: −3.0 (−11,6) (ns)	(ii) No run-out period
			3 dose/day			Low dose group: −5.0 (−11,6) (ns)	(iii) 90% of food was provided according to a dietitian prescribed standardized low-fibre high-protein diet	IS−
Meijers et al., (2009); [32]	Case series	𝑛=22 hemodialysis (15 male)	OF-IN (Orafti Synergy1) total 20 g	0–4 wks	Sodium octanoate,; HPLC, FS	Δ  Serum (mg/L) ^∧	(i) Commenced 1/2 dose: 1/day first wk, increase to full by week 2	Very Low
			(i) Oligofructose degree of polymerization = 4, 10 g			wk 0–4
			(ii) Raftiline HP degree of polymerization = 12, 𝛽 (2,1) linkage, 10 g			PCS 38.5–32.0 (−6.5) (0.01)	(ii) PCS levels remained significantly different 4 weeks post	PC+
			2 dose/day			IS 23.7–22.4 (−1.3) (ns)	(iii) No monitoring of diet	IS–