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

Table 3

Published studies with more than one intervention (Pre-, Pro- and/or Synbiotics) on reducing indoxyl sulphate and p-cresyl sulphate.

Author (year)	Intervention	Study design	Patients	Supplement total dose/day (CFU or g) number of doses/day	Duration	Analysis; method	Main results (preintervention and post intervention (mean difference))	Comments	Grade benefit
De Preter et al., (2006); [28]	Prebiotic; Probiotic; Synbiotic (Group3)	Randomised placebo controlled cross over trial	𝑛=43 healthy; (𝑛=21 male); Group 1 : 14; Group 2 : 14; Group 3 : 15	Probiotic: lyophilized Saccharomyces boulardii A07FA02 (yeast) administered via capsules; Group1 = 2–5 × 10^9; Group2 = 4–10 × 10^9; Group3 = 2–5 × 10^9; Prebiotic: lactulose; Group1 = 20 g; Group2 = 30 g; Group3 = 20 g; Placebo: maltodextrin; 2 dose/day	4 wk in; each arm; Probiotic; Prebiotic; Placebo; (Group 1 and 2); Synbiotic; (Group3)	Heat and acid; deproteinisation, GC, MS	Urinary PC (mg/24 hr) (between placebo and intervention at 4 wk); Prebiotic arm; Group1: 17.9, 9.5 (−8.4) (0.022); Group2: 21.9, 14.7 (−7.2) (0.022); Probiotic arm; Group1: 17.9, 21.0 (+3.1) (ns); Group2: 21.9, 18.4 (−3.5) (ns); ΔUrinary PC (mg/24 hr)(within group, 0–4 wks); Prebiotic arm; Group1: 17.7–9.5 (−8.2) (0.019); Group2: 20.1–14.7 (−5.4) (0.002); Group3: 20.2–16.2 (−4.0) (0.002); Probiotic arm; Group1: 17.7–21.0 (+3.3) (ns); Group2: 20.1–18.4 (−1.7) (ns); Group3: 20.2-20.2 (0.0) (ns); Synbiotic arm; Group3: 20.2–18.9 (−1.3) (ns)	(i) Variability of probiotic dose per capsule (1–2.5 × 10^9); (ii) Δ  Fecal concentration was also assess; however, no trend was evident among the three groups; (iii) 4 week run-out period levels returned towards baseline becoming statistically significant compared to week 4; (iv) Usual diet, advised to keep stable. Avoid intake of fermented milk products and food components containing high quantities of fermentable carbohydrates	Moderate; PC+; (prebiotic); PC–; (probiotic)
De Preter et al., (2004); [29]	Probiotic; Prebiotic	Randomised placebo; controlled cross over trial; (2 independent studies: probiotic and prebiotic)	𝑛=19 healthy; Probiotic, 𝑛=10; Prebiotic, 𝑛=9	Probiotic: Lactobacillus casei Shirota 13 × 10^9 administered in milk product; Placebo: milk product without strain; Prebiotic: lactulose 20 g; Placebo: lactose	2 wks in; each arm; Probiotic; Prebiotic; Placebo	Heat and acid; deproteinisation,; GC, MS; Outcome; markers-total PC and stable isotopes; [^2H4]p-cresol given as; [^2H4]tyrosine; in test meal	ΔUrinary PC (mg 0–24 hr) (difference in intervention Group, difference in placebo; (mean difference) 0–2 wk); Probiotic study; Total: 6.6, 8.4 (−1.8) (ns); Percentage of isotope: 0.10, 0.25 (−0.15) (ns); Prebiotic study; Total: −11.2, 8.3 (−19.5) (0.018)	(i) Theory-based explanation of different phases of total urinary PC, that is, 0–24 hr and 24–48 hr; no other paper measures PC in this way; (ii) Low overall recovery of the label; (iii) 2-week washout period in between each arm; (iv) Usual diet, advised to keep stable. Avoid intake of fermented milk products and food	Moderate; PC+
							Percentage of isotope: −0.87, 0.05 (−0.92) (0.005)	components containing high quantities of fermentable carbohydrates
				2 dose/day			ΔUrinary PC (mg 24–48 hr) (difference in intervention group, difference in placebo (mean difference) 0–2 wk); Probiotic study; Total: −16.2, 8.3 (−24.5) (0.009); Percentage of isotope: −0.70, 0.46 (−1.16) (0.042); Prebiotic study; Total: 8.9, 6.6 (+2.3) (ns); Percentage of isotope: −0.72, −0.10 (+0.28) (ns)
De Preter et al., (2007); [30]	Prebiotic; Probiotic; Synbiotic	Randomized; placebo-controlled; crossover trial	𝑛=19; healthy (𝑛=10 male); Group 1 : 10; Group 2 : 9	Probiotic: Group 1—lyophilized; Bifidobacterium breve Yakult 2 × 10^9; Group 2—Lactobacillus casei Shirota 13 × 10^9 administrated in milk product; Prebiotic: Group 1 and 2—OF-IN (Orafti Synergy1) total 20 g; (i) Oligofructose degree of; polymerization = 4, 10 g; (ii) Raftiline HP degree of; polymerization = 12, 𝛽 (2, 1) linkage, 10 g; Placebo: strain free milk product (probiotic)/ Maltodextrine (prebiotic)	Each Group 4 weeks in each arm; Probiotic; Prebiotic; Placebo; Synbiotic; (Group 2 only); 0–4 wks	Heat and acid deproteinisation, GC, MS	ΔUrinary PC (mg/24 h) ^∧; (within group, 0–4 wks); Probiotic: Group 1: 21.2−16.7 (−4.5) (0.005); Group 2: 24.4–20.5 (−3.9) (0.038); Prebiotic; Short-term effect (start of study); Group 1: 21.2–15.7 (−5.5) (0.013); Group 2: 24.4–14.7 (−9.7) (0.025); Long-term effect (end of study, wk4); Group 1: 21.2−21.3 (+0.2) (ns); Group 2: 24.4–13.4 (−11.0) (0.025); Group 1 + 2: (0.005); Synbiotic: Group 2: 24.4–9.8 (−14.6) (0.021)	(i) Analysis at week 4 was taken the day after prebiotic was ceased; (ii) Increased bifidobacterium levels after prebiotic intervention 𝑃=0.006; (iii) Analysis based on baseline result at week 0 and not baseline of each period following washout; (iv) 2-week washout period in between each arm; values increased during this time (except placebo)	Low; PC+
							Placebo; Group 1: 21.2–22.0 (+0.8) (ns); Group2: 24.2–25.8 (+1.6) (ns)	(v) Usual diet, advised to keep stable. Avoid intake of fermented milk products and food; components containing high quantities of fermentable carbohydrates
Swanson et al., (2002); [31]		Randomised placebo controlled trial	𝑛=62 healthy (𝑛=25 male)	Probiotic: free-dried Lactobacillus acidophilus NCFM powder ≥ 2 × 10^9administered in hard gelatin capsules coated with acid resistant chemical; Placebo: cornstarch	0–4 wks	Freeze thaw deproteinisation, GC, FID	ΔFecal (mg/g dry matter) (within group, wk 0–4)	(i) Concentration of all fecal parameters increased from week 2–4 even in the control group	Very low
	Probiotic; Prebiotic; Synbiotic		Placebo,; 𝑛=15; Prebiotic,; 𝑛=15; Probiotic,; 𝑛=15	Prebiotic: fructose oligosaccharide, (Nutraflora) 6 g administered in non carbonated beverage; Placebo: sucrose			Probiotic; Indole 0.13–0.18 (+0.06) (ns)	(ii) Conclusions were made base on nonstatistically significant data
			Synbiotic,; 𝑛=17	2 dose/day			PC 0.26–0.30 (+0.04) (ns); Prebiotic; Indole 0.10–0.11 (+0.01) (ns); PC 0.23–0.23 (0) (ns) Synbiotic; Indole 0.09–0.08 (−0.01) (ns)	(iii) No runout period; (iv) 3 day food records were analysed for macro nutrients and fibre pre-, during, and postintervention.	PC–; IS–
							PC 0.21–0.26 (+0.05) (ns); Placebo; Indole 0.12–0.13 (+0.01) (ns); PC 0.22–0.19 (−0.03) (ns)	(v) Substantial difference in total fibre intakes, that is, probiotic group had 10 g more than prebiotic group at week 6
Nakabayashi et al.,; [36] (2011)	Synbiotic	Interrupted time series without a parallel control group	𝑛=7; hemodialysis	Probiotic; (i) Lactobacillus casei strain Shirota,	0–2 wk runin	Heat acid deproteinization, HPLC, FS	ΔSerum (mg/L) ^∧; (within group, wk 2−4)	(i) 1 participant used medications that contained live lactic acid bacteria	Very Low
				(ii) Bifidobacterium breve strain Yakult administered in powder form 3 × 10^8 each strain	3–5 wk intervention		PC 17.1–14.2 (−2.9) (0.031)	(ii) No runout period	PC+
				Prebiotic: GOS (oligomate 55 N) ≥5 g; 3 dose/day			IS 32.2–30.1 (−1.8) (ns)	(iii) No monitoring of diet	IS–

Key:  
^∧median difference.  
*estimated value from graph, exact value not reported.
^#paper stated no change, exact figures not reported.  
^@no trend was evident among three groups.
 AXOS: arabinoxylan-oligosaccharide; FID: flame ionisation detection; FS: fluorescence spectroscopy; GC: gas chromatography; GOS: galactooligosaccharide; HPLC: high performance liquid chromatography; IS: indoxyl sulphate; MS, mass spectrometry; OF-IN, oligofructose-enriched inulin; PC/S: p-cresyl/sulphate; SD: standard deviation; TD: transgalactosylated disaccharide; TOS: trans-galaco oligosaccharide; Tx Grp, treatment group; UV: ultra violet; VIS: visible; wk: week.