Table 1.

Human clinical trials of probiotics, pre-biotics, and synbiotics for the treatment of pre-diabetes.

Study	Country	No. of patients	Blind	Inclusion criteria	Intervention	Control	Duration	Outcomes
								Anthropometry and body composition	Blood biochemical analysis and pancreatic function assessment	Fecal compositions and microbiome populations
Mahboobi et al. (33)	Iran	55	Double	FPG of 100–125 mg/dL, 2hr-glucose tolerance test of 140–200 mg/dL, or both, <2 months	Probiotics: 500 mg/day (7 × 109 CFU lactobacillus Casei, 2 × 109 CFU Lactobacillus Acidophilus, 1.5 × 109 CFU Lactobacillus Rhamnosus, 2 × 109 CFU Bifidobacterium Breve, 7 × 109 CFU Bifidobacterium Longum, 1.5 × 109 CFU Streptococcus Thermophilus)	Placebo: capsules containing starch.	8 weeks	SBP, DBP	TC, TG, HDL-C, LDL-C	N.A
Yang et al. (34)	USA	13	Double	FPG of 100–125 mg/dL and/or HgbA1c of 5.7–6.4%	Pre-biotics: 2 g/day XOS	Placebo	8 weeks	BW, BMI, body fat (%), trunk fat (%)	Glucose*, insulin*, TG, HOMA-IR*, active GLP-1*, pancreatic polypeptides*, leptin*, TNF-α*	Howardella↓, Enterorhabdus↓, Slackia↓, Blautia hydrogenotrophica↑
Naito et al. (35)	Japan	98	Double	Aged 20 to 64 years; BMI ≥ 25 kg/m2; and 1-hr post-load plasma glucose level ≥180 mg/dL	Probiotic: ≥1.0 × 1011 CFU LcS (contained in 100 ml milk/day)	Placebo	8 weeks	SBP, DBP, BW, BMI, fat (%)	HbA1c, Glucose‡, FIL, glycoalbumin, TC↓, TG, HDL-C, LDL-C↓, Non-HDL-C↓, HOMA-IR, HOMA-β, Mastsuda Index, Insulinogenic Index	N.A
Canfora et al. (36)	The Netherlands	44	Double	Aged 45–70 years; BMI of 28–40 kg/m2; FPG ≥5.6 mmol/L and/or 2-hr post-load plasma glucose of 7.8–11 mmol/L	Prebiotic: 15 g/d GOS	Placebo: 16.95 g/d maltodextrin	12 weeks	BMI, BW, body fat (% and kg), lean mass (kg), visceral fat (g)	FPG, M-value, HOMA-IR, SCFAs, plasma TAG, plasma free glycerol, plasma FFA, GLP-1, PYY, FIL, leptin, LBP, IL-6, IL-8, TNF-α, energy expenditure, fat oxidation, carbohydrate oxidation	Bifidobacterium↑, Bacteroides stercoris er rel.↓,Prevotella oralis et rel.↑,Prevotella melaninogenica et rel.↑,Sutterella wadsworthia et rel.↓
Baugh (68)	USA	18	Double	Aged 40–75 years; BMI of 25–40 kg/ m2; ADA risk assessment score ≥5, HbA1c of 5.7–6.4%, with FPG of 100–125 mg/dL, or 2-hr OGTT value of 140–200 mg/dL	Prebiotic: 10 g/day (inulin, 5 g/day for first 7 days, then move to 10 g/day)	Placebo	6 weeks	N.A	Fasting and postprandial plasma TMAO, TMA moiety concentrations, choline, betaine, L-carnitine, γ-butyrobetaine concentrations	N.A
Kassaian§	Iran	120	Double	Aged 35–75 years old; FPG of 100–125 mg/dL or 2-hr post-load serum glucose of 140–199 mg/dL	Probiotics: 6 g/day (Lactobacillus acidophilus, Bifidobacterium lactis, Bifidobacterium bifidum, and Bifidobacterium longum, 1 × 109 for each)	Placebo: maltodextrin	24 weeks	BMI	HbA1c, FPG↓, FIL, TG↓, TC, HDL-C, LDL-C, QUICKI, HOMA-IR, HOMA-β	Clostridium perfringens-to- Escherichia coli ratio, Bacteroides fragilis-to-Escherichia coli ratio↑, Clostridium perfringens-to- Bacteroides fragilis ratio↓
					Synbiotics: comprising the mentioned probiotics with an inulin-based prebiotic			BMI	HbA1c↓, FPG↓, FIL↓, TG↓, TC, HDL-C, LDL-C, QUICKI↓, HOMA-IR↓, HOMA-β.	Clostridium perfringens-to- Escherichia coli ratio, Bacteroides fragilis-to-Escherichia coli ratio, Clostridium perfringens-to- Bacteroides fragilis ratio
Stefanaki et al. (37)	Greece	17	No blinding	Adolescents; HbA1c of 5.7–6.4%, and/or FPG 100–125 mg/dL and/or 2-hr post-load serum glucose of 140–199 mg/dL	Probiotics: 450 × 109 CFU for each Streptococcus thermophilus, Bifidobacteria breve, Bifidobacteria longum, Bifidobacteria infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbreuckii subspecies bulgaricus (two times/day)	Counseling	4 months	BMI	HbA1c, FPG	Gut digestion: total fecal fat, cholesterol, TG, long-chain fatty acid, phospholipids, calprotectin, Eosinophil protein X, n-Butyrate concentration; Intestinal microbiome populations: Barnesiella spp.↓, Faecalibacterium prausnitzii↓, Collinsella aerofaciens↓, Methanobrevibacter smithii↓, Escherichia coli↑, Anaerotruncus colihominis↑, Akkermansia muciniphila↑, Butyrivibrio crossotus↑
Tay et al. (38)	New Zealand	26	Double	Aged 18–65 years; BMI of 30–40 kg/m2 or 27–40 kg/m2 for Indian ethnicity; HbA1c of 40–50 mmol/mol;	Probiotics: 6 × 109 CFU Lacticaseibacillus rhamnosus HN001 in each capsule (in total of 90 capsules) with intermittent fasting regimen	Placebo: microcrystalline cellulose and dextrose anhydrate with intermittent fasting regimen	12 weeks	BW, BMI, waist circumference, hip circumference, WHR, neck circumference, fat (kg), fat-free mass	HbA1c, FPG, FIL, fasting c-peptide, TC, TG, HDL-C, LDL-C, AST, ALT, leptin, TNF-α, IL-6	N.A

^*These indicators were measured at 0, 30, 60, and 120 min.

^‡These indicators were measured at 0, 30, 60, 90, and 120 min.

^§Four articles published different outcomes of the same study and were therefore discussed together in this review.

No, Number; FPG, fasting plasma glucose; hr, hour; CFU, colony forming unit; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, serum total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; N.A, Not applicable; HbA1c, glycated hemoglobin; XOS, xylooligosaccharide; BW, body weight; BMI, body mass index; HOMA-IR, homoeostasis model assessment for insulin resistance; GLP-1, Glucagon-like peptide-1; TNF-α, Tumor Necrosis Factor-α; LcS, Lactobacillus casei strain Shirota; FIL, fasting insulin level; HOMA-β, β-cell function; GOS, galacto-oligosaccharides; M-value, the mean glucose infusion rate during the final 30 min of euglycemia; SCFAs, short-chain fatty acids; TAG, triacylglyceride; FFA, free fatty acid; PYY, peptide YY; LBP, Lipopolysaccharide-binding protein; IL, Interleukin; ADA, American Diabetes Association; TMAO, trimethylamine N-oxide; TMA, trimethylamine; QUIKI, quantitative insulin sensitivity check index; WHR, waist-to-hip ratio; AST, aspartate transaminase; ALT, alanine aminotransferase; min, minutes.