Table 5.

Summary of the studies that investigated the effects of synbiotics on intestinal permeability and immunity

Authors, Year of publication	Location	Age (years)	Population Studied	Study design	Intervention/Dose/Duration	Gut effects (intestinal permeability)	Effects on cytokines	Quality score/ degree of trials	Side effects
Kantah et al., (2017) 40	China, Italy, India, and South Korea	Between 38 and 62	120 individuals	A multicenter randomized study	1. A) given a symbiotic 10 mL t.i.d. for 5 months	Zonulin levels decreased by treatment B and C, Bacteroidetes/Firmicutes ratio, normalized by B and C treatment	-	2/Low	Not reported
					2. B) given 1 tablet t.i.d of P3T/J (a probiotic mixture) for 5 months
					3. C) given the symbiotic 10 mL t.i.d. for 1 month and then shifted to 1 tab t.i.d of probiotic mixture for 4 months
					4. Control: Prior study supplemented a marine PUFA extract
Horvath et al., (2020) 59	Austria	54-65	26 diabesity patients	A randomized, double-blind, placebo-controlled pilot study	1. A daily dose of a multispecies probiotic and a prebiotic (Each dose contains a total of approximately 1.5×1010 CFU of a blend containing B. bifidum W23, B. lactis W51, B. lactis W52, L. acidophilus W37, L. casei W56, L. brevis W63, L. salivarius W24, Lc. lactis W58 and Lc. lactis W19 in 6 g of a matrix (maize starch, maltodextrins, vegetable protein, potassium chloride, magnesium sulfate, amylases, and manganese sulfate)	Zonulin and LPS levels	-	5/High	Flatulence and diarrhea in one person
					2. Placebo (The matrix without bacteria was used as a placebo)/6 months	No effects on alpha or beta diversity of the microbiome between groups or time points
Ghavami et al., (2021) 60	Iran	20-50	69 patients with migraine	A multi-center, randomized, double-blind controlled trial	1. Synbiotic (109 CFU of 12 types of probiotics (Each capsule: 500 mg contains 109 CFU of 12 types of probiotics including Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus helveticus, Lactobacillus bulgaricus, Lactobacillus plantarum, Lactobacillus gasseri, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium bifdum, and Streptococcus thermophilus, and FOS as prebiotics)	Zonulin levels decreased	hs-CRP levels decreased.	5/High	No adverse effects were reported following synbiotic supplementation.
					2. placebo (starch) twice per day/12 weeks
Stenman et al., (2016) 55	Finland	18-65 years old	224 participants with a BMI between 28.0-34.9 and a waist-to-hip ratio of ≥0.88 for males and ≥0.83 for females	Double-blind, randomized, placebo-controlled, multi-center clinical trial	1. Placebo, microcrystalline cellulose, 12 g/d	Zonulin levels decreased in the B420 and LU+B420 groups.	No effects on the levels of hs-CRP, IL-6, and sCD4	5/High	At least one adverse event (Gastrointestinal symptoms) (133 were potentially product-related).
					2. Litesse® Ultra polydextrose (LU), 12 g/d	No effects on the levels of LPS
					3. Bifidobacterium animalis ssp. lactis 420 (B420), 1010 CFU/d in microcrystalline cellulose, 12 g/d
					4. LU+B420, 12 g+1010 CFU/d/6 months
Çakir et al., (2017) 42	Turkey	10-12.5 years old	28 children with NAFLD and 30 healthy controls	A longitudinal study of 4 months	1. A capsule/day of synbiotics (Maflor plus capsules®) contained 7×109 CFU active probiotics (Bifidobacterium lactis, Lactobacillus acidophilus, and Lactobacillus casei) and 100 mg chicory inulin. In addition to the medical treatment, patients were prescribed a low-calorie diet (approximately 10%-20% low-calorie according to their age with 50%-60% carbohydrates, 20%-30% fat: two-thirds saturated and one-third unsaturated, and 10%-20% protein) and a moderate exercise program (aerobic exercise 30-45 min/d at least 3 times a week)	No effects on the levels of zonulin	TNF-α and hs-CRP levels decreased.	1/Low	Not reported
					2. Healthy controls/ 4 months.	No effects on the levels of Calprotectin
Wilms E. et al., (2016) 61	Netherlands	Between 18 and 65 years	20 healthy adults	A double-blind, controlled, randomized, parallel-design study	1. Synbiotic (1.5×1010 CFU Ecologic® 825 comprising Bifidobacterium bifidum (W23), B. lactis (W51), B. lactis (W52), Lactobacillus acidophilus (W22), L. casei (W56), L. paracasei (W20), L. plantarum (W62), L. salivarius (W24) and Lactococcus lactis (W19)+10 g fructo-oligosaccharides (FOS P6) per day)	No effects on the levels of zonulin	No effects on the levels of TNF-α, IL-1β, IL-6, IL-8, and MCP-1	5/High	Not reported
					2. Control supplements /2 weeks

PUFA: Polyunsaturated fatty acid; LPS: Lipopolysaccharide; CFU: Colony-forming unit; hs-CRP: High sensitivity C-reactive protein; FOS: Fructooligosaccharide; Il-6: Interleukin-6; sCD4: Stearoyl-CoA desaturase-4; TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; IL-8: Interleukin 8; MCP-1: Monocyte chemoattractant protein-1; BMI: Body mass index; t.i.d.: Three times a day