Table 3.

Studies evaluating the effect of pre-, pro-, and synbiotics on systemic inflammation in children with disease conditions.

Author, Year, Country	Study Design and Population	Intervention(s)	Biomarker(s)	Significant Intervention Effects
				Anti-Inflammatory	Pro-Inflammatory	Overall Effect 1	Clinical Effect 2
Atopic/allergic disorders: atopic dermatitis
D’Auria et al., 2021 Italy [27]	2-arm RCT: 58 children aged 6–36 months with atopic dermatitis	Probiotic: 8g rice-dried powder containing heat-killed L. paracasei CBA L74 powder daily for 12 weeks	G-CSF, GM-CSF, IFN-γ, IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-12, IL-17A, MCP-1, MIP-1β, TNF-α, IL-4, IL-10, and IL-13 measured at 12 weeks	-	-	→	Yes
Jeong et al., 2020 Korea [28]	2-arm RCT: 66 children aged 1–12 years with atopic dermatitis	Probiotic: tyndallized L. rhamnosus (RHT3201) 1010 cfu daily for 12 weeks	Eosinophil cationic protein (ECP), CRP, IL-31, TNF-α, chemokines; IL-4, IL-10 measured at 6 and 12 weeks	Improved ECP level at week 12 (p = 0.022)	-	↓	Yes
Prakoeswa et al., 2017 Indonesia [29]	2-arm RCT: 22 children aged 0–14 years with mild and moderate atopic dermatitis	Probiotic: microencapsulated L. plantarum IS-10506 1010 cfu/day twice daily for 12 weeks	IFN-γ, IL-17; IL-4, forkhead box P3 (Foxp3+)/IL-10 ratio; CD4+ expression of IL-4, IFN-γ, Foxp3+/IL-10 ratio, and IL-17 measured at 12 weeks	IFN-γ decreased more in probiotic group (p = 0.006). CD4+ expression of IFN-γ fell in probiotic but not control group. Increased Foxp3+/IL-10 ratio in probiotic compared with control group (p = 0.001).	IL-4 decreased more in probiotic group (p < 0.001)	↑/↓	Yes
Han et al., 2012 Korea [30]	2-arm RCT: 79 children aged 12 months to 13 years with atopic dermatitis	Probiotic: L. plantarum CJLP133 0.5 × 1010 cfu twice daily for 12 weeks	TNF-α, IFN-γ, and IL-4 measured at 2 and 14 weeks	IFN-γ decreased from baseline (p < 0.001) and was lower in the probiotic than placebo group at 14 weeks (p < 0.05)	IL-4 decreased from baseline (p = 0.049)	↑/↓	Yes
Wang et al., 2015 Taiwan [31]	4-arm RCT: 220 children aged 1–18 years with moderate-to-severe atopic dermatitis	Probiotics: L. paracasei (LP; 2 × 109 cfu) or L. fermentum (LF; 2 × 109 cfu) or both (4 × 109 cfu) daily for 3 months	IFN-γ, TNF-α, and TGF-β, IL-4 measured at baseline and 3 months	Increased IL-4 from baseline (p = 0.04)	-	↓	Yes
Atopic/allergic disorders: allergic rhinitis
Jerzynska et al., 2016 Poland [32]	3-arm RCT: 100 children aged 5–12 years with allergic rhinitis and sensitivity to grass pollen receiving sublingual immunotherapy	Probiotic: L. rhamnosus GG (Dicoflor 30) 3 billion live cultures daily for 5 months	CD4+CD25+Foxp3+ (forkhead box P3) cells, Toll-like receptor (TLR) 4, IL-1, IL-6, TNF-α, TLR activation, IL-10, and TGF β-1 in cell supernatants of grass-stimulated PBMCs measured at baseline and 5 months	Increased forkhead box P3 cell induction at 12 months (p < 0.05)	-	↓	Yes
Lin et al., 2014 Taiwan [33]	2-arm RCT: 60 children aged 6–13 years with perennial allergic rhinitis receiving levocetirizine (antihistamine)	Probiotic: L. paracasei (LP) strain HF. A00232 5 × 109 cfu/day for 8 weeks	IFN-γ, IL-4, IL-10, and TGF-β measured at baseline and weeks 8 and 12	-	-	→	Yes
Atopic/allergic disorders: other
Taylor et al., 2006 Australia [34]	2-arm RCT; 118 newborns of women with a history of allergic disease and positive allergen skin prick test	Probiotic: L. acidophilus LAVRI-A1 3 × 109 daily for first 6 months	IL-5, IL-6, TNF-α, IL-10, IL-13, and TGF- β measured at 6 months	Reduced IL-5 production in response to polyclonal stimulation (p = 0.044); reduced TNF-α responsiveness to house dust mite allergens (p = 0.046)	Reduced TGF-β production in response to polyclonal stimulation (p = 0.015); reduced IL-10 responses to tetanus toxoid vaccine antigen (p = 0.03) and house dust mite allergens (p = 0.014)	↑/↓	N/a
Chen et al., 2010 Taiwan [35]	2-arm RCT: 105 children aged 6–12 years with asthma and allergic rhinitis	Probiotic: L. gasseri PM-A0005 (A5) 2 × 109 cells twice daily for 8 weeks	TNF-α, IFN-γ, IL-12p40, IL-10, and IL-13 produced by PBMCs stimulated with PHA, Dermatophagoides pteronyssinus (Der p), or Der p supplemented with L. gasseri A5 measured at baseline and 8 weeks	Decreased TNF-α in PBMCs in medium alone and stimulated with Der p. (p < 0.05). Decreased IFN-γ, IL-12 in PBMCs stimulated with PHA or Der p (p < 0.05).	Decreased IL-13 in medium alone and stimulated with PHA or Der p (p < 0.05)	↑/↓	Yes
Huang et al., 2018 Taiwan [36]	4-arm RCT: 160 children aged 6–18 years with asthma	Probiotic: L. paracasei GMNL-133 (BCRC 910520, CCTCC M2011331), L. fermentum GM-090 (BCRC 910259, CCTCC M204055), or both for 3 months (frequency and dose not specified)	IFN-γ, TNF α, and IL-4 measured at baseline and 3 months	→	→	→	Yes
Autoimmune disorders: coeliac disease
Drabińska et al., 2019 Poland [24]	2-arm RCT: 34 children aged 4–17 years with coeliac disease	Prebiotic: 10 g of oligofructose-enriched inulin (Synergy 1) daily for three months	IL-1β, IL-1ra, IL-6, IL-8, IL-12p70, TNF-α, and IL-10 measured at baseline and 3 months	→	→	→	N/a
Olivares et al., 2014 Spain [37]	2-arm RCT: 33 children aged 2–17 years with newly diagnosed coeliac disease	Probiotic: B. longum CECT 7347 10⁹ cfu daily for 3 months	Lymphocyte subsets, TNF-α, IF-γ, IL-10, IL-13, and TGF-β measured at baseline and 3 months	Fall in CD3+ (p = 0.013) and HLA-DR+ T lymphocytes (p = 0.029) from baseline; decreased CD3+ T lymphocytes (p = 0.004) compared with controls	-	↓	Yes
Klemenak et al., 2015 Slovenia [38]	3-arm RCT: 49 children with coeliac disease compared to 18 healthy controls	Probiotic: B. breve BR03 and B632 2 × 109 cfu daily for three months	TNF-α and IL-10 measured at baseline and 3 months	Decreased TNF-α levels from baseline (p < 0.05)	-	↓	N/a
Autoimmune disorders: Other
Fortes et al., 2020 Brazil [39]	2-arm RCT: 4 children aged 2–17 years with compensated or partially compensated nephrotic syndrome and dyslipidaemia	Probiotic: L. plantarum Lp-G18 2.5 × 109 cfu daily for 12 weeks	TNF-α and IL-10 measured at baseline and during and at the end of the study	-	-	→	No
Shukla et al., 2016 India [44]	2-arm RCT: 46 children aged 13–19 years with active enthesitis-related juvenile inflammatory arthritis	Probiotic: (S. thermophilus, B. breve, B. longum, B. infantis, L. acidophilus, L. plantarum, L. paracasei and L. delbrueckii (VSL#3) capsules 112·5 billion cells twice daily for 12 weeks	Blood Th1, Th2, Th17 and Treg cells, ESR, CRP, IFN-γ, IL-6, IL-17, TNF-α, IL−4, and IL-10 measured at baseline and 12 weeks	Fall in IL-6 from baseline (p = 0·007)	Increased Th2 cells (p < 0.05) and IL-10 in placebo group (p = 0·013) from baseline	↓/→	No
Preterm infants
Aly et al., 2017 Egypt [25]	4-arm RCT: 40 newborns with gestational age ≤ 34 weeks and age > 3 days	Prebiotic: different doses of medically graded bee honey daily for 14 days	CD4 and CD8 cells measured at baseline and 7 and 14 days	-	-	→	Yes
Fujii et al., 2006 Japan [40]	2-arm RCT: 19 preterm newborns	Probiotic: B. breve M-16V 109 cells twice daily from several hours after birth until discharge	IL-4, IL-5, IL-6, IFN-γ, TGF-β1, and TNF-α measured at baseline and 14 and 28 days	Increased TGF-β1 from baseline on days 14 (p = 0.026) and 28 (p = 0.029); increased TGF-β1 on day 28 (p = 0.005)	-	↓	No
Overweight/obesity
Nicolucci et al., 2017 Canada [26]	2-arm RCT: 42 overweight and obese children aged 7–12 years	Prebiotic: oligofructose-enriched inulin (Synergy1) 8 g/day for 16 weeks	CRP, IFNγ, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-33, monocyte chemoattractant protein-1, TNF-α, and lipopolysaccharide measured at baseline and 16 weeks	Decreased IL-6 from baseline compared with controls (p = 0.01)	-	↓	Yes
Other diseases; severe illness
Wang et al., 2018 China [41]	2-arm RCT: 80 children aged ≤14 years with acute lung injury	Probiotic: Eosinophil Lactobacillus 5 × 106 cfu 3 times daily for 10 days	TNF-α and IL-6 measured at baseline and 10 days	Decreased TNF-α (p = 0.0005) and IL-6 (p = 0.0004)	-	↓	Yes
Angurana et al., 2018 India [45]	2-arm RCT: 100 children aged 3 months to 12 years with severe sepsis	Probiotic: VSL#3 (L. paracasei DSM 24734, L. plantarum DSM 24730, L. acidophilus DSM 24735, L. delbrueckii subsp. bulgaricus DSM 24734, B. longum DSM 24736, B. infantis DSM 24737, B. breve DSM 24732, S. thermophilus DSM 24731; Danisco-Dupont USA, Madison, WI); 450 billion bacteria twice daily for 7 days	IL-12p70, IL-6, IL-17, TNF-α, IL-10, and TGF -β1 measured on days 1 and 7	Decreased IL-6 (p = 0.001), IL-12p70 (p = 0.001); IL-17 (p = 0.01), TNF-α (p = 0.01] and increased IL-10 (p = 0.02), TGF-β1 (p = 0.01) in probiotic vs. controls at day 7. From baseline, fall in IL-6 (p = 0.001), IL-12p70 (p= 0.01], IL-17 (p = 0.01), TNF-α (p = 0.001); increase in IL-10 (p = 0.001) and TGF-β1 (p = 0.001)	-	↓	Yes
Other diseases
de Freitas et al., 2018 Brazil [46]	3-arm RCT: children with cystic fibrosis received synbiotic (n = 22, mean (SD) age: 9.6 ± 2.8 years) vs. healthy controls (n = 17, mean age: 8.6 ± 3.0 years)	Synbiotic: L. paracasei, L. rhamnosus, L. acidophilus, B. lactis 108–109 cfu daily of each strain and FOS (5.5 g/day) (Lactofos®) for 90 days	High sensitivity CRP, IL-1β, IL-6, IL-8, IL-12, TNF-α, myeloperoxidase, nitric oxide metabolites (NOx), and IL-10 measured at baseline and 90 days	Fall from baseline in NOx (p = 0.030)	-	↓	No
Wang et al., 2015 China [43]	2-arm RCT: 60 children < 18 years with Hirschsprung’s disease at risk of enterocolitis	Probiotic: Bifidobacterium, L. acidophilus, and E. faecalis; (BIFICO; strains not specified) >108 cfu daily for 4 weeks	T lymphocyte subsets, TNF-α, IFN-γ, IL-6, IL-10 unclear when measured	Increased CD4+ cells (p = 0.048) and CD4+/CD8+ ratio (p = 0.005) compared with controls; decreased TNF-α p < 0.01), IFN-γ (p = 0.029), IL-6 (p = 0.015); increased IL-10 (p = 0.011) compared with controls	-	↓	Yes
Ellis et al., 2013 USA [42]	2-arm RCT: 16 term infants with congenital heart disease at risk of necrotising enterocolitis	Probiotic: B. longum ssp. infantis ATCC 15,697 4.2 × 109 cfu twice two daily for 8 weeks or until death or discharge if sooner	IFN-γ, IL-1β, IL-8, TNF-α, and IL-10 measured weekly	-	Increased IFN-γ (p = 0.007) and IL-1β (p = 0.04)	↑	N/a

¹ ↑ = pro-inflammatory; ↓ = anti-inflammatory; ↑/↓ = both pro-and anti-inflammatory; → = no effect observed; ² statisticially significant benefit in one or more primary or secondary clinical outcomes in the intervention group compared with controls; N/a = not applicable; no clinical outcomes reported, RCT—randomised controlled trial; GOS—galacto-oligosaccharides; PBMC—peripheral blood mononuclear cells; PHA—phytohemagglutinin.