Use of probiotics and similar in pediatric patients with Type 1 Diabetes Mellitus: a systematic review

Neiva, Luisa Pinheiro; Lopez, Luiza Correia; Pasiani, Rafaela Orsi; Serra, Mayco José Reinaldi; Rullo, Vera Esteves Vagnozzi

doi:10.1590/1984-0462/2024/42/2023097

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Revista Paulista de Pediatria

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Review Article • Rev. paul. pediatr. 42 • 2024 • https://doi.org/10.1590/1984-0462/2024/42/2023097 copy

Use of probiotics and similar in pediatric patients with Type 1 Diabetes Mellitus: a systematic review

Uso de probióticos e similares em pacientes pediátricos com Diabetes Mellitus tipo 1: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To perform a systematic review of randomized controlled trials, evaluating the effect of probiotics, prebiotics or symbiotics supplementation on glycemic and inflammatory control in children with Type 1 Diabetes Mellitus (T1DM).

Data source:

The Medical Literature Analysis and Retrieval System Online (MEDLINE/PubMed), Clinical Trials, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and Scientific Electronic Library Online (SciELO) databases were searched. Randomized clinical trials of pediatric patients with DM1 using probiotics, prebiotics or symbiotics were included, regardless of year or language of publication. Studies that did not evaluate glycated hemoglobin (HbA1c) were excluded. Metabolic results (HbA1c, total insulin dose and C-peptide) and inflammatory control [interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ)] during probiotic supplementation or similar, related to modification of the intestinal microbiota, were analyzed. PROSPERO ID: CRD42022384485.

Data synthesis:

Five studies were selected for a systematic review. Regarding metabolic markers, only one of the articles that analyzed HbA1c showed a significant decrease (p=0.03) in the intervention group. One study identified a reduction in the total dose of insulin and increased C-peptide levels. Regarding the evaluation of inflammatory parameters (IL-10, TNF-α, INF-γ), there were no statistical relevant modifications.

Conclusions:

Current data from the literature were not conclusive in identifying an improvement in glycemic control and did not observe changes in inflammatory parameters with the use of probiotics, prebiotics or symbiotics in pediatric patients with T1DM.

Keywords:
Glycated hemoglobin A; Diabetes mellitus type 1; Probiotics; Glycemic control; Cytokines

Assessed domain	I	II.1	II.2	III	IV	V	Final classification
Wang et al.¹⁸18 Wang CH, Yen HR, Lu WL, Ho HH, Lin WY, Kuo YW, et al. Adjuvant probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in patients with Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne). 2022;13:754401. https://doi.org/10.3389/fendo.2022.754401 https://doi.org/10.3389/fendo.2022.75440...
Kumar et al.¹⁹19 Kumar S, Kumar R, Rohilla L, Jacob N, Yadav J, Sachdeva N. A high potency multi-strain probiotic glycemic control in children with new-onset type 1 diabetes mellitus: a randomized, double-blind, and placebo controlled pilot study. Pediatr Diabetes. 2021;22:1014-22. https://doi.org/10.1111/pedi.13244 https://doi.org/10.1111/pedi.13244...
Groele et al.²⁰20 Groele L, Szajewska H, Szalecki M, Świderska J, Wysocka-Mincewicz M, Ochocińska A, et al. Lack of effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: a randomized controlled trial. BMJ Open Diabetes Res Care. 2021;9:e001523. https://doi.org/10.1136/bmjdrc-2020-001523 https://doi.org/10.1136/bmjdrc-2020-0015...
Javid et al.²¹21 Javid AZ, Aminzadeh M, Haghighi-Zadeh MH, Jamalvandi M. The effects of symbiotic supplementation on glycemic status, lipid profile, and biomarkers of oxidative stress in type 1 diabetic patients: a placebo-controlled, double-blind, randomized clinical trial. Diabetes Metab Syndr Obes. 2020;13:607-17. https://doi.org/10.2147/DMSO.S238867 https://doi.org/10.2147/DMSO.S238867...
Ho et al.²²22 Ho J, Nicolucci AC, Virtanen H, Schick A, Meddings J, Reimer RA, et al. Effect of prebiotic on microbiota, intestinal permeability, and glycemic control in children with type 1 diabetes. J Clin Endocrinol Metab. 2019;104:4427-40. https://doi.org/10.1210/jc.2019-00481 https://doi.org/10.1210/jc.2019-00481...

Author and country	Age studied	T1DM diagnosis time	Probiotics or similar and doses	No. of the total sample (probiotic x placebo)	Follow-up time
Wang et al.¹⁸18 Wang CH, Yen HR, Lu WL, Ho HH, Lin WY, Kuo YW, et al. Adjuvant probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in patients with Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne). 2022;13:754401. https://doi.org/10.3389/fendo.2022.754401 https://doi.org/10.3389/fendo.2022.75440... ; Taiwan	6–18 years	Long-term diabetic patients who have already experienced the honeymoon period	Probiotics^* * L. salivarius subesp. salicinius AP-32, L. johnsonii MH-68 and B. animalis subesp. lactis CP-9 10¹⁰ CFU/day or placebo orally for 6 months	59 (27×32)	9 months
Kumar et al.¹⁹19 Kumar S, Kumar R, Rohilla L, Jacob N, Yadav J, Sachdeva N. A high potency multi-strain probiotic glycemic control in children with new-onset type 1 diabetes mellitus: a randomized, double-blind, and placebo controlled pilot study. Pediatr Diabetes. 2021;22:1014-22. https://doi.org/10.1111/pedi.13244 https://doi.org/10.1111/pedi.13244... ; India	2–12 years	T1DM of recent onset (within 6 months of enrollment)	Probiotics^† † Live, freeze-dried, lactic and bifidobacteria named L paracasei DSM 24733, L plantarum DSM 24730, L acidophilus DSM 24735, L delbrueckii subsp. bulgaricus DSM 24734, B longum DSM 24736, B children’s DSM 24737, B brief DSM 24732 and Streptococcus thermophilus DSM 24731 112.5 billion CFU/day or microcrystalline cellulose for 3 months	96 (47×49)	3 months
Groele et al.²⁰20 Groele L, Szajewska H, Szalecki M, Świderska J, Wysocka-Mincewicz M, Ochocińska A, et al. Lack of effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: a randomized controlled trial. BMJ Open Diabetes Res Care. 2021;9:e001523. https://doi.org/10.1136/bmjdrc-2020-001523 https://doi.org/10.1136/bmjdrc-2020-0015... ; Varsovia, Poland	8–17 years	Recent diagnosis (within 60 days)	Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 10⁹ CFU colony or placebo (maltodextrin) orally capsule once a day for 6 months	96 (48×48)	12 months
Javid et al.²¹21 Javid AZ, Aminzadeh M, Haghighi-Zadeh MH, Jamalvandi M. The effects of symbiotic supplementation on glycemic status, lipid profile, and biomarkers of oxidative stress in type 1 diabetic patients: a placebo-controlled, double-blind, randomized clinical trial. Diabetes Metab Syndr Obes. 2020;13:607-17. https://doi.org/10.2147/DMSO.S238867 https://doi.org/10.2147/DMSO.S238867... ; Shiraz, Iran	4–18 years	At least 1 year with diagnosis of DM1	2 g symbiotic powder^‡ ‡ Symbiotic powder: Lactobacillus sporogenes GBI-30 (probiotic), maltodextrin and fructooligosaccharide (prebiotic). (109 CFU) for 8 weeks	50 (25×25)	8 weeks
Ho et al.²²22 Ho J, Nicolucci AC, Virtanen H, Schick A, Meddings J, Reimer RA, et al. Effect of prebiotic on microbiota, intestinal permeability, and glycemic control in children with type 1 diabetes. J Clin Endocrinol Metab. 2019;104:4427-40. https://doi.org/10.1210/jc.2019-00481 https://doi.org/10.1210/jc.2019-00481... ; Canada	8–17 years	At least 1 year with diagnosis of DM1	8g oligofructose-enriched inulin orally once a day or placebo 3.3g maltodextrin orally once a day for 12 weeks	43 (20×23)	6 weeks

			HbA1c (%)		Total insulin dose (μg/mL)		C-peptide (ng/mL)
			M±SD	p-value	M±SD	p-value	M±SD	p-value
Wang et al.¹⁸18 Wang CH, Yen HR, Lu WL, Ho HH, Lin WY, Kuo YW, et al. Adjuvant probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in patients with Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne). 2022;13:754401. https://doi.org/10.3389/fendo.2022.754401 https://doi.org/10.3389/fendo.2022.75440... ; Taiwan	Basal	I	9.3±0.80	0.883
	Basal	C	9.5±1.90	0.883
	After 6 m	I	8.5±0.90	NI
	After 6 m	C	9.5±2.10	NI
Kumar et al.¹⁹19 Kumar S, Kumar R, Rohilla L, Jacob N, Yadav J, Sachdeva N. A high potency multi-strain probiotic glycemic control in children with new-onset type 1 diabetes mellitus: a randomized, double-blind, and placebo controlled pilot study. Pediatr Diabetes. 2021;22:1014-22. https://doi.org/10.1111/pedi.13244 https://doi.org/10.1111/pedi.13244... ; India	Basal	I	11.7±1.63	0.512	1.0±0.45	0.183	0.3±0.35	0.866
	Basal	C	11.5±2.26		0.9±0.40		0.3±0.45
	After 3 m	I	6.8±1.46		0.6±0.31		0.5±0.40
	After 3 m	C	7.4±1.46		0.7±0.40		0.5±0.35
Groele et al.²⁰20 Groele L, Szajewska H, Szalecki M, Świderska J, Wysocka-Mincewicz M, Ochocińska A, et al. Lack of effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: a randomized controlled trial. BMJ Open Diabetes Res Care. 2021;9:e001523. https://doi.org/10.1136/bmjdrc-2020-001523 https://doi.org/10.1136/bmjdrc-2020-0015... ; Poland	Basal	I	7.7±0.41	NI			1.0±0.27	NI
	Basal	C	8.3±0.72	NI			1.0±0.34	NI
	After 6m	I	6.1±0.35	0.058			0.9±0.26	0.832
	After 6m	C	6.5±0.39	0.058			0.9±0.27	0.832
Javid et al.²¹21 Javid AZ, Aminzadeh M, Haghighi-Zadeh MH, Jamalvandi M. The effects of symbiotic supplementation on glycemic status, lipid profile, and biomarkers of oxidative stress in type 1 diabetic patients: a placebo-controlled, double-blind, randomized clinical trial. Diabetes Metab Syndr Obes. 2020;13:607-17. https://doi.org/10.2147/DMSO.S238867 https://doi.org/10.2147/DMSO.S238867... ; Iran	Basal	I	8.9±1.95	0.270^* * Used the independent t-test between the two groups before and after the intervention	6.4±6.32	0.810^* * Used the independent t-test between the two groups before and after the intervention
	Basal	C	9.6±2.23		6.0±5.02
	After 8 w	I	8.6±1.85	0.960^* * Used the independent t-test between the two groups before and after the intervention	10.9±8.20	0.150^* * Used the independent t-test between the two groups before and after the intervention
	After 8 w	C	9.1±2.59		7.6±7.12
		≠ I	-0.3±0.52	0.030^† † Analysis of covariance (ANCOVA) was performed between the two post-intervention groups after adjustment for confounding factors.	4.5±4.53	0.060^† † Analysis of covariance (ANCOVA) was performed between the two post-intervention groups after adjustment for confounding factors.
		≠ C	-0.5±1.36		1.6±5.46
Ho et al.²²22 Ho J, Nicolucci AC, Virtanen H, Schick A, Meddings J, Reimer RA, et al. Effect of prebiotic on microbiota, intestinal permeability, and glycemic control in children with type 1 diabetes. J Clin Endocrinol Metab. 2019;104:4427-40. https://doi.org/10.1210/jc.2019-00481 https://doi.org/10.1210/jc.2019-00481... ; Canada	Basal	I	8.0±0.82	0.854	0.9±0.25	0.928	0.3±0.75	0.928
	Basal	C	8.1±0.91	0.854	0.9±0.29	0.928	0.2±0.30	0.928
	After 3 m	I	7.9±0.50	0.592	NI	NI	0.3±0.93	0.029
	After 3 m	C	8.1±0.91	0.592	NI	NI	0.1±0.15	0.029

			IL-10		TNF-α		IFN-γ
			M±SD	p-value	M±SD	p-value	M±SD	p-value
Wang et al.¹⁸18 Wang CH, Yen HR, Lu WL, Ho HH, Lin WY, Kuo YW, et al. Adjuvant probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in patients with Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne). 2022;13:754401. https://doi.org/10.3389/fendo.2022.754401 https://doi.org/10.3389/fendo.2022.75440... ; Taiwan	Basal	I			52.5±59.70	0.810
	Basal	C			54.0±56.80	0.810
	After 6 m	I			39.2±47.50	NI
	After 6 m	C			49.3±57.20	NI
Groele et al.²⁰20 Groele L, Szajewska H, Szalecki M, Świderska J, Wysocka-Mincewicz M, Ochocińska A, et al. Lack of effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: a randomized controlled trial. BMJ Open Diabetes Res Care. 2021;9:e001523. https://doi.org/10.1136/bmjdrc-2020-001523 https://doi.org/10.1136/bmjdrc-2020-0015... ; Poland	Basal	I	282.1±105.92	NI	4.6±5.29	NI
	Basal	C	186.6±85.92	NI	3.7±4.28	NI
	After 6 m	I	202.9±80.91	0.470	1.4±1.68	0.594
	After 6 m	C	161.9±75.65	0.470	4.7±5.46	NI
Ho et al.²²22 Ho J, Nicolucci AC, Virtanen H, Schick A, Meddings J, Reimer RA, et al. Effect of prebiotic on microbiota, intestinal permeability, and glycemic control in children with type 1 diabetes. J Clin Endocrinol Metab. 2019;104:4427-40. https://doi.org/10.1210/jc.2019-00481 https://doi.org/10.1210/jc.2019-00481... ; Canada	Basal	I	15.1±36.17	0.816	16.1±52.33	0.292	0.44±1.79	0.285
	Basal	C	13.0±17.91	0.816	3.9±1.75	0.292	0.02±0.04	0.285
	After 3 m	I	18.0±10.88	0.093	17.7±3.95	0.058	0.44±0.01	0.523
	After 3 m	C	7.0±18.16	0.093	3.6±1.52	0.058	0.01±0.04	0.523

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[1] Corresponding author. E-mail: luisapneiva@gmail.com (L. P. Neiva)