Study search overview
The initial search identified 7234 articles, of which 5545 were duplicates and 1658 did not meet eligibility criteria by screening titles and abstracts. Of the remaining 31 documents eligible for full-text reviews, 17 were removed (Fig. 1). Fourteen studies [6, 15–27] were included in qualitative analysis and five [19, 25, 15, 6, 17] in quantitative analysis.
Characteristics Of The Included Studies
Table 2 presents the characteristics of the included studies. Clinical trials were carried out in Argentina [16, 20, 21], Australia [15], Brazil [22], Italy [6], Pakistan [24], Slovenia [18, 19, 23], Spain [17], Sweden [25, 26], and Turkey [27]. Altogether, 871 participants were included in this systematic review, of whom 203 were CDA cases. Most of the included studies were the randomized double-blinded placebo-controlled clinical trials. However, there was one clinical trial with external controls [16], one double-blinded placebo-controlled cross-over trial[21], two randomized clinical trials without any medication in placebo group [24, 27], and one none-randomized clinical trial [22]. The study population of six studies consisted of adults [6, 15, 16, 20–22], while the other eight studies, including all trials on CDA, were conducted on children [17–19, 25, 23, 26, 27, 24]. Approximately half and one fourth of the participants were male in CDA and CD studies, respectively.
Table 2
Characteristics of included studies investigating the effect of probiotics and synbiotics on celiac
Author, year
|
Country of origin
|
Study design
|
Sample size
|
Population characteristics
|
Intervention/placebo
|
Follow up duration
|
outcome definition
|
Findings
|
Adverse events
|
Francavilla et al.
2018[1]
|
Italy
|
DBRCT
|
Probiotics: 54
Placebo: 55
|
Probiotic:
43.3(18.8–62.2)
Male 11%
Placebo:
Age: 44.6(19.3–63.4)
Male: 16%
Dx: biopsy
On GFD > 2 years
Persistent symptoms [IBS-SSS > 75]
|
Mixture of :
Lactobacillus casei LMG 101/37 P-17504 (5×109 CFU), Lactobacillus plantarum CECT 4528 (5×109 CFU), Bifidobacterium animalis subsp. lactis Bi1 LMG P-17502 (10×109 CFU),
Bifidobacterium breve Bbr8 LMG P-17501 (10×109 CFU),
B. breve Bl10 LMG P-17500 (10×109 CFU)
Vs Placebo sachet
Daily
|
2 week run-in;
6 week treatment;
6 week f/u
|
↓aBSC,
↓GSRS;
↓IBS-SSS;
|
↓GI symptoms;
↔bQOL,
Modified gut microbiota
|
No adverse events
|
Harnett et al.
2016[2]
|
Australia
|
DBRCT
|
Probiotics: 21
Placebo: 21
|
Probiotic :
Age 47.1 (± 16.06)
Male 14%
Placebo :
Age 47.5 (± 12.87)
Male 18%
Dx: biopsy
On GFD for at least 12 months
Persistent symptoms
|
VSL#3 (4.5×1011 CFU)
Vs Placebo sachet
Before breakfast and lunch
|
12 week treatment
|
|
Modified gut microbiota,
↓Urinary D-lactate
|
Mild bloating (two in placebo and two in active group)
|
Olivares et al.
2014[3]
|
Spain
|
DBRCT
|
Probiotics: 17
Placebo: 16
|
Probiotic :
Age 6.8 ± 0.9
Male 41%
Placebo :
Age 8.5 ± 1.2
Male 50%
Dx : biopsy
Newly diagnosed
|
Bifidobacterium longum CECT 7347 (109 CFU)
Vs Placebo
At lunch time
|
3 months
|
|
↔Serologic markers of CD ;
↔weight;
↑cHeight ;
↔Symptoms ;
↓CD3+ ;
↓HLA-DR+ ;
↔TNF-α;
↔interferon-γ;
↔TGF-ß1;
↔IL13;
↔IL-10;
↔IgG1;
↔IgG4 ;
↓Fecal IgA ;
Modified fecal microbiota ;
|
No adverse events
|
Pinto-Sa ́nchez et al.
2016[4]
|
Agentina
|
Clinical trial with external controls
|
Active CD: 24
Active CD without GFD treated with probiotic: 12
Control CD on GFD: 5
|
Active CD on probiotics :
Age 41 (22–53)
Male 33%
Active CD w/o treatment :
Age 40 (29–54)
Male 4%
CD on GFD :
Age 35 (31–45)
Male 20%
Dx : biopsy
Active cases
|
Bifidobacterium infantis NSL-SS
|
3 weeks
|
|
↔Macrophage;
↓Paneth cell;
↓HD-5 on duodenal bx ;
|
NR
|
Primec et al.
2018[5]
|
Slovenia
|
DBRCT
|
Probiotic 20
Placebo 19
HC 14
|
Probiotic :
Age 9.15 ± 4.35
Male 20%
Placebo :
Age 10.53 ± 5.05
Male 31%
HC :
Age 10.14 ± 6.01
Male 36%
Dx : biopsy
On GFD from 6 months to 15 years
|
B. breve 72 BR03 (DSM 16604) (2×109 CFU) and B. breve B632 (DSM 24706) (2×109 CFU)
Vs Placebo
Daily
|
3 months ;
3 months f/u
|
|
NGS, SCFAs and TNF-a;
Serologic markers of CD ;
Fecal microbiota
Only reported correlation
|
NR
|
Quagliariello et al.
2016[6]
|
Slovenia
|
DBRCT
|
Probiotic 20
Placebo 20
HC 16
|
Dx : biopsy
On GFD for at least 3 months
|
B. breve BR03 (DSM 16604) (109 CFU) and B. breve B632 (DSM 24706) (109 CFU)
Vs Placebo
With breakfast
|
3 months
|
|
Modified fecal microbiota
|
NR
|
Smecuol et al.
2013[7]
|
Argentina
|
DBRCT
|
Probiotic 12
Placebo 10
|
Probiotic:
Age 46(29–62)
Male 33%
Placebo:
Age 40(20–71)
Male 0%
Dx : serologic
on gluten containing diet
|
B. infantis NLS super strain(4×109 CFU)
Vs Placebo
Three times per day
without GFD
|
2 week run in
3 week treatment
50 day f/u
|
|
↔lactulose/mannitol fractional urinary ratio;
↔GSRS;
↔anti tTG-IgA;
↔anti DGP IgA;
↔IL-1b; ↔IL-2; ↔IL-4; ↔IL-5; ↔IL-6; ↔IL-7; ↔IL-8; ↔IL-10; ↔IL-12; ↔IL-13; ↔IL-17; ↔G-CSF; ↔GM-CSF; ↔MCP-1/CCL2; ↔MIP-1b/CCL4; ↔TNF-α;
↓PBMC-IL-12p70;
↔PBMC-IL-6;
↔PBMC-IL-10/IL-12p70;
|
No adverse events
|
Smecuol et al.
2020[8]
|
Argentina
|
DBRCT
|
Probiotic 7
Placebo 5
|
Probiotic :
Male 0%
Placebo :
Male 20%
Dx : biopsy
On GFD for > 2 years
GSRS > 2
Age 53(43–57)
|
B. infantis NLS-SS (4×109 CFU)
Vs Placebo
Daily
|
One week run in
3 weeks treatment
2 weeks washout
3 weeks switched treatment
|
↓CSI global score [highly symptomatic pts] ;
↓CSI specific CD symptoms[highly symptomatic pts];
|
Modifed fecal microbiota ;
↔Stool and urine GIP ;
↓Symptoms;
|
No adverse events
|
Martinello et al. 2017[9]
|
Brazil
|
Non-randomized clinical trial
|
CD 14
HC 17
|
CD:
Age 38
Male 29%
HC:
Age 26
Male 41%
Dx: biopsy
On GFD and asymptomatic
|
108 CFU of Lactobacillus acidophilus and Bifidobacterium lactis as 100 gr of yogurt per day
|
30 days
|
|
|
NR
|
Klemenak et al. 2015[10]
|
Slovenia
|
DBRCT
|
Probiotic 22
Placebo 24
HC 18
|
Probiotic:
Age 10.43 ± 4.19
Male 27%
Placebo:
Age 10.81 ± 4.99
Male 42%
HC:
Age 8.83 ± 5.95
Male 39%
Dx: biopsy
On GFD from 0.5 to 15 years
|
lyophilized B. breve BR03(109 CFU) and B. breve B632(109 CFU)
Vs Placebo
Daily
|
3 months ;
3 months f/u
|
|
↔TNF-α;
↑TNF-α[pts on GFD < 1 year, on 3 month f/u];
↔IL-10;
|
No adverse events
|
Ali et al. 2021[11]
|
Pakistan
|
Randomized clinical trial
|
Probiotic: 85
No modication: 85
|
Age 8–10
|
Clostridium butyricum and Bifidobacterium
|
28 days
|
Defecation frequency per day
|
↓Stool frequency
|
NR
|
Oscarsson et al. 2021[12]
|
Sweden
|
DBRCT
|
Probiotic 40
Placebo 38
|
Probiotic:
Age 5(3–7)
Male 55%
Placebo:
Age 4(3–6)
Male 37%
Dx: high anti-tTG not diagnosed with CD
|
1.0 g of maltodextrin and lyophilized bacteria (L. plantarum HEAL9 (DSM 15312) and Lactobacillus. paracasei 8700:2 (DSM 13434), at a total dose of 1010 CFU/sachet)
Vs Placebo
Daily
|
6 months
|
|
Modified fecal microbiota;
|
Three in probiotic and four in placebo reported pain, flatulence or diarrhea
One in each group reported GI symptoms
|
Håkansson et al. 2019[13]
|
Sweden
|
DBRCT
|
Probiotic 40
Placebo 38
|
Probiotic:
Age 5(3–7)
Male 55%
Placebo:
Age 4(3–6)
Male 37%
Dx : high anti-tTG not diagnosed with CD
|
1.0 g of maltodextrin and lyophilized bacteria (L. plantarum HEAL9 (DSM 15312) and L. paracasei 8700:2 (DSM 13434), at a total dose of 1010 CFU/sachet)
Vs Placebo
Daily
|
6 months probiotic;
enrollment
3 months
|
|
Diagnosed CD six in probiotic and five in placebo at the end;
↔IgA-tTG;
↔IgG-tTG;
↓CD3 + CD56+;
↓CD3 + CD4 + CD45RA + CD45RO-;
↓CD3 + CD4 + CD45RA-CD45RO+;
↓CD4 + CCR4 + CD45RO+;
↓CD4 + CD25 + CD45RO+;
↓CD4 + CD25high + CCR4 + CD45RO+;
↓CD3 + CD4 + CCR9 + β7+;
|
Three in probiotic and four in placebo reported pain, flatulence or diarrhea
One in each group reported GI symptoms
|
Demiroren 2020[14]
|
Turkey
|
RCT
|
Symbiotic 41
No medication 41
|
Symbiotic:
Age 6(3.5–11)
Male 48%
No medication:
Age 9(4-13.5)
Male 48%
Dx : high anti-tTG w/o CD on biopsy
|
2.5×109 cfu live bacteria including Enterococcus faecium, L. acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum, B. longum, 625 mg fructooligosaccharide, and vitamins A, B1, B2, and B6
Vs no medication
Daily
|
20 days Symbiotic
f/u in 2–6 months
|
|
↓IgA-tTG;
|
NR
|
Dx: Diagnosis. DBRCT: Double-blinded Placebo-controlled Randomized Clinical Trial. DBRCoT: Double-blinded Placebo-controlled Randomized Cross-over Trial. RCT: Randomized Clinical Trial. GFD: Gluten Free Diet. IBS-SSS: Irritable Bowel Syndrome Severity Scoring System. CFU: Colony Forming Unit. GI: Gastrointestinal. QOL: Quality of Life. CD: Celiac Disease. HLA: Human Leukocyte Antigen. TNF-α: Tumor Necrosis Factor alpha. TGF: Transforming Growth Factor. IL: Interleukin. IgG: immunoglobulin G. IgA: Immunoglobulin A. NR: Not Reported. w/o: without. bx: biopsy. HD-5: Human α-Defensins 5. f/u: follow-up. HC: Healthy Control. GSRS: Gastrointestinal Symptom Rating Scale. GIP: Gluten Immunogenic Peptide. CSI: Celiac Symptom Index. pts: patients. tTG: tissue Transglutaminase. BSC: Btistol Stool Chart. GCSF: Granulocyte Colony-Stimulating Factor. GMCSF: Granulocyte Monocyte Colony-Stimulating Factor. MCP-1/CCL2: Monocyte Chemoattractive Protein. MIP-1b/CCL4: Macrophage Inflammatory Protein. PBMC: Peripheral Blood Mononuclear Cell. asignificantly lower in probiotic group. bno significant difference. csignificantly higher in probiotic group. |
References |
1. Francavilla R, Cristofori F, Vacca M, Barone M, De Angelis M (2020) Advances in understanding the potential therapeutic applications of gut microbiota and probiotic mediated therapies in celiac disease. Expert Rev Gastroenterol Hepatol 14:323–333. https://doi.org/10.1080/17474124.2020.1745630 |
2. Harnett J, Myers SP, Rolfe M (2016) Probiotics and the microbiome in celiac disease: a randomised controlled trial. Evidence-Based Complementary and Alternative Medicine 2016 |
3. Olivares M, Castillejo G, Varea V, Sanz Y (2014) Double-blind, randomised, placebo-controlled intervention trial to evaluate the effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed coeliac disease. British journal of nutrition 112:30–40 |
4. Pinto-Sánchez MI, Smecuol EC, Temprano MP, Sugai E, González A, Moreno ML, Huang X, Bercik P, Cabanne A, Vázquez H (2017) Bifidobacterium infantis NLS super strain reduces the expression of α-defensin-5, a marker of innate immunity, in the mucosa of active celiac disease patients. Journal of Clinical Gastroenterology 51:814–817 |
5. Primec M, Klemenak M, Di Gioia D, Aloisio I, Cionci NB, Quagliariello A, Gorenjak M, Mičetić-Turk D, Langerholc T (2019) Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-α and short-chain fatty acids. Clinical nutrition 38:1373–1381 |
6. Quagliariello A, Aloisio I, Bozzi Cionci N, Luiselli D, D’Auria G, Martinez-Priego L, Pérez-Villarroya D, Langerholc T, Primec M, Mičetić-Turk D (2016) Effect of Bifidobacterium breve on the intestinal microbiota of coeliac children on a gluten free diet: a pilot study. Nutrients 8:660 |
7. Smecuol E, Hwang HJ, Sugai E, Corso L, Chernavsky AC, Bellavite FP, González A, Vodánovich F, Moreno ML, Vázquez H (2013) Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease. Journal of clinical gastroenterology 47:139–147 |
8. Smecuol E, Constante M, Temprano MP, Costa AF, Moreno ML, Pinto-Sanchez MI, Vázquez H, Stefanolo JP, Gonzalez AF, D’Adamo CR (2020) Effect of Bifidobacterium infantis NLS super strain in symptomatic coeliac disease patients on long-term gluten-free diet–an exploratory study. Beneficial Microbes 11:527–534 |
9. Martinello F, Roman CF, Souza PAd (2017) Effects of probiotic intake on intestinal bifidobacteria of celiac patients. Arquivos de Gastroenterologia 54:85–90 |
10. Klemenak M, Dolinšek J, Langerholc T, Di Gioia D, Mičetić-Turk D (2015) Administration of Bifidobacterium breve Decreases the Production of TNF-α in Children with Celiac Disease. Digestive diseases and sciences 60:3386–3392 |
11. Ali B, Khan AR (2022) Efficacy of Probiotics in Management of Celiac Disease. Cureus 14 |
12. Oscarsson E, Håkansson Å, Andrén Aronsson C, Molin G, Agardh D (2021) Effects of probiotic bacteria Lactobacillaceae on the gut microbiota in children with celiac disease autoimmunity: A placebo-controlled and randomized clinical trial. Frontiers in Nutrition 8:354 |
13. Håkansson Å, Andrén Aronsson C, Brundin C, Oscarsson E, Molin G, Agardh D (2019) Effects of Lactobacillus plantarum and Lactobacillus paracasei on the peripheral immune response in children with celiac disease autoimmunity: a randomized, double-blind, placebo-controlled clinical trial. Nutrients 11:1925 |
14. Demiroren K (2020) Can a Synbiotic Supplementation Contribute to Decreasing Anti-Tissue Transglutaminase Levels in Children with Potential Celiac Disease? Pediatric Gastroenterology, Hepatology & Nutrition 23:397 |
In terms of following GFD before enrolling in the studies, three out of all CD [20, 17, 16] and CDA trials [26, 25, 27] included the participants who were not on GFD prior to the beginning of the study. In other studies, the duration of GFD before the enrolment varies from three months to fifteen years. In addition, three studies [6, 21, 15] included patients with refractory CD. Contrary to other studies, in Smecuol et al. ‘s (2013), participants were still on GCD during the study [20].
Regarding the probiotics’ species, Smecuol et al. (2013), Smecuol et al. (2020), and Pinto-Sa ́nchez et al. (2016) used Bifidobacterium infantis NSL-SS as an intervention group [20,21,16]. Smecuol et al. (2020) used two probiotic capsules -containing 2×109 CFU/capsule each day. However, in studies conducted by Smecuol et al. (2013) and Pinto-Sa ́nchez et al. (2016 ), two similar capsules were administered three times a day [20,16]. Primec et al. (2018), Quagliarie et al. (2016), and Klemenak et al. (2015 )prescribed a combination of Bifidobacterium breve 72 BR03 and B. breve B632 as powder to be mixed with fluids ingested in the morning [18,19,23]. Primec et al. (2018) and Klemenak et al. (2015) administered 2×109 CFU/strain each day [18,23]. However, Quagliarie et al. (2016) used half this dosage [19].
Only studies conducted on CDA, including Demiroren et al., Oscarsson et al., and Håkansson et al. investigated the effects of synbiotics. Demiroren et al. administered Bifidobacterium longum, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus rhamnosus, Enterococcus faecium, and fructooligosaccharide, and vitamins A, B1, B2, and B6 [27]. While Oscarsson et al., and Håkansson et al. used Lactobacillus plantarum, Lactobacillus paracasei and maltodextrin[26, 25]. Probiotics were provided as sachets in most studies, except for Martinello et al., who used probiotic yoghurt [22] and Olivares et al., Pinto-Sa ́nchez et al., Smecuol et al. 2013, and Smecuol et al. 2020 who provided probiotics as capsules [20,21,16,17]. Oscarsson et al. (2021) [25] and Håkansson et al. (2019) [26] published two documents using the different outcomes of the same clinical trial.
Among CD studies, the longest treatment was three months [19, 18, 17, 23, 15] and Pinto-Sa ́nchez et al., Smecuol et al. (2013), and Smecuol et al. (2020) treated patients for three weeks which were the shortest ones [20,21,16]. In CDA studies, Demiroren et al. treated participants for 20 days, and the other two studies continued the intervention for six months [25–27].
Qualitative Findings
Qualitative results of this systematic review are summarized in four domains as follows.
Gastrointestinal Symptoms
Francavilla et al. [6] and Smecuol et al. [21], involving 129 patients, studied adult CD patients who were symptomatic despite following GFD at least for two years (refractory CD). Francavilla et al. (6) conducted the only study assessing gastrointestinal symptoms when administering a mixture of Bifidobacterium and Lactobacillus, while Smecuol et al. 2020 [21] only administered Bifidobacterium as probiotic. Francavilla et al. [6] reported a significant reduction in irritable bowel syndrome severity scoring system (IBS-SSS) and gastrointestinal symptom rating scale (GSRS) in the probiotic arm in comparison to placebo after a six-week treatment period. Moreover, the number of participants with at least 50% reduction in IBS-SSS was significantly higher in the probiotic arm. In their study, Smecuol et al. (2020) [21] did not report any significant differences between probiotic and placebo groups in terms of GSRS and celiac symptom index (CSI) changes. However, in the study, a sub-analysis including only highly symptomatic patients revealed a significantly higher reduction in CSI in the probiotic arm compared to the placebo.
Smecuol et al. 2013 [20], who conducted the only study on adult CD patients consuming GCD during probiotic treatment, reported no differences between groups in terms of GSRS, diarrhoea, distension, gas, and abdominal pain after three weeks of Bifidobacterium treatment. However, indigestion and constipation were significantly alleviated in the probiotic group.
Olivares et al. [17] and Ali et al. [24] prescribed Bifidobacterium in children with CD. Olivares et al. [17] found that height percentile was significantly increased in the probiotic group compared to the placebo group after 12 weeks of treatment. The increased weight did not reach statistical significance. No significant difference was reported regarding diarrhoea, constipation, abdominal pain, and vomiting after treatment. Ali et al. [24] reported a significant higher reduction in stool frequency in probiotic arm compared to placebo after four-weeks of treatment.
Inflammatory And Immune Responses And Intestinal Permeability
Smecuol et al. 2013, Håkansson et al., and Demiroren et al. measured celiac specific markers [20, 26, 27]. Smecuol et al. 2013 administered probiotics in adult CD patients for three weeks. The serum concentrations of tissue transglutaminase-immunoglobulin A (tTG-IgA) and Deamidated Gliadin Peptide-immunoglobulin A (DGP-IgA) were lower in the probiotic group; however, this change did not reach statistical significance [20]. Participants were children with CDA in studies conducted by Håkansson et al., and Demiroren et al. Former provided Lactobacillus and maltodextrin for six months, while the latter administered synbiotic containing both Bifidobacteria and Lactobacilus and fructooligosaccharide, and vitamins A, B1, B2, and B6 for 20 days[26, 27]. tTG-IgA and tTG-IgG were similar in the probiotic and placebo groups for Håkansson et al.’s [26]. In the contrary, Demiroren et al. reported a significant reduction in tTG-IgA in both groups. Additionally, the reduction was significantly more pronounced in the synbiotic group [27].
Three RCTs assessed the effects of probiotics on TNF-α in the pediatric population[18, 17, 23]. Only Bifidobacterium was administered for three months in all three RCTs. Prior GFD was similar for Primec et al. and Klemenak et al. ranging from half to 15 years[18, 23], whereas Olivares et al. included participants on GCD prior to study[17]. According to Primec et al., TNF-α had a positive correlation with 'Verrucomibrobia' and a negative correlation with 'Parcubacteria' at baseline, and a positive correlation with Firmicutes after the probiotic treatment[18]. TNF-α was not significantly different between groups in studies performed by Klemenak et al. and Olivares et al.However, it was reduced in both studies[17, 23]. This reduction was more prominent, bit was not statistically significant in patients who were on GFD for less than a year prior to the study [23].
Four articles studied immunologic response, two on adult CD patients and two on children, of which one studied CDA[20, 16, 17, 26]. Pinto-Sa ́nchez et al. compared a three-week course of Bifidobacterium supplementation and one year of GFD prescription. Paneth cell count and expression of human α-defensin-5 (HD-5) significantly reduced independent of GFD. In contrary, a significant reduction in macrophage count was only reported after one year of GFD[16]. In another three-week Bifidobacterium trial, macrophage inflammatory protein-1-β (MIP-1β) significantly increased in the probiotic group. Changes in other cytokines, including macrophage chemoattractant protein-1 (MCP-1), were insignificant [20]. Twelve weeks of Bifidobacterium significantly decreased mature T cells (CD45 + CD3+) in CD children. It also increased regulatory T cells (CD45 + CD4 + FoxP3+); however, it did not reach statistical significance. Cytokines were similar in to the placebo group[17]. In their study, Håkansson et al. assessed T helper cells after six months of Lactobacillus and maltodextrin. Memory T helper cells and naive T helper cells increased and decreased significantly less than the placebo group, respectively [26].
One RCT, assessinmg intestinal permeability after three weeks of Bifidobacterium ingestion using a urinary lactulose/mannitol ratio, showed no difference between groups [20].
Gut Microbiota
Faecal microbiota was assessed in seven CD studies [21, 19, 18, 17, 22, 15, 6], and in one CDA study [25] (Table 3). Four CD studies and one CDA study assessed Lactobacillus and Bifidobacterium abundance, so we conducted a meta-analysis [19, 25, 17, 15, 6]. In the study conducted by Smecuol et al. 2020, symptoms of highly symptomatic patients were significantly lower after a three-week course of Bifidobacterium compared to a placebo. Accordingly, highly symptomatic patients had 6.4 times higher B. longum compared to patients with mild symptoms [21]. Bifidobacterium administration significantly increased Lactobacillus abundance to the extent that it resembled healthy controls in one study [19]. In a study condcuted on CDA, six-month Lactobacillus and maltodextrin supplement significantly increased Lactobacillus genus and Lactobacillaceae family compared to placebo [25]. No significant difference in the abundance of Bifidobacterium and Lactobacillus was detected between probiotic and placebo groups in three studies, of which two studied refractory CD and one assessed pediatric population [17, 15, 6].
Table 3
Significant fecal findings after probiotic or synbiotic intake
Author, year
|
Fecal sampling
|
Increased bacteria
[taxonomic]
[time / group]
|
Decreased bacteria
[taxonomic]
[time/ group]
|
SIgA
|
Fecal PH
|
Francavilla, 2019[1]
|
End of week 2, 8, and 14
|
-Total anaerobes [time]
- Enterococcus
[Genus] [pr time]
-Lactobacillus
[Genus] [pr time]
-Lactococcus
[Genus] [pr time]
-Staphylococcus
[Genus] [pr time]
-Bifidobacterium
[Genus] [pr time]
|
|
|
|
Primec, 2019[2]
|
Enrollment
End of 3 months probiotic
|
|
|
|
|
Olivares, 2014[3]
|
Enrollment
End oof 3 months after CD Dx
|
- Bacteroides fragilis
[Species] [pl time]
Enterobacteriaceae
[Family] [pl time]
|
- B. fragilis
[Species] [group]
|
Decreased
[group]
|
|
Quagliariello, 2016[4]
|
Enrollment
End of 3 months probiotic
|
-Firmicutes
[Phylum] [group]
-Firmicutes
[Phylum] [time]
-Lactobacillaceae
[Family] [time]
-Gracilibacteraceae
[Family] [time]
-Unclass deltaproteobacteria
[Family] [time]
|
|
|
|
Smecuol, 2020[5]
|
After run-in;
end of 3 weeks treatment;
after 2 week wash-out;
after 3 weeks switch treatment;
|
- Bifidobacterium infanti
[Subspecies]
[group]
|
-Ruminococcus
[Genus] [group]
-Bifidobacterium adolescentis
[Species] [group]
|
|
|
Martinello, 2017[6]
|
Enrolment
End of 30 days probiotic
|
-
|
-
|
|
None significant
|
Harnett, 2016[7]
|
Enrolment
End of 12 week probiotic
|
Mycoplasma
[Species] [group]
Escherichia coli
[Species] [time]
Streptomyces
[Species] [group]
|
Bifidobacteria
[Genus] [time]
|
|
|
Oscarsson, 2021[8]
|
Enrolment
End of 6 months probiotic
|
-Lactobacillaceae
[Family][group]
-Lactobacillaceae
[Family] [time]
-Lactobacillus
[Genus] [group]
-Lactobacillus
[Genus] [time]
|
-Actinobacteria
[Phylum] [time]
-Bifidobacteriaceae
[Family] [time]
-Bifidobacterium
[Genus] [time]
-Lactococcus
[Genus] [time]
|
|
|
Pr: Probiotics group, Pl: Placebo group |
References |
1. Francavilla R, Cristofori F, Vacca M, Barone M, De Angelis M (2020) Advances in understanding the potential therapeutic applications of gut microbiota and probiotic mediated therapies in celiac disease. Expert Rev Gastroenterol Hepatol 14:323–333. https://doi.org/10.1080/17474124.2020.1745630 |
2. Primec M, Klemenak M, Di Gioia D, Aloisio I, Cionci NB, Quagliariello A, Gorenjak M, Mičetić-Turk D, Langerholc T (2019) Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-α and short-chain fatty acids. Clinical nutrition 38:1373–1381 |
3. Olivares M, Castillejo G, Varea V, Sanz Y (2014) Double-blind, randomised, placebo-controlled intervention trial to evaluate the effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed coeliac disease. British journal of nutrition 112:30–40 |
4. Quagliariello A, Aloisio I, Bozzi Cionci N, Luiselli D, D’Auria G, Martinez-Priego L, Pérez-Villarroya D, Langerholc T, Primec M, Mičetić-Turk D (2016) Effect of Bifidobacterium breve on the intestinal microbiota of coeliac children on a gluten free diet: a pilot study. Nutrients 8:660 |
5. Smecuol E, Constante M, Temprano MP, Costa AF, Moreno ML, Pinto-Sanchez MI, Vázquez H, Stefanolo JP, Gonzalez AF, D’Adamo CR (2020) Effect of Bifidobacterium infantis NLS super strain in symptomatic coeliac disease patients on long-term gluten-free diet–an exploratory study. Beneficial Microbes 11:527–534 |
6. Martinello F, Roman CF, Souza PAd (2017) Effects of probiotic intake on intestinal bifidobacteria of celiac patients. Arquivos de Gastroenterologia 54:85–90 |
7. Harnett J, Myers SP, Rolfe M (2016) Probiotics and the microbiome in celiac disease: a randomised controlled trial. Evidence-Based Complementary and Alternative Medicine 2016 |
8. Oscarsson E, Håkansson Å, Andrén Aronsson C, Molin G, Agardh D (2021) Effects of probiotic bacteria Lactobacillaceae on the gut microbiota in children with celiac disease autoimmunity: A placebo-controlled and randomized clinical trial. Frontiers in Nutrition 8:354 |
Adverse Events
Adverse events were assessed in eight studies, of which two were on CDA [20, 21, 25, 17, 23, 15, 26, 6] and no major adverse events were reported in these studies. Only three studies reported mild symptoms, including bloating, diarrhoea, and flatulence in both probiotic and placebo groups [25, 15, 26].
Quality Assessment
Seven out of fourteen included studies had high quality [20, 19, 18, 17, 23, 15, 6], and the remaining seven studies had low quality mostly due to selection, performance, detection, and attrition biases [21, 16, 25, 22, 26, 27, 24]. All three studies assessing CDA were of low quality due to the possibility of selection, performance, and detection biases [25–27].
Quantitative Synthesis
Figure 2 illustrates the pooled association of probiotic supplementation and intestinal bacterial flora. As shown in Fig. 2, the overall abundance of intestinal flora (SMD:0.60, 95%CI (0.29, 0.92), I2:71.9%) and stratified abundance of intestinal genera, including Bifidobacterium (SMD:0.72, 95%CI (0.13,1.30), I2:82.7%) and Lactobacillus (SMD:0.49, 95%CI (0.18,0.80), I2:41.6%) within the treatment group were significantly higher than those in the controls. In sub-group analysis (Fig. 3), after including studies on participants following GFD, the significance of the findings did not differ (intestinal total bacteria abundance: (SMD: 0.77, 95%CI (0.48,1.06), I2:54.1%) Bifidobacterium: (SMD:0.94, 95%CI (0.47,1.41), I2:61.8%) and Lactobacillus (SMD:0.63, 95%CI (0.35,0.91), I2:7.4%). Moreover, the results did not differ substantially in the leave-one-out analysis, as seen in Fig. 4, after omitting each study.
Furthermore, in studies comparing the abundance of the intestinal flora of patients on probiotic supplementation with non-celiac healthy individuals, the pooled reported amounts of Bifidobacterium within the treatment group did not significantly differ from healthy individuals (SMD:0.45, 95%CI (-0.38,1.29), I2: 68.27%).
There was no significant heterogeneity among studies evaluating the association between probiotic supplementation and adverse events. Based on the fixed effects model, there was no significant change in the risk of adverse events between groups (Risk ratio:0.64, 95%CI (0.34,1.22), I2 :0%). Moreover, there were no significant associations between probiotic supplementation and decreased diarrheal events (Risk ratio:1.12, 95%CI (0.40,3.14), I2:0%), GI symptoms (SMD: -0.28, 95%CI (-0.62,0.06), I2:0%) and GSRS (SMD: -0.31, 95%CI (-0.65,0.03), I2:0%) in the treatment group as compared with the control group.
There was also no significant difference between the treatment and control groups with respect to TNF-α levels (SMD:-0.22, 95%CI (-0.65,0.21), I2:0%).
Publication Bias
Based on Egger’s test, there was no significant publication bias across all studies (β:-0.82, SE:2.84, P-value: 0.77) after probiotic type stratification (Bifidobacterium (β:-1.16, SE:5.45, P-value: 0.83), and Lactobacillus consumption (β:-0.77, SE:3.09, P-value: 0.80))