Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials

Clinical Nutrition xxx (xxxx) xxx

Contents lists available at ScienceDirect

Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials Asma Kazemi a, Sepideh Soltani b, Sima Ghorabi c, Abbas Keshtkar d, Elnaz Daneshzad c, Fatemeh Nasri e, Seyed Mohammad Mazloomi a, * a

Nutrition Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran Department of Clinical Nutrition, School of Nutritional Sciences and Dietetic, Tehran University of Medical Sciences, Tehran, Iran d Department of Health Science Educational Development, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran e Department Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran b c

a r t i c l e i n f o

s u m m a r y

Article history: Received 1 March 2019 Accepted 1 April 2019

The current systematic review and meta-analysis investigated the effect of probiotic/synbiotic on a wide range of inflammatory and anti-inflammatory markers in healthy and various disease conditions. PubMed, SCOPUS and Web of Science databases were searched. All clinical trials which investigated the effect of oral administration of probiotic or synbiotic on inflammatory markers (C-reactive protein (CRP), interleukin (IL) 1b, IL-4, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor (TNF) a, interferon (IFN) g and transforming growth factor (TGF) b) for more than one week with concurrent control groups were included. One-hundred sixty seven publications was analysed. Results were as follows: CRP decreased in healthy, metabolic disorders, inflammatory bowel disease (IBD), arthritis and critically ill condition but not in renal failure. IL-1B: no change in healthy subjects and arthritis. TNF-a: decreased in healthy, fatty liver, IBD and hepatic cirrhosis, no change in diabetes, metabolic syndrome (MS) þ PCOS (polycystic ovary syndrome) and arthritis. IL-6: no change in healthy, metabolic disorders and arthritis, increased in cirrhosis and renal failure, decreased in PCOS þ MS. IL-10: no change in healthy, IBD and metabolic disorders, increased in arthritis. IL-4, IL-8, IL-12, IFN-g and TGF-b: no change in healthy subjects. In conclusion, probiotic/synbiotic decreased some of the inflammatory markers. The intervention was most effective in CRP and TNF-a reduction in healthy or disease state. Moreover, the intervention decreased inflammation most effectively in the following disease conditions, respectively: IBD, arthritis, fatty liver. PROSPERO registration number: CRD42018088688. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Probiotic Synbiotic Inflammation Interleukin Cytokine Meta-analysis

1. Introduction

Abbreviations used: Coef, coefficient; CRF, chronic renal failure; CRP, C-reactive protein; CVD, cardiovascular disease; IBD, inflammatory bowel disease; IBS, inflammatory bowel syndrome; IFN, interferon; IL, interleukin; LPS, lipopolysaccharides; MS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; PBMC, peripheral blood mononuclear cell; RA, rheumatoid arthritis; SMD, Standardized mean difference; TGF, transforming growth factor; TNF, tumor necrosis factor. * Corresponding author. Department of Food Hygiene and Quality Control, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, PO Box 71645-111, Shiraz, Iran. E-mail addresses: [email protected], [email protected] (S.M. Mazloomi).

Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit to the host” [1]. The health-beneficial effects of probiotics are increasingly recognised. Oral delivery of probiotics that are then integrated into the gut ecosystem has the potential to healthfully modulate the gut microbiome [2]. A great deal of research focus has been attracted on probiotics in recent years and the effects of probiotic on many disease conditions such as gastrointestinal disease [3,4], allergic and viral disease [5], Helicobacter pylori infection [6], nonalcoholic fatty liver disease [7], diabetes [8e10], hypertension [11], hyperlipidemia [12], autoimmune disease [13], cancer [14], postoperative

https://doi.org/10.1016/j.clnu.2019.04.004 0261-5614/© 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

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A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

complications [15,16], obesity [17], critically ill patients [18] and osteopenia [19] have been studied. Probiotics induce their effects principally due to their role in immune system modulation and the anti-inflammatory response [20]. Disturbance in the equilibrium of the gut microbiota leads to change in gut barrier function and increases in permeability of intestinal mucosa and as a consequence, translocation of gram negative bacteria into lymph node and blood stream [21]. Lipopolysaccharides (LPS) of gram-negative bacteria activate the innate immune system resulting in the production of pro-inflammatory cytokines [22,23]. Modulation of intestinal microbiota via probiotic bacteria has been claimed to induce epithelial healing and prevent bacterial translocation across the epithelium [24]. “Prebiotic is a non-digestible compound that, through its metabolism by microorganisms in the gut, modulates composition and/or activity of the gut microbiota, thus conferring a beneficial physiologic effect on the host” [25]. The combination of one or more probiotics with prebiotics is termed as synbiotic. Several meta-analyses have investigated the effects of probiotics on inflammatory markers in various disease conditions such as diabetes [8,9,26,27], nonalcoholic fatty liver disease (NAFLD) [7] and rheumatoid arthritis (RA) [13,28,29] and to the best of our knowledge, no study have examined the effect of probiotic on inflammation in healthy individuals. The aim of the current study was to provide a strong combination of evidence that demonstrates the direct and biological effects of probiotics on inflammatory markers. Moreover, cytokines and inflammatory mediators operate in network [30], and while several meta-analyses have examined some standard inflammatory markers such as CRP, TNF-a and interleukin (IL)-6, no study has simultaneously examined a wide range of inflammatory and anti-inflammatory markers reflecting the cytokine network. The current systematic review and metaanalysis investigates the effect of probiotic and synbiotic supplementation on a wide range of inflammatory and anti-inflammatory markers in healthy and various disease conditions. 2. Method The protocol of this systematic review has been registered on PROSPERO website (www.crd.york.ac.uk/PROSPERO) (PROSPERO registration number ¼ CRD42018088688). This systematic review protocol has been developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [31]. 2.1. Study selection criteria 2.1.1. Type of studies The systematic review included all clinical trials with either parallel or cross-over design and at least two arms that investigated the effect of oral administration of probiotic or synbiotic on inflammatory markers (CRP, IL-1B, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-a and IFN-g) for more than one week with concurrent control groups. Cytokines were measured in serum, peripheral blood mononuclear cell (PBMC), or secreted from mitogen (LPS, phytohemagglutinin, phorbol myristate acetate-ionomycin, concanavalin A) stimulated PBMC. The studies were open label (single, double or triple blind) and either randomised or non-randomised. 2.1.2. Type of participants Both male and female adults with the age >18 year were included while studies with adolescents participants (under 18 years of age), pregnant and lactating women were excluded. Four reviewers (AK, SS, SG, ED) assessed titles and abstracts of all primary articles that met the search strategy in order to

determine studies eligible for inclusion. Then, two reviewers independently evaluated the full text of potentially relevant nonduplicated articles (AK, SS). Any disagreements were resolved by discussion to reach consensus. When consensus was not reached, a third reviewer (SMM) acted as an arbitrator. 2.2. Search strategy We searched the following electronic database from 1990 until 31 May 2018 with no restriction in English language: PubMed, Scopus, Web of Science, National Institute of Health Clinical Trials Register (https://clinicaltrials.gov/) to identify unpublished studies and the Cochrane Central Register of Controlled Trials (Clinical Trials). Relevant search terms in accordance with an intervention and outcome component of current systematic review were extracted from Mesh and key word of the studies in the primary search. Full search strategy for PubMed, Scopus, and Web of Science are presented in supplementary (sup) Table 1. Moreover, bibliographies of all relevant prior reviews and primary studies identified by search strategy were scanned for additional relevant paper. Scopus and Web of Science and annual meetings were searched for conference papers. 2.3. Data extraction Data extraction from primary articles was performed independently by two reviewers (AK, SS) using a quantitative data extraction form. The data extraction form has been piloted previously. Any discrepancies were resolved by consensus between the two reviewers and, when this was not possible, a third reviewer (SMM) acted as an arbitrator and made a decision on the data entered. Data collected from the studies included participants' characteristics such as gender, age, disease, BMI and country; study design, duration of the study, sample size, the sample in which the outcomes were measured (serum, PBMC, stimulated PBMC), publication year, composition and dose of supplements and methodological quality. If data was presented as graph only, it was extracted using Plot Digitiser software (http://plotdigitizer. sourceforge.net/). Corresponding authors of included studies, in which required data were not provided, were contacted to request the data needed for the purpose of meta-analysis. 2.4. Risk of bias (quality) assessment Quality assessments were performed with the Jadad scale [32], based on the following parameters: randomisation, random description, blinding of participants and personnel, incomplete outcome data and selective reporting. Two investigators independently rated each study and settled any differences by consensus or referring to a third investigator. 2.5. Statistical analysis Statistical analysis of data was performed using Stata software version 13 (StataCorp LP, College Station, TX, USA). Data from clinical trials was analysed using mean difference with standard deviation. Mean change and its corresponding standard deviation (SD) of inflammatory markers within the intervention and placebo groups were used to calculate the unstandardised difference in means (MD) to be used as effect size for meta-analysis. In case the studies had reported the baseline and after intervention values, based on the studies that had reported standard deviation for preand post-intervention and changes in outcomes, we estimated the correlation coefficient for cytokines levels and used it to calculate

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

the standard deviation for change. Study heterogeneity was measured using the Q test and I2 test. Sources of heterogeneity were explored in meta-regression and subgroup analysis. Subgroup analysis was conducted by the following variables: sample in which cytokines were measured (serum, PBMC, secretion from stimulated PBMC), strains of bacteria (where it was probable), sex, age (<49 vs. 49), single vs. multiple strains of probiotics, BMI (25 (kg/m2) vs. >25 (kg/m2), dose and study duration (lower than 8 weeks/8 weeks and more). The potential for publication bias was assessed using funnel plot, the Begg rank correlation method, and the Egger weighted regression method. A p-value of 0.05 was considered to be statistically significant. When publication bias was suspected based on visual inspection, Duval and Tweedie's Trim and Fill method was applied to estimate the impact of publication bias on the observed summary effect size. A sensitivity analysis was performed to test the small study effect. We also implemented sensitivity analyses to explore the effects of methodological quality and sample size on the robustness of review conclusions. 3. Results

Identification

Figure 1 shows the process for the inclusion of studies. A total of 183 publications were considered to have met the eligibility criteria and were included. We could not gain access to enough data to analyse six of the studies [33e39]. Seven studies were published two or three times while they were related to the same studies, so eight studies were excluded. Finally, 169 were

3

analysed. Table 1 shows a description of the included studies that examined the effect of probiotic/symbiotic on inflammatory markers in healthy participants, Table 2 shows patients with metabolic disorders and Table 3 shows patients with disease other than metabolic disorders. Quality assessment of studies are presented in Sup Table 2. The results have been summarised in Table 4. Sensitivity analysis for the small study effect was significant for none of the outcomes. Since non-randomized and nonblind studies were also included in the meta-analysis, we conducted the analysis either in the presence or in the absence of non-randomized and non-blind studies to assess the effect of methodological quality. No significant difference was seen except for TNF-a in healthy patients. Such that after excluding nonrandomized and non-blind studies, the reduction in TNF-a was no more significant (Sup Table 3). Publication bias was significant for none of outcomes except IL-12; however, no studies was imputed with the trim-and-fill method. 3.1. CRP A total of 136 clinical trials measured CRP (healthy (30), diabetes (16), NAFLD (5), PCOS (4), metabolic syndrome (MS) (4), arthritis (8), inflammatory bowel disease (IBD) (7), inflammatory bowel syndrome (IBS) (1), (chronic renal failure) CRF(4), surgery (10), HIV (4), critically ill (8), cirrhosis (3), atopic dermatitis (1), multiple sclerosis (1), allergy (2), Alzheimer's disease (1), schizophrenia (1), patients with pulmonary symptoms due to mustard (1). The studies with three arms were considered as two and the studies with four arms were considered as three studies.

Records identified through PubMed, Scopus, WOS (n =43235)

Eligibility

Screening

Records after duplicates removed (n =30682)

Records screened (n =30682)

Records excluded (n =28225)

Full-text articles assessed for eligibility (n = 2457)

Full-text articles excluded, (n =2282)

Included

Studies included in qualitative synthesis (n =175)

Studies included in quantitative synthesis (meta-analysis) (n =168) Fig. 1. Flow diagram.

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

4

Author,Year

Country

Sex

Age

Design

Duration (weeks) Participants Intervention (Probiotic strains) (Intervention, Control)

Control status

Outcome

Ahn, 2015 [46]

South Korea

Both

53.4

Parallel

12

Placebo

hs-CRP

Arunachalam, 2000 [47] Brahe, 2015 [48] Burton, 2017 [49]

New Zealand Denmark Switzerland

Both 69 Female 59.9 Male 24

Parallel 6 Parallel 6 Cross-over 2

13, 12 18, 16 40, 40

Milk Placebo Placebo

IFN-g hs-CRP, IL-6, TNF IL-6, TNF

Cavallini, 2016 [50]

Brazil

Male

45.75

Parallel

17, 15

hs-CRP

Childs, 2014 [51]

UK

Both

43

Cross-over 3

11, 11, 11, 11

Unfermented soy product Placebo

IL-4, IL-6, IL-10

Christensen, 2006 [52]

Denmark

Both

27

Parallel

42, 42

Placebo

IL-10, INF

Costabile, 2017 [53] Cox, 2010 [54] Cox, 2014 [55] Dong, 2013 [56]

UK Australia Australia UK

Both Male Both Both

70 Cross-over 1.2 27.3 Cross-over 4 40.55 20 55e74 Cross-over 4

Placebo Placebo

Gleeson, 2011 [57]

Spain

Both

Parallel

16

25, 20

Gomes, 2017 [58]

Brazil

Female

Parallel

8

21, 22

hs-CRP, IL-6, IL-8 IL-4, IL-12, INF hs-CRP IL1B, IL-6, TNF, IL-8, IL-10, IL-12, IL-17, INF IL1B, IL-4, IL-6, TNF, IL-8, IL-10, INF IL-6, TNF, IL-10

Hirose, 2013 [59] Hor, 2018 [60] Irwin, 2017 [61] Iwasa, 2013 [41] Jung, 2015 [62]

Japan Malaysia Australia Japan North Korea

Both Both Both Male Both

50.6 44.6 27.75

Parallel Parallel Parallel

39

Parallel

12 52 8 1 day 12

20, 43, 15, 12, 49,

Kazemi, 2019 [63] Kekkonen, 2008 [64]

Iran Finland

Both Both

44

Parallel Parallel

8 3

27, 25 13, 16

kim, 2018 [40] Lamprecht, 2012 [65]

Korea Austria

Both Male

38.7 37.9

Parallel Parallel

12 14

30, 30 11, 12

Lee, 2017 [66]

USA

Both

28

Cross-over 4

25, 25

Lee, 2017 [67]

Korea

Both

65.7

Parallel

73, 79

Lefevre, 2015 [68] Macfarlane,2013

France Scotland

Both Both

63.1 71.9

Parallel Cross-over 4

50, 50 42, 42

Maneerat, 2013 [69]

UK

Both

66.75

Cross-over 3

10, 9

Mangalat, 2012 [70] Manzoni, 2017 [71]

USA Brazil

Both Both

33.75 >65

Parallel Parallel

8 6

23, 10 14, 15

Marcial, 2017 [72] Marcos, 200 [73]4

USA Spain

Both Both

23.2

Parallel Parallel

8 6

21, 20 69, 53

Marinkovic, 2016 [74] Meyer, 2007 [75]

Serbia Austria

Both 23.2 Female 24.4

Parallel Parallel

14 4

20, 19 17, 16

6

3

12

46, 46

55, 20, 39, 30,

56 20 45 30

15 37 14 12 46

L. curvatus HY7601 and L. plantarum KY1032 Milk supplemented with B. lactis L. paracasei F19 L. rhamnosus GG, L. delbrueckii Bulgaricus, S. thermophilus Synbiotic (Soy product fermented with Enterococcus faecium and L. helveticus) 1. Probiotic (B. animalis subsp. lactis Bi07)þ 2. xylo-oligosaccharide 3.synbiotic (B. animalis subsp. lactis þ xylo-oligosaccharide) B. animalis ssp. lactis (BB-12) and L. paracasei ssp. paracasei (CRL-431) L. rhamnosus GG combined with SCF L. fermentum VRI-003 B. animalis subsp. lactis Bl-04 probiotic drink containing 1.3  1010 L. casei Shirota L. casei Shirota Symbiotic (prebiotic þ L. acidophilus, L. casei, Lactococcus lactis, B. bifidum, and B. lactis BL-4) þ Dietary intervention L. plantarum L-137 L. casei Zhang L. acidophilus and B. lactis Bi-07 L. helveticus plus exercise L. curvatus HY7601 and L. plantarum KY1032 L. Helvetius, B. longum Milk based drink containing L. Rhamnsus GG L. gasseri BNR17 6 probiotic strains: B. bifidum, B. lactis, Enterococcus faecium, L. acidophilus, L. brevis, and Lactococcus lactis Yogurt smoothie with B. animalis subsp. lactis BB-12 Yogurt containing L. casei, B. lactis and heat-treated L. plantarum Bifidobacterium Synbiotic (B. longum and an insulinbased prebiotic) Synbiotic (galacto-oligosaccharides plus B. lactis Bi-07) L. reuteri DSM 17938 Synbiotic (Soy and yacon extracts containing B. animalis ssp. lactis) L. johnsonii N6.2 Milk fermented with yogurt cultures plus Lacto- bacillus casei L. helveticus Lafti L10

Skimmed milk Milk Dietary intervention Placebo Placebo Placebo Exercise Placebo

INF IL1B, IL-4, IL-10 hs-CRP hs-CRP, TNF hs-CRP

Placebo Placebo

IL1B, IL-10, IL-6, TNF hs-CRP, IL1B, IL-6, TNF

Placebo Placebo

hs-CRP, INF IL-6, TNF

Yogurt

hs-CRP

Yogurt

hs-CRP, TNF, IL-12, INF

Placebo Placebo Placebo

INF hs-CRP, IL1B, IL-4, IL-6, TNF, IL8, IL-10, INF IL1B, IL-6, IL-8, IL-10, INF

Placebo Placebo

IL1B, IL-6, TNF, IL-8, IL-12, INF IL-6, TNF, IL-10

Placebo Placebo

TNF, INF IL-4, IL-5, TNF, INF

Placebo Yogurt

IL-10, INF IL1B, IL-6, TNF, IL-10, INF

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

Table 1 Characteristic of randomized controlled trials that evaluated the effect of the probiotic/synbiotic on the serum level of inflammatory biomarkers in apparently healthy participants.

Japan Iran

Both Male

60.5 32.65

Parallel Parallel

12 6

19, 25 12, 13, 10

MoroGarcia, 2013 [78] Naruszewicz, 2002 [79] Neto, 2013[80]

Spain Poland Brazil

Both Both Both

70 42.3 67.9

Parallel Parallel Parallel

24 6s 12

26, 21 18, 18 9, 8

Nova, 2011 [81]

Spain

Both

Parallel

6

18, 18

Nyangale, 2014 [82] Olivares, 2006 [83]

UK Spain

Both Both

65e80 Cross-over 4 23e43 Parallel 4

18, 18 15, 15

Osterberg, 2015 [84]

USA

Male

22.65

Ouwehand, 2008 [85]

Finland

Both

Rajkumar, 2015 [86] Ramijn, 2017 Sanchez, 2014 [87]

India Australia Canada

Both Both

35.4 35

Seifert, 2011 [88] Simons, 2006 [89] Spanhaak, 1998 [90]

Germany Australia Netherlands

Male Both Male

Parallel

4

9, 11

Parrallel

24

19, 18

Parallel Parallel Parallel

6 8 24

15, 15, 15 38, 39 52, 53

31.5 51.5 55.8

Parallel Parallel

4 10 4

34, 34 23, 21 10, 10

Both Both

48.7 40.3

Parallel Parallel

24 4

25, 36 6, 6

Valentini, 2015 [93]

France, Germany, Italy Both

70.1

Parallel

8

31, 31

West, 2014 [94] Wilms, 2016 [95]

Australia Netherlands

Both Both

49.5 20.7

Parallel Parallel

20 2

39, 39 10, 10

Zarrati, 2013 [96]

Iran

Both

36

Parallel

8

25, 25

Zhang, 2018 [97]

china

Both

33.4

Parallel

12

67, 67

Stenman, 2016 [91] Finland Tomohiko Ogawa, 2006 [92] Japan

probiotic drink contain L. casei Shirota L. fermentum Fermented milk containing L.casei shirota B. animalis ssp. lactis 420 Symbiotic (L. casei subsp. casei together and dextran) B. infantis, B. longum, B. breve, L. acidophilus, L. delbrückii ssp. bulgaricus, L. paracasei, L. plantarum, and S.thermophilus B. animalis subsp. lactis Synbiotic (B. bifidum, B. lactis, B. lactis, L. acidophilus, L. casei, L. paracasei, L. plantarum, L. salivarius, Lactococcus lactis þ FOS L. acidophilus La5, B. BB12, and L. casei plus weight loss diet L. paracasei, L. casei 431, L. fermentium PCC

Placebo Conventional yogurt

hs-CRP hs-CRP, INF

Placebo Placebo Placebo

IL-8 IL-6 IL-6, TNF

Placebo

hs-CRP

Placebo Dairy product

hs-CRP, IL1B, IL-6, TNF, IL-10 IL-4, TNF, IL-10, IL-12

Placebo and hypercaloric diet

hs-CRP, IL-6, TNF

Oat drink

TNF, IL-10

Placebo Placebo Placebo plus weight loss Placebo Placebo Unfermented milk

hs-CRP, IL1B, IL-6, TNF hs-CRP, IL1B, IL-6, TNF hs-CRP hs-CRP, TNF hs-CRP hs-CRP

Placebo Placebo

hs-CRP, IL-6 INF

Placebo

hs-CRP, IL-6, TNF, IL-10

Placebo Placebo

IL-4, IL-6, IL-8, IL-12 IL1B, IL-6, TNF, IL-8

Yogurt þ weight loss Yogurt

IL-4, TNF, IL-10, IL-17, INF

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

Minami, 2015 [76] Mohammadi, [77]2015

Yogurt containing L. bulgaricus and S.thermophilus þ L. casei B. breve B-3 1. Probiotic yoghurt containing L. acidophilus and B. lactis 2. Multispecies probiotic capsule contains L. casei, L. acidophilus, L. bulgaricus, B. longum, L. rhamnosus, B. breve, S. thermophilus L. delbrueckii subsp. Bulgaricus L. plantarum Synbiotic (FOS þ L. paracasei, L. rhamnosus, L. acidophilus and B. lactis Synbiotic (L. acidophilus, B. animalis ssp. lactis, L. delbrueckii ssp. bulgaricus, S.thermophilus, and L. paracasei ssp. paracasei þ FOS) Bacillus coagulans GBI-30 Dairy product contained S. thermophilus, L. coryniformis, L. gasseri S.thermophilus, L. acidophilus, L. delbrueckii ssp. Bulgaricus, L. paracasei, L. plantarum, B. longum, B. infantis, and B. breve þ dietary intervention 1. Oat-based drink supplemented with B. longum 2. fermented oat drink containing B. animalis ssp. lactis 1- L. salivarius þ FOS 2. L. salivarius L. helveticus þ B. longum L. rhamnosus þ weight loss

hs-CRP

B., bifidobacterium; hsCRP high sensitive C-reactive protein; FOS, fructooligossacaride; IFN, interferon; IL, interleukin; L., lactobacillus; S, streptococcus; TNF, tumor necrosis factor.

5

6

Author,Year

Country

Sex

Age

Design

Intervention (Probiotic strains) Duration Participants (Intervention, Control)

Control status

Participants disease

Outcome

Abbaszadeh, 2016 [98]

Iran

Both

44.7

Parallel

8

21, 21

Placebo

NAFLD

IL-6, TNF

Ahmadian, 2017 [99]

Iran

Both

60

Parallel

6

30, 29

Placebo

T2DM

IL-6, TNF

Aller, 2011 [100] Andreasen, 2010 [33] Asemi, 2013 [101]

Spain Both Denmark Male Iran Both

0 57.5 51.5

Parallel Parallel Parallel

12 4 8

14, 14 21, 24 27, 27

Placebo Placebo Placebo

NAFLD T2DM T2DM

IL-6, TNF hs-CRP, IL-6, TNF hs-CRP

Asemi, 2014 [102] Asgharian, 2016 [103]

Iran Iran

Both Both

53 47

Cross-over 6 Parallel 8

62, 62 38, 36

Placebo Placebo

T2DM NAFLD

hs-CRP hs-CRP

Barreto, 2013 [104] Bayat, 2016 [105] Ekhlasi, 2017 [106]

Brazil Iran Iran

Female 62.5 Both 50.5 Both 44

Parrallel Parallel Parallel

12 8 8

12, 12 20, 20 15, 15

Eslamparast, 2014 [107]

Iran

Both

46

Parallel

28

26, 26

Farrokhian, 2017 [108]

Iran

Both

64

Parallel

12

30, 30

Feizollahzadeh, 2017 [109] Firuzi, 2017 [110]

Iran Iran

Both Both

55.25 Parallel 53.5 Parallel

8 12

20, 20 48, 53

Ghanei, 2018 [111]

Iran

Female 29.5

Parallel

12

30, 30

L. casei, L. acidophilus, L. rhamnosus, L. bulgaricus, B. breve, B. longum, and S.thermophilus L. casei, L. acidophilus, L. bulgaricus, L. rhamnsus, L. longum,B. breve, S. thermophilus, þ FOS L. bulgaricus and S.thermophilus L. acidophilus NCFM L. acidophilus, L. casei, L. rhamnosus, L. bulgaricus, B. breve, B. longum, S.thermophiles, þ FOS Synbiotic (L. sporogenes and inulin) L. acidophilus, L. casei, L. rhamnosus, L. bulgaricus, B. breve, B. longum, S.thermophiles þ FOS L. plantarum Not mentioned Syniotic (L. casei, L. rhamnosus, S.thermophilus, B. breve,L. acidophilus, B. longum, L. bulgaricus þ FOS) Synbiotic (L. casei, L. rhamnosus, S.thermophilus, B. breve, L. acidophilus, B. longum, L. bulgaricus) þ FOS L. acidophilus, L. casei, B. bifidum, plus 800 mg inulin L. planetarum L. acidophilus, L. casei, L. lactis and B. bifidum, B. longum and B. infantis L.acidophilus, L. Plantarum, L. Fermentum, L.Gasseri

Hove, 2015 [112]

Denmark Male

Parallel

12

23, 18

Milk fermented with L. helveticus

Karamali, 2018 [113]

Iran

Female 27

Parallel

12

30, 30

L. acidophilus, L. casei and B. bifidum

Karimi, 2018 [114]

Iran

Female 28.5

Parallel

12

50, 49

Kobyliak, 2018 [115]

Ukraine

Both

54.5

Parallel

8

31, 22

Kooshki, 2015 [116] Mazloom, 2013 [117] Mobini, 2017 [118] Mofidi, 2017 [119]

Iran Iran Sweden Iran

Both Both Both Both

54 53 64.5 45.35

prallel Parallel parallel Parallel

8 6 12 28

22, 16, 14, 25,

Mohamadshahi, 2014 [120] Iran

Both

51

Parallel

8

21, 21

Mohseni, 2018 [121]

Iran

Both

60.55 Parallel

12

30, 30

Nasri, 2018 [122] Rabiei, 2018 [123]

Iran Iran

Female 25.8 Both 59

12 12

30, 30 20, 20

synbiotic (L. acidophilus, L. casei, L. bulgaricus, L.rhamnosus, B. longum, B. breve, S.thermophilus þ FOS) Synbiotic (14 probiotic strains: Lactobacillus, Lactococcus, Bifidobacterium, Propionibacterium, Acetobacter) Synbiotic L. acidophilus, L. bulgaricus, L. bifidum, and L. casei L. reuteri DSM 17938 Symbiotic (seven strains (L. casei, L. rhamnosus, S.thermophilus, B. breve, L. acidophilus, B. longum and L. bulgaricus) and fructooligosaccharide) probiotic yogurt: L. delbrueckii subsp. bulgaricus and S. thermophilus þ B. animalis subsp. lactis þ L. acidophilus L. acidophilus, L. casei, L. Fermentum and B. bifidum with antibiotic L. acidophilus, L. casei and B. bifidum

59.5

Parallel Parallel

22 18 15 25

Fermented milk Metabolic syndrome Dietary advisement NAFLD Placebo NAFLD

hs-CRP, IL-6, TNF hs-CRP TNF

Placebo

NAFLD

hs-CRP, TNF

Placebo

T2DM þ CHD

hs-CRP

Placebo Placebo

T2DM T2DM

hs-CRP, IL1B hs-CRP

Placebo

hs-CRP, IL-6, TNF, IL-10

PCOShttps://www. mayoclinic.org/ diseases-conditions/ pcos/symptomscauses/syc-20353439 Artificially acidified T2DM milk Placebo PCOShttps://www. mayoclinic.org/ diseases-conditions/ pcos/symptomscauses/syc-20353439 Placebo PCOS

hs-CRP

Placebo

T2DM

IL1B,IL-6,TNF,IL-8,INF

Placebo Placebo Placebo Placebo

T2DM T2DM T2DM NAFLD

hs-CRP, IL-6, TNF hs-CRP, IL-6 hs-CRP hs-CRP, TNF

Conventional yogurt

T2DM

hs-CRP, IL-6, TNF

Placebo

T2DM

hs-CRP

Placebo Placebo

PCOS Metabolic Syndrome

hs-CRP hs-CRP, IL-6

hs-CRP, TNF hs-CRP

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

Table 2 Characteristic of randomized controlled trials that evaluated the effect of the probiotic/synbiotic on the serum level of inflammatory biomarkers in patients with metabolic disorders.

IL1B, IL-6, TNF, IL-8, IL10, IL-12

Diabetic hemodialysis T2DM T2DM

Metabolic Syndrome

Placebo Bread Conventional fermented milk Placebo 23, 22 8 Brazil Xavier-Santos, 2018 [132]

Both

48.25 Parallel

30, 30 27, 27 23, 22 12 8 6 56.5 Parallel 52.3 Parallel 51.39 Parallel Both Both Both Iran Iran Brazil Soleimani, 2017 [129] Tajadadi, 2014 [130] Tonucci, 2015 [131]

B., bifidobacterium; CHD, coronary heart disease; FOS, fructooligossacaride; hsCRP high sensitive C-reactive protein; IFN, interferon; IL, interleukin; L., lactobacillus; NAFLD, non-alcoholic fatty liver disease; PCOS, polycystic ovary syndrome; S, streptococcus; TNF, tumor necrosis factor T2DM, type 2 diabetes mellitus.

hs-CRP hs-CRP IL-6, TNF, IL-10

PCOS Placebo 32, 33 8 Parallel Iran Shoaei, 2017 [128]

Female 26.1

Iran Iran Japan Israel Raygan, 2018 [124] Rezaei, 2017 [125] Sato, 2017 [126] Sherf-Dagan, 2018 [127]

Both Both Both Both

61.25 50 64.5 43

Parallel Parallel Parallel Parallel

12 4 16 24

30, 45, 34, 40,

30 45 34 40

Symbiotic (L. casei, L. rhamnosus, S.thermophilus, B. breve, L. acidophilus,B. longum, L. bulgaricus þ FOS Bifdobacterium bifdum, L. casei, L. acidophilus L. acidophilus La5 and B. lactis Bb12 L. casei strain Shirota-fermented milk L. acidophilus, B. bifidum, L. rhamnosus, Lactococcus lactis, L. casei, B. breve, S.thermophiles, B. longum, L. paracasei, L. plantarum, B. infatis Familact (L. casei, L. acidophilus, L. rhamnosus, L. bulgaricus, B. breve, B. longum, S.thermophiles) L. acidophilus, L. casei and B. bifidum Symbiotic bread (L. sporogenes and inulin) Fermented milk containing L. acidophilus La-5 and B. animalis subsp lactis BB-12 Synbiotic (mousse containing L. acidophilus La-5)

hs-CRP

T2DM þ CHD T2DM T2DM NAFLD Placebo Placebo Placebo Placebo

hs-CRP hs-CRP hs-CRP, IL-6, TNF hs-CRP, IL-6, TNF, IL-10

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

7

3.1.1. Healthy From 30 clinical trials, two were excluded since data were reported as geometric mean [33] and least square mean [40], so 28 studies in healthy subjects with normal weight or obese with 2395 participants were included. Twenty studies had two arms, five had three arms and three had four arms. Participants of three studies were subjects with elevated serum cholesterol, hypertriglyceridemia and migraine that were analysed in healthy class. In the pooled analysis of studies, a significant effect of probiotic on serum CRP reduction (SMD ¼ 0.20 mg/l, 95%CI -0.33 to 0.06, p ¼ 0.005) was observed with a heterogeneity of 59% (p¼<0.001) (Fig. 2 and Table 5). Effect of probiotic on CRP remained significant with a larger effect on subjects with BMI 25 (kg/m2) (SMD ¼ 0.29, p ¼ <0.001, I2 ¼ 68.8%, p ¼ <0.001), whereas for BMI>25 (kg/m2), it was not significant (SMD ¼ 0.008, p ¼ 0.24, I2 ¼ 0.0 p ¼ 0.46) (Sup Fig. 1). Moreover, the supplement was most effective at dose 5  1010 compared to the >109-<5  1010 and <109. Meta-regression for age, duration of studies, and BMI did not show a significant trend. Meta-regression for age after adjusting for BMI, indicated a significant inverse association (Coef ¼ 0.01, p ¼ 0.03, I2_residual ¼ 51.39%, Adjusted R2 ¼ 17.93%). We also conducted subgroup-analysis by the strains of bacteria (we pooled healthy individuals with patients with metabolic disorders). L. casei increased CRP, while B.breve, L. rhamnosus, L. sporogenes þ inulin and two multiple strains formula containing (Bifidobacterium longum, B. infantis, B. breve, L.acidophilus, L. paracasei, L. bulgaricus, Lactobacillus plantarum) and (Lactobacillus acidophilus, L. casei, B. bifidum) decreased CRP. Lactobacillus helveticus, L. curvatus þ L. plantarum, B. lactis, L. reuteri and L. plantarum had no effect. The results are presented in Table 6 and Sup Fig. 2. 3.1.2. Metabolic disorders From 29 clinical trials in participants with metabolic disorders (diabetes (16), polycystic ovary syndrome (PCOS) (4), fatty liver (5) and metabolic syndrome (MS) (4)), 1815 participants were included. Twenty-six studies had two arms and three had three arms. In the pooled analysis of studies, a significant effect of probiotic on serum CRP reduction (SMD ¼ 0.32 mg/l, 95% CI -0.57 to 0.08, p ¼ 0.009) was observed with a heterogeneity of 84.2% (p¼<0.001) (Fig. 3 and Table 5). Meta-regression for age, duration of studies and BMI was not significant. The subgroup analysis by disease revealed a significant decrease of CRP in diabetes (SMD ¼ 0.41, p¼<0.001, heterogeneity (79.5%, p¼<0.001)) and fatty liver (SMD ¼ 0.38, p¼<0.0011, heterogeneity (82.4%, p¼<0.001)) while no change was observed in PCOS (SMD ¼ 0.20, p ¼ 0.08, heterogeneity (92.4%, p¼<0.001)) and metabolic syndrome (SMD ¼ 0.13, p ¼ 0.11, heterogeneity (28%, p ¼ 0.25) (Sup Fig. 3, Table 5). 3.1.3. IBD From seven clinical trials in patients with IBD, 1868 participants were included. Four studies had two arms and one had four arms. In the pooled analysis of studies, a significant effect of probiotic on serum CRP reduction (SMD ¼ 1.37, 95% CI -1.81 to 0.47, p ¼ 0.002) was observed with a heterogeneity of 84.1% (p ¼ <0.001) (Fig. 4, Table 5). Meta-regression for duration of studies was not significant. 3.1.4. Arthritis From eight clinical trials in patients with arthritis (seven rheumatoid arthritis, one spondyloarthritis), 750 participants were included. In the pooled analysis of studies, a significant effect of probiotic on serum CRP reduction (SMD ¼ 0.58, 95% CI -1.15 to 0.01, p ¼ 0.04) was observed with a heterogeneity of 90.3%

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

8

Author,Year

Country

Sex

Age (year)

Design

Duration Participants Intervention (Probiotic strains) (weeks) (Intervention, Control)

Control status

Participants disease

Outcome

Abbas, 2014 [98] Akbari, 2016 [133]

Pakistan Iran

Both Both

35.3 80

Parallel Parallel

6 12

37, 35 30, 30

Placebo pacebo

IBS Alzheimer's Disease

TNF, IL-8, IL-10, IL-12 hs-CRP

Akkasheh, 2016 [134] Alberda, 2007 [135]

Iran Canada

Both Both

37.25 62

Parallel Parallel

8 1

20, 20 10, 9

Placebo Placebo

Major depression hs-CRP Multiple organ dysfunction hs-CRP syndrome

Alipour, 2014 [136]

Iran

Female 42.5

Parallel

8

22, 24

Saccharomyces boulardii L. acidophilus, L. casei, B. bifidum, and L. fermentum L. acidophilus, L. casei, B. bifidum L. casei, L. plantarum, L. acidophilus, and L. Bulgaricus), 3 strains of Bifidobacterium (B. longum, B. breveand B. infantis) and S.salivarius subsp. Thermophilus L. casei

Placebo

RA

Anderson, 2004 [137]

UK

Both

71

Parallel

2

67, 55

Placebo

Bajaj, 2008 [138]

USA

53

Parallel

8

14, 6

Synbiotic (L.acidophilus, B. lactis, S.thermophilus, L. bulgaricus þ FOS Probiotic yogurt

Bajaj, 2014 [139] Borges, 2018 [140]

USA Brazil

58.5 51.95

Parallel

8 12

14, 16 16, 17

Costanza, 2015 [141] Cui, 2013 [142] Pineda, 2011 [143]

Brazil China Canada

Parallel

12 2 12

8, 8 23, 25 15, 14

De Roos, 2017 [144]

Netherlands Female 40

Parallel

12

31, 32

Dhiman, 2014 [145]

India

Both

49

Parallel

24

16, 13

Drago [146],2012 Ebrahimi-Mameghani, 2013 [147]

Italy Iran

Both Both

30.46 34.6

Parallel Parallel

16 1

19, 19 20, 20

Fang, 2018 [148] Federico, 2009 [149]

China Italy

Both Both

46 47

Parallel Parallel

1 8

34, 34 9, 9

Fernandes, 2016 [150]

Brazil

37

Parallel

2

3, 3

Fujimori, 2009 [151] Giamarellos-Bourboulis, 2009 [152]

Japan Greece

Both Both

36 54.4

Parallel Parallel

4 2

10,10,12 31, 23

Gilbey, 2015 [153] Groeger, 2013 [154]

Israel Ireland

Both Both

31.6

Parallel Parallel

1.4 8

27, 26 22, 26, 48

Gupta, 2013 [155]

India

Both

44

Parallel

8

25, 26

Han, 2015 [156]

South Korea Both

52.7

Parallel

1

60, 57

Both Both

Parallel Female 61.45

L. GG S. thermophilus, L. acidophilus, B. longum Saccharomyces boulardii Bifidobacterium þ Enteral feeding L. rhamnosus GR-1 and L. reuteri RC-14 Probiotic (B. bifidum, B. lactis, L. acidophilus, B. brevis, B. casei, B.salivarius, Lactococcus lactis) 4 Lactobacillus species (paracasei, plantarum, acidophilus, and delbrueckii subspecies bulgaricus), 3 Bifidobacterium species (longum, infantis and breve), and S.thermophilus. L. salivarius VSL#3 (4 strains of Lactobacillus (casei, plantarum, acidophilus, Bulgaricus), 3 strains of Bifiobacterium (longum, breve, infantis) and S.Thermophilus) Probiotic þ antibiotics Synbiotic (L. paracasei þ Glutamine and Zinc and XOS þ Inulin and Vitamin B6) Synbiotic (FOS þ L.paracasei, L. rhamnosus, L.acidophilus, and B.lactis) Synbiotic (B. longum þ psyllium) Synbiotic 2000FORTE, (Pediococcus pentoseceus, Leuconostoc mesenteroides, L. paracasei ssp paracasei and L. plantarum, þ inulin, oat bran, pectin and resistant starch) Streptococu Salivarius þ antibiotics Bifiobacterium infantis 35264

No placebo

hs-CRP, IL1B, IL-6, TNF, IL10, IL-12 Elective abdominal surgery hs-CRP, IL-6 IL-6,TNF

Placebo Placebo

Nonalcoholic minimal hepatic encephalopathy cirrhotics Patients with cirrhosis Hemodialysis

Placebo Enteral feeding Placebo

Heart failure Acute pancreatitis Rheumatoid arthritis

Placebo

Migraine

hs-CRP hs-CRP, TNF, IL-8 IL1B, IL-6, TNF, IL-8, IL-10, IL-12, IL-17 hs-CRP, TNF

Placebo

Cirrhosis

IL1B, IL-6, TNF

Placebo Placebo

Atopic Dermatitis Surgical ICU

IL-4, INF hs-CRP, IL-6

Antibiotics Placebo

Severe acute pancreatitis Ulcerative colitis

hs-CRP, IL-6 IL1B, IL-6, TNF, IL-8, IL-10

Placebo

Roux-en-Y Gastric Bypass

hs-CRP, IL1B, IL-6, TNF

Psyllium Placebo

Ulcerative colitis Multiple Injuries

hs-CRP hs-CRP

Antibiotics Placebo

Acute tonsillitis UC, Psoriasis, chronic fatigue syndrome Cirrhosis

hs-CRP hs-CRP, IL-6, TNF

Alcoholic hepatitis

IL1B,TNF

Probiotic (four strains of lactobacillus, Placebo þ three strains of bifidobacterium and S. Propranolol Thermophilus) þ Propranolol L. subtilis/S.faecium Placebo

IL1B,IL-6,TNF, IL-10,IL-17 hs-CRP, IL-6

IL-6, TNF

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

Table 3 Characteristic of randomized controlled trials that evaluated the effect of the probiotic/synbiotic on the serum level of inflammatory biomarkers in unhealthy participants.

Finland

Both

Hod, 2017 [158]

Israeal

Horvath, 2016 [159]

Austria

Hummelen, 2011 [160] Inoue, 2014 [161]

Netherlands Both Japan Both

Ivory, 2008 [162] Jafarnejad, 2017 [19]

UK Iran

Jain, 2004 [163]

UK

Jenks, 2010 [164] Kanazawa, 2005 [165]

51

Parallel

52

8, 13

L. rhamnosus GG

Placebo

RA

Female 29.5

Parallel

8

54, 53

Placebo

IBS

Both

58

Parallel

24

44, 36

Placebo

Cirrhosis

hs-CRP

29.6

Parallel Parallel

10 8

19, 25 24, 25

L. rhamnosus; L. casei; L. paracasei; L. plantarum; L. acidophilus; B. bifdum; B. longum; B. breve; B. infantis; S.thermophilus; L. bulgaricus; and Lactococcus lacti B. bifidum, B. lactis, L. acidophilus, L. brevis, L. casei W56, L. salivariu, Lactococcus lactis and Lactococcus lactis L. rhamnosus GR-1 and L. reuteri RC-14 L. acidophilus

hs-CRP, IL1B, IL-6, TNF, IL10, IL-12 hs-CRP

Placebo Placebo

HIV Atopic Dermatitis

Both 18e45 Female 58

Parallel Parallel

20 24

10, 10 20, 21

Milk Calcium and Vitamin D

Seasonal allergic rhinitis Osteopenic Postmenopausal Women

IL-10, INF IL-4, IL-5, IL-6, TNF, IL-10, IL-12, IL-17, INF IL1B, IL-5, IL-6, TNF, INF IL1B, TNF

Both

72.5

Parallel

1

45, 45

Placebo

Critically ill patients

hs-CRP

New Zealand Both Japan Both

43.3 63.75

Parallel Parallel

12 2

32, 31 21, 23

Placebo Entral feeding

hs-CRP hs-CRP

Karbaschian, 2018 [166]

Iran

Both

34.65

Parallel

16

23, 23

Spondylo arthritis Biliary cancer undergoing high-risk hepatectomy Mini Gastric Bypass

Karlsson, 2010 [167]

Sweden

Male

68.5

Parallel

4

9, 7

Oat drink

Cardiovascular disease

hs-CRP,,,,IL-6,TNF,,,,,

Kawase, 2009 [168] Koga, 2013 [169] kouchaki, 2016 [170]

Japan Japan Iran

Both Both Both

36.8 53.2 33.5

Parallel Parallel Parallel

6 2 12

20, 18 18, 19 30,30

Placebo Placebo Placebo

Japanese cedar pollinosis Alcoholic liver cirrhosis Multiple sclerosis

hs-CRP hs-CRP, IL-6 hs-CRP

Krebs, 2013 [171]

Slovenia

Both

No placebo

Patients with preceding large bowel operation for colorectal cancer

hs-CRP, IL-6

Krebs, 2016 [172]

Slovenia

Both

64.5

No placebo

IL-6

Krebs, 2016

Slovenia

Both

62

Patients with preceding large bowel operation for colorectal cancer Patients with preceding large bowel operation for colorectal cancer

Lei, 2017 [173] Liu, 2014 [174]

China China

Both Both

66.8 41.5

Skimmed milk Salofalk

Osteoarthritis Ulcerative colitis

hs-CRP TNF, IL-8, IL-10

Liu, 2015 [175] Mandel, 2010 [176] Malaguarnera, 2012 [177]

China USA Italy

Both Both Both

Diet therapy Placebo Lifestyle modification

Ulcerative colitis RA Non Alcoholic Steatohepatitis

hs-CRP

McNaught, 2002 [178]

UK

Both

Without placebo

Elective surgical patients

Parallel

Parallel

20, 16

0.5

18, 16

1

18, 16

Parallel Parallel

24 8

215, 218 21, 21

39.88 62.5 46.8

Parallel Parallel Parallel

8 8 24

30, 30 22, 22 34, 32

68.5

Parallel

1.2

64, 65

Milk containing L. casei Shirota (L. casei, B. longum, L. acidophilus, L. rhamnosus, L. bulgaricus, Bifiobacteriumbreve, and S.thermophilus) þ Ca VitD Synbiotic (L. acidophilus, B. lactis, S thermophilus and L. bulgaricus with oligofructose) S.salivarius, B. lactis, and L. acidophilus Synbiotic (B. breve and L. casei strain Shirota þ GOS) Synbiotic (L. casei, L. rhamnosus, S.thermophilus, B. breve, L. acidophilus, B. longum, and L. bulgaricus þ FOS) þ multivitamin and mineral Synbiotic (oat drink drink with L. plantarum) L. GG, L. gasseri TMC0356 L. casei Shirota YIT 9029 Probiotic (L. acidophilus, L. casei, B. bifidum and L. fermentum) Symbiotic (Pediacoccus pentosaceus, Leuconostoc mesenteroides, L. paracasei, L. plantarum and bioactive plant fibers:beta- glycan, inulin, pectin, resistant starch) Prebiotic (2.5 g of each of the four fermentable fibres: betaglucan, inulin, pectin and resistant starch.) Synbiotic: (Pediacoccus pentosaceus, Leuconostoc mesenteroides, L. paracasei subsp paracasei, and L. plantarum) þ prebiotic (2.5 g of each of the four fermentable fibres: betaglucan, inulin, pectin and resistant starch.) Skimmed milk containg L. casei Shirota Bifidobacterium triple viable bacterial preparation þ Salofalk Probiotic and diet therapy Bacillus coagulans Symbiotic (B. longum and fructooligosaccharide) plus lifestyle modification and vitamin B

Multivitamin and mineral

No placebo

hs-CRP, IL-6, TNF

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

Hatakka, 2003 [157]

IL-6,

hs-CRP, TNF

hs-CRP (continued on next page) 9

Author,Year

10

Country

Sex

Age (year)

Design

Duration Participants Intervention (Probiotic strains) (weeks) (Intervention, Control)

McNaught, 2005 [178]

UK

Both

71

Parallel

1.2

52, 51

Mimura, 2017 [179]

Brazil

Both

37.45

Parallel

16

22, 23

Minami, 2018 [180] Mizuta, 2016 [181]

Japan Japan

Both Both

45.5 70

Parallel Parallel

12 3

40, 40 31, 29

Nagata, 2010 [182] Natarajan, 2014 [183]

Japan USA

Female 22 Both 54

Parallel 6 Cross-over 8

16, 17 21, 21

Nilsson, 2018 [184]

Sweden

Female

Parallel

48

45, 45

Panahi, 2017 [185]

Iran

Male

41.8

Parallel

6

40, 20

Rayes, 2002 [186]

Germany

Both

61

Parallel

1.2

30, 30,30

Roller, 2007 [187]

Ireland

Both

Parallel

12

19, 15

Rossi, 2016 [188]

Australia

Both

Schunter, 2012 [189]

USA

Female 47.6

Shadnoush, 2013 [190]

Iran

Shariaty, 2017 [191]

Iran

Sharma, 2011 [192]

69

Cross-over 6

31, 31

Parallel

4

14, 13

37.69

Parallel

8

86, 90

Both

57.8

Parallel

4

18, 18

India

Both

40.5

Parallel

1

22, 18

Singh, 2013 [193] Smecuol, 2013 [194]

Switzerland Argentina

Both Both

30 Parallel 43 (median) Parallel

8s 3

10, 10 10, 7

Stadlbauer, 2008 [195] Tan, 2011 [196]

UK China

Both Both

54.2 40

Parallel Parallel

4 3

10, 8 22, 21

Tomasik, 2015 [197]

USA

Both

46.45

Parallel

14

30, 27

Usami, 2011 [198]

Japan

Both

65.6

Parallel

4

32, 29

Vaghef-Mehrabany, 2014 [199] Villar-García, 2015 [200] Viramontes-Horner, 2014 [201]

Iran

Female 42.7

Parallel

8

22, 24

Spain Mexico

Both Both

Parallel Parallel

12 8

22, 22 20, 15

47.5 39.8

Synbiotic (oatmeal based drink per ml of L. plantarum 299v) Synbiotic (oatmeal based drink per ml of L. plantarum 299v) Synbiotic (FOS and L. paracasei, L. rhamnosus, L. acidophilus, and of B. lactis) B. breve B. longum BB536

Control status

Participants disease

Outcome

Placebo

Critically ill patient

IL-6

Placebo

Recurrent aphthous stomatitis

IL-4, TNF, IL-10, IL-12, IL17, INF

Placebo Without placebo

pre-obese adults Patients undergoing colorectal resection Seasonal allergic disease Dialysis

hs-CRP hs-CRP, IL-6

L. plantarum No.14 Placebo S. thermophilus KB 19, L. acidophilus KB Placebo 27, and B. longum KB 31 L. reuteri Placebo Probiotic (L. acidophilus, L. bulgaricus, L. rhamnosus, L. casei, B. breve, B. longum and S.thermophilusthe) 1. Enteral feeding contains synbiotic (fiber and lactobacillus) 2. Enteral feeding contains heat killed lactobacillus Synbiotic (L. rhamnosus GG,B. lactis Bb12 and inulin enriched with oligofructose) Synbiotic (nine different strains contained Lactobacillus, Bifidobacteria, and Streptococcus þ FOS and GOS Symbiotic (Pediococcus pentosaceus, Leuconostoc mesenteroides, L. paracasei subsp paracasei,L. plantarum and betaglucan, inulin, pectin, and resistant starch) B. BB-12 and L. acidophilus

Placebo

old women with low bone hs-CRP, TNF mineral density Pulmonary diseaes due to hs-CRP sulfur mustard exposure

Enteral feeding (no placebo)

Major abdominal surgery

hs-CRP

Placebo

Cancer patients

TNF, IL-10, IL-12, INF

Placebo

Renal Failure

IL1B, IL-6, TNF, IL-10

Betaglucan, inulin, pectin, and resistant starch

HIV

hs-CRP

Placebo

IBD CRF under hemodialysis

hs-CRP, IL1B, IL-6, TNF, IL10 hs-CRP

Acute Pancreatitis

hs-CRP

Seasonal allergic rhinitis Celiac Disease

IL1B, IL-5, TNF IL-4, IL-5, IL-6, TNF, IL-10, IL-12, IL-17, INF hs-CRP hs-CRP, IL-4, IL-6, IL-10, IL-12, INF hs-CRP

L. casei, L. acidophilus, L. rhamnosus, L. Placebo bulgaricus, B. breve, B. longum, and S.thermophilus L. acidophilus, B. longum, B. bifidum, Placebo and B. infantis B. lactis NCC2818 Placebo B. infantis Placebo L. casei Shirota B. longum, L. bulgaricus, S. thermophilus L. rhamnosus strain GG and B. animalis subsp. lactis Synbiotic (B. breve, L casei strain Shirota þ GOS) L. casei

hs-CRP hs-CRP

Without placebo No placebo

Cirrhosis Traumatic brain injury

Placebo

Schizophrenia

Without placebo

Hepatic surgery with or without cirrhosis Rheumatoid arthritis

Placebo

Saccharomyces boulardii Placebo Synbiotic gel (L. acidophilus, B. lactis Placebo and Inulin) plus nutritional counseling

HIV Hemodialysis

hs-CRP, IL-6 IL1B, IL-6, TNF, IL-10, IL12, hs-CRP, IL-6 hs-CRP

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

Table 3 (continued )

B., bifidobacterium; FOS, fructooligossacaride; GOS, galactooligosaccharide; hsCRP high sensitive C-reactive protein; IFN, interferon; IL, interleukin; IBS, inflammatory bowel syndrome; JCP, Japanese cedar pollinizes; L., lactobacillus; RA, rheumatoid arthritis; S, streptococcus; TNF, tumor necrosis factor.

Placebo Symbiotic (Bifidobacterium plus mesalazine) 33, 32 Both

Both

39.8 China Zhou, 2017 [211]

Parallel

6

45, 45 China Zhou, 2017 [210]

Parallel

38, 38 8 36 Both China Zhang, 2018 [97]

Parallel

30, 30 27, 27 8 8 51.4 49.4 Both Both Iran Iran Zamani, 2016 [208] Zamani, 2017 [209]

Parallel Parallel

IL-6, TNF, INF

IL-6, TNF

Diarrhea secondary to chemotherapy Active ulcerative colitis

Moderate ulcerative colitis hs-CRP, IL-4, IL-8 Placebo

hs-CRP hs-CRP Placebo Placebo

Allergic rhinitis JCP Atopic dermatitis HIV Patients with oesophageal cancer Rheumatoid arthritis Rheumatoid arthritis Placebo Yogurt Placebo Placebo Without placebo 30 20 26 7 21 30, 20, 24, 10, 21, 4 14 24 12 3 Cross-over Parallel Parallel Parallel Parallel 26.8 36.6 26.25 50 65.5 Both Both Both Male Both Switzerland Japan Japan USA Japan Wassenberg, 2011 [203] Xiao, 2006 [204] Yamamoto, 2016 [205] Yang, 2014 [206] Yokoyama, 2014 [207]

24 52.5 Both China Wang, 2015 [202]

Parallel

21, 18

B.bifidum. catenulatum, B. longum, and L. plantarum L. helveticus, L. paracasei Yogurt containing B. bifidum536 L. acidophilus L-92 Bacillus coagulans GBI-30 Synbiotic (L. casei strain Shirota, B. breve and GOS) L. acidophilus, L. casei, B. bifidum Symbiotic (L. acidophilus, L. casei and B. bifidum plus inulin) Symbiotic (Bifidobacterium plus mesalazine) Bifidobacterium triple viable

Placebo

Peritoneal dialysis

IL-5, IL-6, TNF, IL-10, IL17, INF IL-4, IL-5, IL-8, IL-10, INF IL-10, INF TNF, IL-8, IL-12 hs-CRP, TNF hs-CRP

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

11

(p ¼ <0.001) (Fig. 5, Table 5). Meta-regression for age and duration of studies was not significant. 3.1.5. Critically ill patients From eight clinical trials in critically ill patients, 428 participants were included (Multiple organ dysfunction syndrome (1), acute pancreatitis (2), critically ill patients (1), surgical ICU (1), patients with multiple injuries (1), traumatic brain injury (1), acute tonsillitis (1)). Seven studies had two arms and one had three arms. In the pooled analysis of studies, a significant effect of probiotic on serum CRP reduction (SMD ¼ 0.66, 95% CI 1.03 to 0.29, p ¼ <0.001) was observed with a heterogeneity of 69.4% (p ¼ 0.001) (Fig. 6, Table 5). Meta-regression for duration was not significant. Egger test showed no publication bias (p ¼ 0.11). Influence analysis showed that none of the trials had significant effect on pooled effect size. 3.1.6. Surgery Effect of probiotic on CRP was examined in 10 studies where participants underwent surgery. In these studies, serum level of CRP was assessed immediately before surgery and maximum up to two weeks after the surgery except one that measure CRP four weeks before and 12 weeks after the surgery so this study was excluded. In the pooled analysis of nine studies in subjects who underwent surgery (519 participants), no significant change in serum CRP (SMD ¼ 0.06, 95% CI -0.35 to 0.22, p ¼ 0.66) was observed with a heterogeneity of 59.9% (p ¼ 0.008) (Fig. 7, Table 5). 3.1.6.1. CRF patients under hemodialysis. In the pooled analysis of four studies in CRF patients under hemodialysis (134 participants), no significant effect of probiotic on serum CRP (SMD ¼ 0.12, 95% CI -0.47 to 0.22, p ¼ 0.48) was observed with a heterogeneity of 36.5% (p ¼ 0.19) (Table 5). 3.1.7. HIV In the pooled analysis of four studies in patients with HIV (118 participants), no significant effect of probiotic on serum CRP (SMD ¼ 0.23, 95% CI -0.60 to 0.13, p ¼ 0.21) was observed with a heterogeneity of 49.4% (p ¼ 0.12) (Table 5). 3.1.8. Cirrhosis In the pooled analysis of three studies in cirrhotic patients (135 participants), no significant effect of probiotic on serum CRP (SMD ¼ 0.80, 95% CI -2.80 to 1.14, p ¼ 0.41) was observed with a heterogeneity of 94.9% (p¼<0.001) (Table 5). 3.2. IL-10 Forty-two clinical trials measured IL-10 (healthy (22), diabetes (1), NAFLD (1), PCOS (1), MS (2), RA (4), IBD (4), IBS (1), CRF (2), cancer (1), HIV (1), aphthous stomatitis (1), trauma (1), atopic dermatitis (1). 3.2.1. Healthy From 22 clinical trials in healthy subjects with normal weight or obese, 1555 participants were included. Seventeen studies had two arms, three had three arms, three had four arms and one had five arms. Nine studies measured IL-10 in serum, four in PBMC and seven measured IL-10 secretion from mitogen stimulated PBMC. In the pooled analysis of studies, no significant effect of probiotic on IL-10 (SMD ¼ 0.14 pg/ml, 95% CI -0.35 to 0.08, p ¼ 0.21) was observed with a heterogeneity of 75.7% (p¼<0.001) (Fig. 8, Table 5). Subgroup analysis by the sample in which IL-10 was measured revealed a significant increase in IL-10 measured in PBMC

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

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A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Table 4 Summary of the results. CRP Healthy Metabolic disorders Diabetes NAFLD MS þ PCOS MS IBD Arthritis Cihrrosis Critically ill Surgery CRF

TNF-a

IL-1B

No change No change

IL-6

(In PBMC) No No No No

IL-10

change (In PBMC) change No change change change

IFN-g

IL-4

IL-8

IL-12

TGF-B

(IFN secreted from PBMC) No change No change No change No change

No change No change No change No change No change No change No change

No change

No change No change

B., bifidobacterium; CHD, coronary heart disease; FOS, fructooligossacaride; hsCRP high sensitive C-reactive protein; IFN, interferon; IL, interleukin; L., lactobacillus; NAFLD, non-alcoholic fatty liver disease; PCOS, polycystic ovary syndrome; S, streptococcus; TNF, tumor necrosis factor T2DM, type 2 diabetes mellitus. or : Small effect Or : Moderate effect Or : Large effect.

Study ID

SMD (95% CI)

% Weight

Iwasa (2013) Ahn (2015) Akkasheh (2016) Brahe (2015) Cavallini (2016) Costabile (2017) Costabile (2017) De Roos (2017) Irwin (probiotic) (2017) Irwin (synbiotic) (2017) Jung (2015) Kekkonen (2008) Kekkonen (2008) Kekkonen (2008) Lee (2017) Lee (2017) Lee (2017) Lee A (2017) Macfarlane (2013) Minami (2018) Minami (2015) Mohammadi (2015) Mohammadi (2015) Nilsson (2018) Nyangale (2014) Osterberg (2015) Rajkumar (2014) Rajkumar (2015) Rajkumar (2015) Sanchez (2014) Seifert (2011) Simons (2006) Stenman (2016) Stenman (2016) Stenman (2016) Valentini (2015) Zarrati (2014) cox (2014) cox (2014) Overall (I-squared = 59.2%, p = 0.000)

-0.31 (-1.12, 0.49) 0.04 (-0.37, 0.45) -0.78 (-1.43, -0.14) 1.14 (0.41, 1.87) -0.32 (-1.02, 0.38) -1.01 (-1.49, -0.52) -0.70 (-1.08, -0.32) 0.19 (-0.31, 0.68) -0.18 (-0.91, 0.55) -0.74 (-1.49, 0.02) -0.19 (-0.59, 0.22) -0.43 (-1.12, 0.26) 0.03 (-0.67, 0.72) -0.62 (-1.37, 0.13) 0.13 (-0.42, 0.68) 0.63 (0.07, 1.19) -0.15 (-0.71, 0.40) -0.12 (-0.44, 0.20) -0.51 (-0.95, -0.08) -0.31 (-0.75, 0.13) -0.51 (-1.12, 0.10) 0.07 (-0.77, 0.91) -0.22 (-1.05, 0.61) 0.03 (-0.38, 0.44) 0.59 (-0.07, 1.26) -0.56 (-1.46, 0.34) -0.69 (-1.42, 0.05) -0.00 (-0.72, 0.71) -0.00 (-0.72, 0.71) 0.01 (-0.40, 0.42) 0.27 (-0.21, 0.75) -0.37 (-0.97, 0.22) -0.20 (-0.66, 0.26) -0.50 (-1.02, 0.02) -0.13 (-0.59, 0.33) -1.39 (-1.94, -0.83) 0.37 (-0.19, 0.93) 0.00 (-0.43, 0.43) -0.28 (-0.70, 0.13) -0.20 (-0.33, -0.06)

1.78 3.27 2.29 2.00 2.10 2.93 3.39 2.88 2.00 1.93 3.30 2.13 2.12 1.94 2.65 2.60 2.63 3.69 3.15 3.12 2.43 1.69 1.72 3.25 2.20 1.55 1.98 2.05 2.05 3.28 2.96 2.46 3.04 2.78 3.03 2.62 2.61 3.18 3.24 100.00

NOTE: Weights are from random effects analysis -1.94

0

1.94

Fig. 2. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on C-reactive protein (CRP) levels in healthy subjects. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

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Table 5 Meta-analysis of the change in inflammatory markers in health and disease conditions. Cytokine

Participants health condition

Num study (sample size)

SMD

95% CI

p

Heterogeneity

p

CRP

Healthy Metabolic dis. Diabetes NAFLD MS PCOS IBD Arthritis CRF HIV Surgery Cirrhosis Critically ill Healthy Arthritis Healthy Metabolic dis. IBD Arthritis Healthy Healthy Healthy Healthy Healthy Healthy Metabolic dis. DM Fatty liver MS þ PCOS Cirrhosis Surgery Arthritis CRF IBD Healthy Metabolic dis. IBD Cirrhosis Fatty liver PCOS þ MS Diabetes Arthritis

28 (2395) 29 (1815) 16 (1065) 5 (322) 3 (84) 5 (344) 7 (1868) 8 (750) 4 (134) 3 (88) 9 (519) 3 (135) 8 (428) 15 (838) 4 (142) 21 (1477) 5 (358) 4 (253) 4 (142) 24 (1515) 11 (869) 11 (1055) 7 (567) 6 (411) 23 (1456) 16 (707) 6 (344) 3 (150) 6 (213) 5 (167) 5 (319) 4 (142) 4 (167) 5 (4 32 (2087) 20 (955) 6 (450) 4 (130) 7 (378) 5 (178) 7 (357) 4 (142)

0.20 0.37 0.41 0.38 0.33 0.2 1.37 0.67 0.12 0.16 0.065 0.8 0.66 0.32 0.16 0.14 0.38 3.1 0.51 0.02 0.07 0.06 0.01 0.13 0.09 0.025 0.14 0.04 0.31 0.36 0.9 0.32 0.35 0.11 0.30 0.30 0.87 0.43 0.75 0.25 0.02 0.51

0.33 to 0.06 0.61 to 0.13 0.53 to 0.28 0.60 to 0.15 0.10 to 0.77 0.02 to 0.42 1.81 to 0.47 1.25 to 0.09 0.47 to 0.22 0.59 to 0.26 0.35 to 0.22 2.80 to 1.14 1.03 to 0.29 0.64 to0.005 0.51 to 0.18 0.35 to 0.08 0.39 to 1.14 2.06 to 8.27 0.17 to 0.86 0.25 to 0.21 0.21 to 0.06 0.18 to 0.07 0.33 to 0.30 0.18 to 0.21 0.24 to 0.06 0.25 to 0.20 0.08 to 0.35 0.28 to 0.36 0.58 to 0.03 0.05 to 0.68 1.6 to 0.18 0.71 to 0.08 0.029 to 0.67 1.35 to 1.57 0.49 to 0.10 0.62 to 0.03 1.23 to 0.50 0.78 to 0.08 0.97 to 0.54 0.05 to 0.56 0.23 to 0.19 0.17 to 0.86

0.005 0.002 <0.001 0.001 0.13 0.08 0.002 0.02 0.48 0.45 0.66 0.41 <0.001 0.053 0.35 0.21 0.34 0.24 0.003 0.86 0.29 0.35 0.94 0.9 0.24 0.83 0.21 0.81 0.03 0.02 0.003 0.11 0.03 0.88 0.006 0.07 <0.001 0.02 <0.001 0.1 0.86 0.003

58.5% 84.1% 79.5% 82.4% 28% 92.4% 84.1% 89.2% 36.5% 63.8% 59.9% 94.9% 69.4% 79.5% 71.4% 75.7% 88.4% 99.0% 0.0% 77.7% 0.0 22.1% 68.3% 0.0% 52.2% 54.1% 10.7% 59.5% 66% 41.8% 85.5% 21.3% 0.0% 97.7% 73.9% 84.8% 67.5% 0.0% 83.9% 46% 84.2% 0.0%

<0.001 <0.001 <0.001 <0.001 0.25 <0.001 <0.001 <0.001 0.19 0.06 0.008 <0.001 0.001 <0.001 0.02 <0.001 <0.001 <0.001 0.57 <0.001 0.57 0.19 0.001 0.65 <0.001 0.005 0.35 0.08 0.01 0.14 <0.001 0.28 0.94 <0.001 <0.001 <0.001 0.003 0.78 <0.001 0.12 <0.001 0.57

IL-1B IL-10

IFN-g IL-4 IL-8 IL-12 TGF-B IL-6

TNF-a

CRF: chronic renal failure; dis., disorders; DM, diabetes mellitus; IBD: inflammatory bowel disease; MS: metabolic syndrome; NAFLD: non-alcoholic fatty liver disease; PCOS, Polycystic ovary syndrome.

significant effect of probiotic on IL-10 (SMD ¼ 0.38, 95% CI -0.39 to 1.14, p ¼ 0.34) was observed with a heterogeneity of 88.4% (p¼<0.001) (Fig. 9, Table 5).

(SMD ¼ 0.47, p ¼ 0.001), while serum IL-10 decreased significantly (SMD ¼ 0.29, p¼<0.001) and secreted IL-10 from mitogen stimulated PBMC (SMD ¼ 0.13, p ¼ 0.11) did not change significantly (Sup Fig. 4). Subgroup analysis by age indicated a significant reduction of IL-10 in subjects with age >49 (SMD ¼ 0.44, p ¼ 0.0.0, I2 ¼ 87.0%, p ¼ <0.001) while for age 49, no significant change as observed (SMD ¼ 0.02, p ¼ 0.74, I2 ¼ 60.0%, p ¼ <0.001). The greatest decrease was observed at dose 5  1010 compared to the >109-<5  1010 and <109 (Sup Table 4). Results of subgroupanalysis by the strains of bacteria (in healthy individuals and patients with metabolic disorders) are presented in Table 6 and Sup Fig. 5. IL-10 was decreased only in one of the subgroups (B. lactis). Meta-regression for age and duration of studies was not significant while meta-regression for BMI (Coefficient (Coef) ¼ 0.13, p ¼ 0.02, I2_residual ¼ 79.21%, Adjusted R2 ¼ 31.7%) revealed a significant association. Meta-regression for age after adjusting for BMI (Coef ¼ 0.03, p ¼ 0.009, I2_residual ¼ 66.44%, Adjusted R2 ¼ 63.34%) was significant.

3.3. IL-1B

3.2.2. Metabolic disorders From five clinical trials in subjects with metabolic disorders (diabetes (1) fatty liver (1), PCOS (1), metabolic syndrome (2)), 358 participants were included. In the pooled analysis of studies, no

3.3.1. Healthy Thirty-three clinical trials measured IL-1B (healthy (17), diabetes (1), MS (1), alcoholic hepatitis (1), arthritis (4), IBD (2), allergy (2), CRF (1), cirrhosis (2), gastric bypass (1), celiac disease (1).

3.2.3. IBD In the pooled analysis of four studies in IBD patients (253 participants), no significant effect of probiotic on IL-10 was seen (SMD ¼ 3.1, 95%CI -2.06 to 8.27, p ¼ 0.24) with a heterogeneity of 99% (p¼<0.001). 3.2.4. Arthritis In the pooled analysis of four studies in patients with arthritis (142 participants), a significant increase was observed in IL-10 (SMD ¼ 0.51, 95%CI 0.17 to 0.86, p ¼ 0.003) with a heterogeneity of 0.00% (p ¼ 0.57).

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

14

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Table 6 Sub group analysis by the strains of bacteria. Strains CRP L. helveticus B.breve L. sporogenes þ inulin B. (longum, infantis, breve) þ L.(acidophilus, paracasei, bulgaricus, plantarum) L. acidophilus, casei, B,bifidum L. casei L. curvatus þ L. plantarum B.lactis L. reuteri L. plantarum L.rhamnosus L.aidophilus þ B.lactis L. (casei, rhamnosus, acidophilus, bulgaricus) þ B.(breve, longum) þ S. thermophiles þ FOS Other strains Overall TNF-a L.rhamnosus B.lactis L. casei L.reuteri B.longum þ prebiotic L.plantarum L.aidophilus þ B.lactis FOS þ L. paracasei, L. rhamnosus, L. acidophilus, and B. lactis B.(infantis, longum, breve) þ L.(acidophilus, bulgaricus, paracasei, plantarum) þ S.thermophilus L.(casei, rhamnosus, acidophilus, bulgaricus) þ B.(breve, longum) S.thermophilus þ FOS Other strains Overall IL-6 L.rhamnosus B.lactis L. casei L.plantarum L.aidophilus þ B.lactis L.(casei, rhamnosus, acidophilus, bulgaricus) þ B.(breve, longum) S.thermophilus þ FOS Other strains IL-1B L.casei B.lactis Other strains Overall IL-10 L.casei B.lactis B. longum L.helveticus B.lactis þ L.casei B.lactis þ L.acidophilus Other strains Overall IFN-g L.casei B.lactis B.lactis þ L.acidophilus B.longum Other strains Overall IL-4 L.casei B.lactis Other strains Overall

SMD

P

I2

P

0.30 0.38 0.36 1.02 0.56 0.65 0.08 0.04 0.02 0.16 0.53 0.30 0.17 0.13 0.22

0.23 0.04 0.02 <0.001 <0.001 <0.001 0.60 0.71 0.90 0.46 <0.001 0.03 0.08 0.045 79.3

0.0 0.0 0.0 0.42 62.3 89.8 0.0 43.2 0.0 26.3 82.3 21.7 90.9 79.9 79.3

0.98 0.60 0.46 0.17 0.004 <0.001 0.44 0.12 0.91 0.26 0.003 0.28 <0.001 <0.001 <0.001

0.01 0.19 0.01 0.13 0.09 0.32 0.28 0.26 0.04 0.26 0.2 0.03

0.97 0.22 0.89 0.48 0.55 0.32 0.08 0.30 0.86 0.02 0.002 0.44

0.0 58.1 56.2 0.0 95.4 0.0 73.4 0.0 0.0 80.9 65.6 70.8

0.89 0.07 0.02 0.62 <0.001 0.80 0.02 0.91 0.47 <0.001 <0.001 <0.001

0.21 0.18 0.05 0.71 0.13 0.51 0.19

0.10 0.13 0.67 0.005 0.41 0.02 0.02

0.0 54.6 0.0 87.1 24.9 0.0 57.1

0.73 0.05 0.47 <0.001 0.26 0.88 0.002

0.20 0.12 0.05 0.05

0.14 0.50 0.54 0.26

0.0 8.2 86.1 58.3

0.99 0.34 <0.001 <0.001

0.04 0.47 0.09 0.36 0.31 0.22 0.13 0.07

0.69 0.003 0.55 0.08 0.08 0.25 0.14 0.17

54.1 65.9 0.0 30.8 0.0 96.8 88.8 79.7

0.04 0.03 0.50 0.23 0.94 <0.001 <0.001 <0.001

0.04 0.21 0.30 0.20 0.26 0.14

0.68 0.24 0.14 0.27 0.001 0.009

3.5 0.0 0.0 51.2 86.3 75.8

0.40 0.59 0.40 0.15 <0.001 <0.001

0.15 0.14 0.17 0.07

0.24 0.43 0.09 0.36

9.1 0.0 0.0 0.0

0.64 0.33 0.77 0.57

B, bifidobacterium; hsCRP high sensitive C-reactive protein; IFN, interferon; IL, interleukin; L, lactobacillus; S, streptococcus; TNF, tumor necrosis factor.

From 17 clinical trials in healthy subjects, one was excluded as it measured IL-1. Therefore, 16 studies (916 participants) were included. Eleven studies had two arms, two studies had three and one had four arms. Five studies measured IL-1B in serum, two in PBMC and seven measured IL-10 secretion from mitogen stimulated PBMC.

In the pooled analysis of studies, effect of probiotic on IL-1B (SMD ¼ 0.32 pg/ml, 95% CI -0.64 to 0.005, p ¼ 0.053) was marginally significant with a heterogeneity of 79.5% (p ¼ <0.001) (Fig. 10, Table 5). A subgroup analysis for the sample revealed a significant decrease in IL-1B measured in PBMC (SMD ¼ 0.53, p ¼ 0.021),

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

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15

Study ID

SMD (95% CI)

% Weight

Asemi (2014) Asemi (2013) Bayat (2016) Bayat (2016) Karamali, (2018) Mazloom (2013) Mohamadshahi, (2014) Tajadadi (2014) Tajadadi (2014) Hove (2015) Rabiei, (2018) Tripolt (2015) Mobini (2017) Mobini (2017) Eslamparast (2014) Ghanei (2018) Soleimani (2017) Sato (2017) Mofidi (2017) Kooshki (2015) Nasri (2018) Firuzi (2017) Farrokhian (2017) Malaguarnera (2012) Raygan (2018) Asgharian (2016) Karimi, (2018) Shoaei (2017) Sherf-Dagan (2018) Karlsson (2010) Rezaei (2017) Feizollahzadeh (2017) Overall (I-squared = 84.2%, p = 0.000)

-0.44 (-0.79, -0.08) -3.19 (-4.00, -2.38) -1.14 (-1.81, -0.47) -1.66 (-2.38, -0.94) -1.05 (-1.59, -0.51) -0.21 (-0.88, 0.47) -0.76 (-1.39, -0.14) -0.19 (-0.73, 0.34) -0.30 (-0.83, 0.24) -0.30 (-0.92, 0.32) -0.01 (-0.63, 0.61) 0.82 (0.05, 1.60) 0.12 (-0.61, 0.85) -0.11 (-0.82, 0.61) -0.78 (-1.35, -0.22) 1.54 (0.97, 2.12) -0.56 (-1.07, -0.04) 0.16 (-0.31, 0.64) -0.50 (-1.06, 0.07) -0.69 (-1.30, -0.09) -0.54 (-1.06, -0.03) 0.21 (-0.19, 0.60) -0.73 (-1.25, -0.21) -1.25 (-1.78, -0.72) -0.62 (-1.13, -0.10) -0.11 (-0.57, 0.35) 0.50 (0.10, 0.90) 0.48 (-0.02, 0.97) 0.29 (-0.15, 0.73) 0.43 (-0.57, 1.43) -0.11 (-0.52, 0.31) -0.07 (-0.69, 0.55) -0.32 (-0.57, -0.08)

3.52 2.67 2.95 2.85 3.21 2.94 3.04 3.22 3.21 3.05 3.05 2.74 2.84 2.86 3.16 3.13 3.25 3.32 3.16 3.07 3.25 3.47 3.24 3.23 3.25 3.36 3.45 3.29 3.39 2.32 3.43 3.05 100.00

NOTE: Weights are from random effects analysis -4

0

4

Fig. 3. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on C-reactive protein (CRP) levels in patients with metabolic disorders. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

while serum IL-1B (SMD ¼ 0.059, p ¼ 0.59) and secreted IL-1B from mitogen stimulated PBMC (SMD ¼ 0.188, p ¼ 0.09) did not change significantly (Sup Fig. 6). Results of subgroup-analysis by the strains of bacteria (in healthy individuals) are presented in Table 6 and Sup Fig. 7. IL-1b was decreased only in one of the subgroups (B. lactis). Meta-regression for age and duration of studies was not significant while metareg for BMI (Coef ¼ 0.23, p ¼ 0.13, I2_residual ¼ 80.65%, Adjusted R2 ¼ 15.14%) revealed a significant association. 3.3.2. Arthritis In the pooled analysis of four studies in patients with arthritis (142 participants), no significant effect of probiotic on serum IL-1B (SMD ¼ 0.16, 95% CI -0.51 to 0.18, p ¼ 0.35) was observed with a heterogeneity of 71.4% (p ¼ 0.02).

studies measured IFN-g in serum, three in PBMC and ten measured IFN-g secretion from mitogen stimulated PBMC. In the pooled analysis of 21 studies (1455 participants), no significant effect of probiotic on IFN-g (SMD ¼ 0.006 pg/ml, 95% CI -0.27 to 0.24, p ¼ 0.91) was observed with a heterogeneity of 79.8% (p¼<0.001) (Fig. 11, Table 5). A subgroup analysis for the sample revealed no significant change in PBMC levels of IFN-g (SMD ¼ 0.05, p ¼ 0.76) and IFN-g from mitogen stimulated PBMC (SMD ¼ 0.16, p ¼ 0.07), whereas there was a significant increase in IFN-g measured in serum (SMD ¼ 0.44, p¼<0.001) (Sup Fig. 8). Subgroup-analysis by the strains of bacteria indicated that neither L. casei nor B. lactis had no effect on IFN-g (Table 6 and Sup Fig. 9). Meta-regression for age was not significant, while it was significant for BMI (Coef ¼ 0.08, p ¼ 0.095, I2_residual ¼ 78.38%, Adjusted R2 ¼ 13.16%).

3.4. IFN-g

3.5. IL-4

Thirty four studies measured IFN-g (healthy (23), diabetes (1), atopic dermatitis (2), trauma (1), HIV(1) cancer (1), celiac (1), allergy (2), ulcerative colitis (1), CRF (1). From 23 clinical trials in healthy subjects, two studies were excluded as they measured IFN-a and IFN-b. Seventeen studies had two arms, three had three arms and one had four arms. Eight

Eighteen studies measured the effect of probiotic on IL-4 (healthy (11), atopic dermatitis (2), trauma (1), celiac (1), allergy (1), ulcerative colitis (1) and aphthous stomatitis (1)). From 11 clinical trials in healthy subjects (869 participants), eight studies had two arms, two had three arms and one had four arms.

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

16

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Study

%

ID

SMD (95% CI)

Weight

Fujimori (2009)

-0.47 (-1.32, 0.39)

12.84

Groeger (2016)

-1.78 (-2.45, -1.11)

13.92

Groeger (2016)

-0.67 (-1.28, -0.06)

14.29

Groeger (2016)

-0.40 (-0.91, 0.11)

14.82

Liu (2015)

-0.59 (-1.11, -0.07)

14.77

Shadnoush (2013)

-0.75 (-1.06, -0.45)

15.67

Zhang (2018)

-3.44 (-4.15, -2.72)

13.69

Overall (I-squared = 90.4%, p = 0.000)

-1.14 (-1.81, -0.47)

100.00

NOTE: Weights are from random effects analysis -4.15

0

4.15

Fig. 4. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on C-reactive protein (CRP) levels in patients with IBD. (The studies with more than two arms, (different strains of probiotic was investigated in each arm) were considered as more than one studies.).

Study

%

ID

SMD (95% CI)

Weight

Alipour (2014)

-0.39 (-0.97, 0.19)

14.32

Hatakka, (2003)

-0.27 (-1.16, 0.61)

12.05

Lei (2017)

-1.62 (-1.84, -1.41)

16.38

Zamani (2017)

-1.15 (-1.73, -0.57)

14.37

Zamani (2016)

-0.92 (-1.45, -0.39)

14.68

Pineda (2011)

0.09 (-0.64, 0.82)

13.25

Jenks (2010)

-0.17 (-0.67, 0.32)

14.94

Overall (I-squared = 89.2%, p = 0.000)

-0.67 (-1.25, -0.09)

100.00

NOTE: Weights are from random effects analysis -1.84

0

1.84

Fig. 5. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on C-reactive protein (CRP) levels in patients with arthritis. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

In the pooled analysis of studies, no significant effect of probiotic on IL-4 (SMD ¼ 0.07 pg/ml, 95% CI -0.21 to 0.06, p ¼ 0.29) was observed with a heterogeneity of 0.0% (p ¼ 0.57) (Fig. 12, Table 5). However, a significant reduction was observed when analysis was performed for the final value of IL-4 (SMD ¼ 0.15, 95% CI -0.30 to 0.004, p ¼ 0. 04).

A subgroup analysis for the sample revealed no significant change in PBMC IL-4 (two studies) (SMD ¼ 0.05, p ¼ 0.76), IFN-g measured in serum (seven studies) (SMD ¼ 0.1, p ¼ 0.29) and IL-4 from mitogen stimulated PBMC (seven studies) (SMD ¼ 0.11, p ¼ 0.47) (Sup Fig. 10). Subgroup-analysis by the strains of bacteria indicated that neither L. casei nor B. lactis had no effect on IL-4

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

17

%

Study ID

SMD (95% CI)

Weight

Alberda (2007)

-0.38 (-1.31, 0.56) 8.11

Alberda (2007)

-2.01 (-3.13, -0.88) 6.57

Cui, (2013)

-0.06 (-0.63, 0.50) 12.07

Ebrahimi-Mameghani (2013)

-1.43 (-2.13, -0.73) 10.52

Fang (2018)

-1.05 (-1.55, -0.54) 12.78

Giamarellos-Bourboulis, (2009)

-0.84 (-1.40, -0.28) 12.11

Gilbey (2015)

-0.27 (-0.81, 0.27) 12.38

Jaina (2004)

-0.08 (-0.49, 0.33) 13.92

Min Tan (2011)

-0.55 (-1.16, 0.06) 11.55

Overall (I-squared = 69.4%, p = 0.001)

-0.66 (-1.03, -0.30) 100.00

NOTE: Weights are from random effects analysis -3.13

0

3.13

Fig. 6. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on C-reactive protein (CRP) levels in critically ill patients. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

%

Study

Weight

ID

SMD (95% CI)

Usami (2011)

-0.10 (-0.60, 0.41) 11.57

Anderson (2004)

0.25 (-0.17, 0.68)

Yokoyama (2014)

-0.29 (-0.90, 0.32) 9.92

McNaught (2002)

0.20 (-0.15, 0.55)

14.27

Krebs (2013)

0.21 (-0.46, 0.88)

9.10

Kanazawa (2005)

0.01 (-0.58, 0.61)

10.17

Ebrahimi-Mameghani (2013)

-1.43 (-2.13, -0.73) 8.68

Rayes (2002)

-0.04 (-0.60, 0.53) 10.56

Rayes (2002)

-0.07 (-0.63, 0.48) 10.73

Fernandes (2016)

1.42 (-0.46, 3.30)

Overall (I-squared = 59.9%, p = 0.008)

-0.06 (-0.35, 0.22) 100.00

12.94

2.05

NOTE: Weights are from random effects analysis -3.3

0

3.3

Fig. 7. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on C-reactive protein (CRP) levels in patients underwent surgery. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

(Table 6 and Sup Fig. 11). Meta-regression for age, duration of studies and BMI was not significant. 3.6. IL-8 Twenty-one studies measured the effect of probiotic on IL-8 (healthy (11), diabetes (2), MS (1), IBS (1), UC (3), atopic dermatitis (1), RA (1), acute pancreatitis (1). From 11 clinical trials in healthy subjects (1055 participants), five studies had two arms, three had three arms, two had four arms and one had five arms. In the pooled analysis of studies, no

significant effect of probiotic on IL-8 (SMD ¼ 0.06 mg/l, 95% CI -0.18 to 0.07, p ¼ 0.35) was observed with a heterogeneity of 22.1% (p ¼ 0.19) (Fig. 13, Table 5). A subgroup analysis for the sample revealed no significant change in PBMC IL-8 (four studies) (SMD ¼ 0.11, p ¼ 0.30), IL-8 measured in serum (two studies) (SMD ¼ 0.004, p ¼ 0.96) and secreted IL-8 from mitogen stimulated PBMC (five studies) (SMD ¼ 0.08, p ¼ 0.54) (Sup Fig. 12). The decrease induced by synbiotic was greater than probiotic. Moreover, the supplement was most effective at dose 5  1010 compared to the >109<5  1010 and <109 (Sup Table 4). Meta-regression for age was not

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

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A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Study ID

SMD (95% CI)

% Weight

Childs (2014) Childs (2014) Childs (2014) Christensen (2006) Christensen (2006) Christensen (2006) Christensen (2006) Dong (2013) Kekkonen (2008) Kekkonen (2008) Kekkonen (2008) Mangalat (2012) Marcos (2004) Marinkovic (2016) Meyer (2007) Gomes (2017) Hor (2018) Hor (2018) Macfarlane (2013) Olivares (2006) Ouwehand (2008) Ouwehand (2008) Valentini (2015) West (2014) West (2014) Zhang (2018) Gleeson (2011) Nyangale (2014) Seifert (2011) Zarrati (2013) kazemi (2019) Overall (I-squared = 74.8%, p = 0.000)

-0.80 (-1.67, 0.07) -0.14 (-0.97, 0.70) -0.34 (-1.18, 0.50) -0.21 (-0.95, 0.52) -0.44 (-1.19, 0.31) -0.48 (-1.25, 0.28) -0.08 (-0.81, 0.64) 0.38 (-0.14, 0.89) -0.11 (-0.81, 0.58) -0.30 (-1.03, 0.44) 0.25 (-0.44, 0.93) 0.29 (-0.45, 1.04) 0.09 (-0.26, 0.45) -0.67 (-1.31, -0.02) -0.88 (-1.60, -0.17) 0.27 (-0.33, 0.87) 0.41 (-0.25, 1.06) 0.17 (-0.43, 0.77) 0.03 (-0.40, 0.46) 0.01 (-0.70, 0.73) -0.09 (-0.74, 0.55) 0.04 (-0.61, 0.69) -1.76 (-2.35, -1.17) -1.00 (-1.47, -0.53) -1.00 (-1.47, -0.53) 0.02 (-0.31, 0.36) -0.39 (-0.99, 0.20) 0.61 (-0.06, 1.28) 0.33 (-0.15, 0.81) 1.63 (0.98, 2.27) -0.17 (-0.73, 0.39) -0.14 (-0.35, 0.08)

2.58 2.67 2.66 2.96 2.90 2.86 2.96 3.59 3.06 2.94 3.08 2.91 4.00 3.20 2.99 3.33 3.18 3.33 3.82 3.00 3.20 3.18 3.36 3.70 3.71 4.04 3.35 3.13 3.68 3.21 3.43 100.00

NOTE: Weights are from random effects analysis -2.35

0

2.35

Fig. 8. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on IL-10 levels in healthy subjects. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

%

Study ID

SMD (95% CI)

Weight

Tonucci (2015)

1.26 (0.62, 1.91)

19.68

Sherf-Dagan (2018)

0.24 (-0.20, 0.68)

21.23

Ghanei (2018)

1.37 (0.81, 1.94)

20.32

Tripolt (2013)

-0.44 (-1.19, 0.32)

18.73

Xavier-Santos (2018)

-0.61 (-1.21, -0.01)

20.04

Overall (I-squared = 88.4%, p = 0.000)

0.38 (-0.39, 1.14)

100.00

NOTE: Weights are from random effects analysis -1.94

0

1.94

Fig. 9. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on IL-10 levels in subjects with metabolic disorders. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

19

%

Study ID

SMD (95% CI)

Weight

Jafarnejad (2017)

-0.67 (-1.30, -0.04)

5.49

Rajkumar (2015)

-2.26 (-3.19, -1.33)

4.40

Rajkumar (2015)

-2.81 (-3.84, -1.79)

4.07

Dong (2013)

-0.19 (-0.69, 0.32)

5.93

Wilms (2016)

1.83 (0.77, 2.89)

3.96

Macfarlane (2013)

0.15 (-0.28, 0.58)

6.19

Mangalat (2012)

0.58 (-0.18, 1.33)

5.02

Seifert (2011)

-0.27 (-0.75, 0.20)

6.03

Kekkonen (2008)

-0.39 (-1.12, 0.35)

5.09

Kekkonen (2008)

-0.11 (-0.80, 0.59)

5.25

Kekkonen (2008)

-0.01 (-0.69, 0.68)

5.29

Meyer (2007)

-0.69 (-1.40, 0.01)

5.21

Singh (2013)

-0.32 (-1.21, 0.56)

4.56

Gleeson (2011)

-0.17 (-0.76, 0.42)

5.64

Nyangale (2014)

-1.04 (-1.74, -0.34)

5.24

Spanhaak (1998)

-0.16 (-1.04, 0.72)

4.58

West (2014)

0.32 (-0.12, 0.75)

6.18

West (2014)

0.28 (-0.14, 0.71)

6.20

Kazemi (2019)

-0.68 (-1.26, -0.10)

5.67

Overall (I-squared = 79.5%, p = 0.000)

-0.32 (-0.64, 0.00)

100.00

NOTE: Weights are from random effects analysis -3.84

0

3.84

Fig. 10. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on IL-1B levels in healthy subjects (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

Study ID

SMD (95% CI)

% Weight

Christensen (2006) Christensen (2006) Christensen (2006) Christensen (2006) Cox (2010) Dong (2013) Gleeson (2011) Lee (2017) Lefevre (2015) Macfarlane (2013) Mangalat (2012) Marcial (2017) Marcos (2004) Marinkovic (2016) Matsumoto (2017) Meyer (2007) Mohammadi (2015) Mohammadi (2015) Seifert (2011) Spanhaak (1998) Wassenberg (2011) West (2014) West (2014) Zarrati (2013) Zhang (2018) Overall (I-squared = 79.8%, p = 0.000)

-0.50 (-1.25, 0.26) -0.70 (-1.46, 0.05) -0.26 (-0.99, 0.47) -0.80 (-1.59, -0.01) 0.50 (-0.13, 1.12) -0.18 (-0.68, 0.33) 0.09 (-0.50, 0.67) 1.35 (1.00, 1.70) 0.05 (-0.34, 0.44) -0.38 (-0.81, 0.05) -0.19 (-0.93, 0.56) -0.62 (-1.25, 0.01) 0.08 (-0.28, 0.43) 0.42 (-0.22, 1.05) -0.18 (-1.03, 0.67) 0.02 (-0.66, 0.71) 0.01 (-0.81, 0.84) -0.02 (-0.86, 0.82) -0.26 (-0.73, 0.22) -0.07 (-0.95, 0.80) -0.24 (-0.74, 0.27) 0.38 (-0.06, 0.83) 0.33 (-0.12, 0.77) -0.63 (-1.20, -0.06) 1.14 (0.78, 1.51) 0.01 (-0.24, 0.25)

3.54 3.54 3.61 3.43 3.93 4.32 4.06 4.77 4.67 4.55 3.57 3.94 4.76 3.91 3.24 3.76 3.32 3.28 4.41 3.17 4.32 4.52 4.51 4.13 4.74 100.00

NOTE: Weights are from random effects analysis -1.7

0

1.7

Fig. 11. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on IFN-ˠ levels in healthy subjects (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

20

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

%

Study ID

SMD (95% CI)

Weight

Marcos (2004)

0.07 (-0.28, 0.43)

14.99

Cox (2010)

-0.16 (-0.78, 0.46)

4.99

Zarrati (2013)

0.07 (-0.49, 0.62)

6.25

Macfarlane (2013)

-0.24 (-0.67, 0.19)

10.43

Childs (2014)

-0.67 (-1.53, 0.19)

2.59

Childs (2014)

-0.56 (-1.41, 0.30)

2.64

Childs (2014)

-0.14 (-0.98, 0.70)

2.74

West, (2014)

0.04 (-0.41, 0.48)

9.75

West, (2014)

0.05 (-0.39, 0.48)

10.00

Hor (2018)

-0.01 (-0.61, 0.58)

5.37

Hor (2018)

0.51 (-0.15, 1.16)

4.47

Gleeson (2011)

0.23 (-0.36, 0.82)

5.52

Olivares (2006)

-0.28 (-1.00, 0.44)

3.71

Zhang (2018)

-0.32 (-0.66, 0.02)

16.54

Overall (I-squared = 0.0%, p = 0.567)

-0.07 (-0.21, 0.06)

100.00

-1.53

0

1.53

Fig. 12. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on IL-4 levels in healthy subjects (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

significant, whereas it was significant for BMI (Coef ¼ 0.1, p ¼ 0.02, I2_residual ¼ 0.0%, Adjusted R2 ¼ 83.54%). 3.7. IL-12 Nineteen studies examined the effect of probiotic on IL-12 (healthy (7), MS (1), IBS (1), atopic dermatitis (2), RA (4), trauma (1), cancer (1), aphthous stomatitis (1) and celiac disease (1)). 3.7.1. Healthy From seven clinical trials in healthy subjects (567 participants), five studies had two arms, one had three arms and one had four arms. In the pooled analysis of studies, no significant effect of probiotic on IL-12 (SMD ¼ 0.01 pg/ml, 95% CI -0.33 to 0.30, p ¼ 0.94) was observed with a heterogeneity of 68.3% (p ¼ 0.001) (Fig. 14, Table 5). Meta-regression for BMI, duration and age was not significant. Meta-regression for age after adjusting for BMI (Coef ¼ 0.03, p ¼ 0.04, I2_residual ¼ 32.87%, Adjusted R2 ¼ 77.60%) was significant. 3.7.2. Arthritis In the pooled analysis of four studies in patients with arthritis (142 participants), the decrease in serum IL-12 was not significant (SMD ¼ 0.55, 95% CI -1.56 to 0.46, p ¼ 0.29, heterogeneity of 86.3% (p ¼ 0.02). 3.8. TGF-b Eight studies measured TGF-b or TGF-b1 (healthy (6), atopic dermatitis (2)). From six clinical trials in healthy subjects (four

measured TGF-b1 and two measured TGF-b) (411 participants), four studies had two arms and two had three arms. In the pooled analysis of studies, no significant effect of probiotic on TGF-b (SMD ¼ 0.13 pg/ml, 95% CI -0.18 to 0.21, p ¼ 0.9) was observed with a heterogeneity of 0.00% (p ¼ 0.65) (Fig. 15, Table 5). 3.9. IL-6 Sixty-nine clinical trials measured IL-6 (healthy (22), diabetes (7), fatty liver (3), PCOS (1), MS (4), CVD (1), liver cirrhosis (5), arthritis (4), surgery (6), IBD (4), celiac disease (1), CRF (4), HIV (3), atopic dermatitis (1), allergy (1) and burn injury (1). 3.9.1. Healthy From 22 clinical trials in healthy subjects (1404 participants), sixteen studies had two arms, two had three arms, three had four arms and one had five arms. In the pooled analysis of studies, no significant effect of probiotic on IL-6 (SMD ¼ 0.04 pg/ml, 95% CI -0.17 to 0.10, p ¼ 0.59) was observed with a heterogeneity of 55.5% (p¼<0.001) (Fig. 16, Table 5). A subgroup analysis for the sample revealed no significant change in serum IL-6 (nine studies) (SMD ¼ 0.05, p ¼ 0.42), PBMC (four studies) (SMD ¼ 0.138, p ¼ 0.18) and secreted IL-6 from mitogen stimulated PBMC (seven studies) (SMD ¼ 0.08, p ¼ 0.52) (Sup Fig. 13). Subgroup analysis by age revealed a significant decrease of IL-6 in subjects <49 year (SMD ¼ 0.21, p ¼ 0.005) while for age 49, no change was observed (SMD ¼ 0.07, p ¼ 0.33). The decrease induced in serum IL-6 by synbiotic was greater than probiotic (Sup Table 4). Results of subgroup-analysis by the strains of bacteria (in healthy individuals and patients with metabolic disorders) are presented in Table 6 and Sup Fig. 14.

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

21

%

Study ID

SMD (95% CI)

Weight

Costabile (2017)

-0.04 (-0.50, 0.41)

7.53

Costabile (2017)

-0.29 (-0.75, 0.17)

7.45

Costabile (2017)

0.15 (-0.31, 0.60)

7.51

Costabile (2017)

-0.11 (-0.57, 0.34)

7.52

Dong (2013)

-0.29 (-0.80, 0.22)

6.04

Gleeson (2011)

-0.36 (-0.96, 0.23)

4.45

Kekkonen (2008)

0.15 (-0.54, 0.83)

3.35

Kekkonen (2008)

0.45 (-0.30, 1.19)

2.84

Kekkonen (2008)

0.19 (-0.50, 0.89)

3.24

Macfarlane (2013)

-0.37 (-0.80, 0.06)

8.40

Macfarlane (2013)

-0.52 (-0.95, -0.08)

8.26

Mangalat (2012)

-0.44 (-1.19, 0.31)

2.78

MoroGarcia (2013)

0.37 (-0.21, 0.95)

4.65

Wassenberg (2011)

-0.22 (-0.72, 0.29)

6.07

West (2014)

0.22 (-0.22, 0.66)

8.08

West (2014)

0.38 (-0.06, 0.83)

7.79

Wilms (2016)

0.17 (-0.71, 1.05)

2.03

Wilms (2016)

0.17 (-0.70, 1.05)

2.03

Overall (I-squared = 22.1%, p = 0.191)

-0.06 (-0.18, 0.07)

100.00

-1.19

0

1.19

Fig. 13. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration IL-8 in healthy subjects. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

Study

%

ID

SMD (95% CI)

Dong

-0.11 (-0.61, 0.40) 11.02

Cox

0.22 (-0.40, 0.84) 9.62

Mangalat

-0.38 (-1.13, 0.36) 8.22

West,

0.28 (-0.17, 0.73) 11.78

West,

0.19 (-0.25, 0.63) 11.86

Kekkonen

-0.33 (-1.06, 0.41) 8.34

Kekkonen

-0.34 (-1.04, 0.36) 8.75

Kekkonen

-0.61 (-1.31, 0.09) 8.74

Lee

0.78 (0.45, 1.12) 13.20

Olivares

-0.47 (-1.20, 0.25) 8.45

Overall (I-squared = 68.3%, p = 0.001)

-0.01 (-0.33, 0.30) 100.00

Weight

NOTE: Weights are from random effects analysis -1.31

0

1.31

Fig. 14. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration IL-12 in healthy subjects (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

3.9.2. Metabolic disorders From 16 clinical trials in subjects with metabolic disorders (diabetes (7) fatty liver (3), PCOS (1), MS (4), CVD (1)), 707 participants were included.

In the pooled analysis of studies, no significant effect of probiotic on serum IL-6 (SMD ¼ 0.025, 95% CI -0.25 to 0.20, p ¼ 0.83) was observed with a heterogeneity of 54.1% (p ¼ 0.005) (Fig. 17, Table 5). A subgroup analysis for the disease, revealed no significant change

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

22

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

%

Study

Weight

ID

SMD (95% CI)

Sashihara (2013)

-0.18 (-0.91, 0.55) 7.07

Zarrati (2013)

0.24 (-0.32, 0.80)

West, (2014)

-0.09 (-0.53, 0.36) 19.09

West, (2014)

-0.25 (-0.69, 0.19) 19.44

Marinkovic D (2016)

-0.10 (-0.73, 0.53) 9.54

Ouwehand (2008)

-0.06 (-0.70, 0.59) 9.06

Ouwehand (2008)

0.21 (-0.45, 0.86)

8.77

Gueniche (2014)

0.39 (-0.11, 0.89)

14.88

Overall (I-squared = 0.0%, p = 0.646)

0.01 (-0.18, 0.21)

100.00

-.912

0

12.16

.912

Fig. 15. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration TGF-B in healthy subjects (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

Study ID

SMD (95% CI)

% Weight

Wilms (2016) Brahe (2015) Burton (2017) Childs (2014) Childs (2014) Childs (2014) Costabile et al. (2017) Costabile et al. (2017) Costabile et al. (2017) Costabile et al. (2017) Dong (2013) Gleeson (2011) Gomes (2017) Kekkonen (2008) Kekkonen (2008) Kekkonen (2008) Lamprecht (2012) Macfarlane (2013) Mangalat (2012) Meyer (2007) Naruszewicz (2002) Neto (2013) Nyangale (2014) Osterberg (2015) Rajkumar (2015) Rajkumar (2015) Stenman (2016) Stenman (2016) Stenman (2016) Valentini (2015) West (2014) West (2014) Wilms (2016) Overall (I-squared = 52.2%, p = 0.000)

-0.46 (-1.35, 0.43) 0.50 (-0.19, 1.18) 0.07 (-0.36, 0.51) 0.09 (-0.74, 0.93) 0.29 (-0.55, 1.13) 1.13 (0.23, 2.04) 0.25 (-0.21, 0.71) 0.30 (-0.16, 0.76) 0.22 (-0.23, 0.68) 0.18 (-0.28, 0.63) -0.26 (-0.77, 0.25) -0.02 (-0.61, 0.57) 0.34 (-0.26, 0.94) -0.29 (-0.98, 0.40) -0.06 (-0.76, 0.63) -0.35 (-1.09, 0.39) -0.28 (-1.10, 0.54) -0.36 (-0.79, 0.07) -0.36 (-1.10, 0.39) -0.13 (-0.82, 0.55) -1.99 (-2.80, -1.19) -0.10 (-1.05, 0.85) -0.49 (-1.16, 0.17) -0.24 (-1.13, 0.64) -1.30 (-2.09, -0.50) -0.71 (-1.45, 0.03) -0.26 (-0.72, 0.21) -0.24 (-0.70, 0.22) 0.30 (-0.21, 0.81) 0.07 (-0.43, 0.57) 0.29 (-0.15, 0.73) 0.05 (-0.39, 0.50) -0.46 (-1.35, 0.43) -0.09 (-0.24, 0.06)

2.00 2.76 4.10 2.17 2.15 1.95 3.98 3.98 3.98 3.99 3.67 3.23 3.16 2.75 2.72 2.53 2.22 4.15 2.49 2.77 2.27 1.82 2.86 2.01 2.32 2.53 3.94 3.96 3.65 3.74 4.09 4.07 2.00 100.00

NOTE: Weights are from random effects analysis -2.8

0

2.8

Fig. 16. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration IL-6 in healthy subjects (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

23

Study

%

ID

SMD (95% CI)

Weight

Mazloom (2013)

0.23 (-0.45, 0.90)

5.74

Mohamadshahi, (2014)

-0.31 (-0.92, 0.30)

6.36

Kobyliak (2018)

0.21 (-0.34, 0.76)

6.98

Abbaszadeh (2016)

-0.54 (-1.16, 0.08)

6.29

Rabiei, (2018)

-0.48 (-1.10, 0.15)

6.17

Xavier-Santos, (2018)

0.47 (-0.13, 1.06)

6.52

Ghanei (2018)

-1.00 (-1.54, -0.46)

7.09

Sherf-Dagan (2018)

0.20 (-0.24, 0.64)

8.19

Sato (2017)

0.05 (-0.42, 0.53)

7.77

Karlsson (2010)

0.12 (-0.87, 1.10)

3.61

Kooshki (2015)

-0.19 (-0.78, 0.40)

6.52

Kobyliak (2018)

0.61 (0.08, 1.14)

7.20

Aller (2011)

0.42 (-0.33, 1.17)

5.13

Barreto (2013)

0.01 (-0.79, 0.81)

4.75

Tonucci (2015)

0.25 (-0.34, 0.84)

6.58

Tripolt (2013)

-0.47 (-1.23, 0.28)

5.10

Overall (I-squared = 54.1%, p = 0.005)

-0.02 (-0.25, 0.20)

100.00

NOTE: Weights are from random effects analysis -1.54

0

1.54

Fig. 17. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration IL-6 in patients with metabolic disorders (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

in diabetes and fatty liver but a significant decrease in PCOS þ MS (SMD ¼ 0.31, p ¼ 0.03, heterogeneity (66%, p ¼ 0.01)) (Sup Fig. 15, Table 5). 3.9.3. Liver cirrhosis In the pooled analysis of five studies in liver cirrhosis patients (167 participants), a significant increase in serum IL-6 (SMD ¼ 0.36, 95% CI 0.05 to 0.68, p ¼ 0.02) was observed with a heterogeneity of 41.8% (p ¼ 0.14); however, no change was observed when analysis was performed for the final value (SMD ¼ 0.15, 95% CI -0.46 to 0.17, p ¼ 0.36). 3.9.4. IBD In the pooled analysis of four studies in IBD patients and one study in celiac patients (487 participants), no change in IL-6 (SMD ¼ 0.36, 95% CI -1.35 to 1.57, p ¼ 0.88) was observed with a heterogeneity of 97.7% (p¼<0.001). 3.9.5. CRF In the pooled analysis of four studies in CRF patients (167 participants), no significant change in serum IL-6 (SMD ¼ 0.35, 95% CI -1.35 to 1.57, p ¼ 0.88) was observed with a heterogeneity of 0.0% (p ¼ 0.94). 3.9.6. Surgery In the pooled analysis of five studies in patients who underwent surgery (319 participants), probiotic led to a significant change in serum IL-6 compared to the control (SMD ¼ 0.9, 95% CI -1.62 to 0.18, p ¼ 0.01) with a heterogeneity of 85.8% (p ¼ <0.001).

3.9.7. Arthritis In the pooled analysis of four studies in patients with arthritis (142 participants), no significant effect of probiotic on IL-6 reduction (SMD ¼ 0.32, 95% CI -0.71 to 0.07, p ¼ 0.11) was observed with a heterogeneity of 21.3% (p ¼ 0.28). 3.9.8. HIV In the pooled analysis of four studies in HIV infected subjects (94 participants), no significant change in serum IL-6 (SMD ¼ 0.28, 95% CI -0.67 to 0.11, p ¼ 0.16) was observed with a heterogeneity of 0.0% (p ¼ 0.59). 3.10. TNF-a Eighty-three clinical trials examined the effect of probiotic on TNF-a (healthy (35), diabetes (7), fatty liver (7), PCOS (1), MS (3), arthritis (4), CVD (1), IBD (5), celiac disease (1), liver cirrhosis (4), alcoholic hepatitis (1), CRF (2), HIV (2), atopic dermatitis (2), allergy (2), IBS (1), pancreatitis (1), aphthous stomatitis (1), cancer (1), patients with diarrhoea secondary to chemotherapy (1), gastric bypass (2). 3.10.1. Healthy Thirty-five studies measured TNF-a in healthy. After excluding 3 studies (2 reported geometric mean [33] and least square mean [40], one duration was 1 day [41]), 32 clinical trials with 2165 participants were included. Twenty-seven studies had two arms, four had three arms and three had four arms. Twenty-three studies measured TNF-a in serum, 3 in PBMC and 9 measured TNF-a secretion from mitogen stimulated PBMC.

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

24

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

Study ID

SMD (95% CI)

% Weight

Gleeson (2011) Nyangale (2014) Zarrati (2013) Zarrati (2014) Dong (2013) Mangalat (2012) Marcos (2004) Meyer (2007) Singh (2013) Brahe (2015) Burton (2017) De Roos, (2017) Gomes (2017) Jafarnejad, (2017) Kekkonen (2008) Kekkonen (2008) Kekkonen (2008) Lamprecht (2012) Lee (2017) Macfarlane (2013) Marcial (2017) Neto (2013) Nilsson (2018) Olivares (2006) Osterberg (2015) Ouwehand (2008) Ouwehand (2008) Rajkumar (2015) Rajkumar (2015) Seifert (2011) Wilms (2016) west (2014) west (2014) kazemi (2019) Overall (I-squared = 75.4%, p = 0.000)

-0.12 (-0.71, 0.47) -0.60 (-1.27, 0.07) -1.25 (-1.86, -0.64) -0.55 (-1.12, 0.01) 0.46 (-0.05, 0.97) 0.29 (-0.45, 1.04) 0.03 (-0.32, 0.38) -1.41 (-2.18, -0.64) -0.74 (-1.65, 0.17) 0.11 (-0.56, 0.79) 0.02 (-0.42, 0.46) 0.31 (-0.19, 0.81) 1.29 (0.63, 1.96) -0.77 (-1.40, -0.13) -0.10 (-0.79, 0.58) 0.35 (-0.35, 1.05) -0.04 (-0.77, 0.69) -1.34 (-2.26, -0.43) -0.10 (-0.42, 0.22) -0.83 (-1.28, -0.39) -0.06 (-0.67, 0.56) -0.22 (-1.17, 0.74) 0.08 (-0.33, 0.49) -0.05 (-0.77, 0.66) 0.24 (-0.64, 1.13) -0.71 (-1.38, -0.05) -0.79 (-1.47, -0.11) -3.47 (-4.62, -2.31) -1.73 (-2.58, -0.89) 0.00 (-0.48, 0.48) 0.16 (-0.72, 1.04) -0.03 (-0.47, 0.41) -0.13 (-0.57, 0.31) -0.22 (-0.78, 0.35) -0.29 (-0.49, -0.08)

3.10 2.88 3.04 3.16 3.30 2.68 3.71 2.63 2.29 2.87 3.50 3.34 2.90 2.97 2.84 2.80 2.72 2.28 3.78 3.47 3.03 2.18 3.56 2.76 2.34 2.89 2.85 1.79 2.43 3.40 2.36 3.48 3.49 3.16 100.00

NOTE: Weights are from random effects analysis -4.62

0

4.62

Fig. 18. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on TNF-a in healthy subjects. (The studies with more than two arms (different strains of probiotic was investigated in each arm), were considered as more than one studies.).

In the pooled analysis of studies, a significant decrease in TNF-a (SMD ¼ 0.30 pg/ml, 95% CI -0.49 to 0.08, p ¼ 0.006) was observed with a heterogeneity of 75.4% (p ¼ <0.001) (Fig. 18, Table 5). A subgroup analysis by the sample revealed a significant change in TNF-a measured in PBMC (SMD ¼ 0.62, p¼<0.001) and serum (SMD ¼ 0.16, p ¼ 0.006) while no change was observed in secreted TNF-a from mitogen stimulated PBMC (SMD ¼ 0.04, p ¼ 0.73) (Sup Fig. 16). Meta-regression for duration of studies, age and BMI was not significant. Results of subgroup-analysis by the strains of bacteria (in healthy individuals and patients with metabolic disorders) are presented in Table 6 and Sup Fig. 17). None of the subgroups indicated a significant change in TNF-a except one sub-group indicated a significant increase (multiple strains supplement containing L. (casei, rhamnosus, acidophilus, bulgaricus) þB (breve, longum)þ S. thermophilus þ FOS).

3.10.3. IBD From six clinical trials in subjects with IBD (5) and celiac (1), 450 participants were included. In the pooled analysis of studies, a significant effect of probiotic on TNF-a (SMD ¼ 0.87, 95% CI -1.23 to 0.50, p¼<0.001) was observed with a heterogeneity of 67.5% (p ¼ 0.003) (Fig. 20, Table 5).

3.10.2. Metabolic disorders From 19 clinical trials in subjects with metabolic disorders (diabetes (7) fatty liver (7), PCOS (1), MS (3), CVD (1)), 878 participants were included.

3.10.4. Liver cirrhosis In the pooled analysis of four studies in subjects with cirrhosis and one study in alcoholic hepatitis (247 participants), a significant decrease in TNF-a (SMD ¼ 0.42, 95% CI -0.67 to 0.16, p ¼ 0.001) was observed with a heterogeneity of 0.0% (p ¼ 0.90).

In the pooled analysis of studies, no significant effect of probiotic on serum TNF-a (SMD ¼ 0.29, 95% CI -0.65 to 0.06, p ¼ 0.1) was observed with a heterogeneity of 84.8% (p¼<0.001) (Fig. 19, Table 5). A subgroup analysis by disease, revealed a significant decrease of TNF-a in fatty liver (SMD ¼ 0.75, p¼<0.001) while no change was observed in diabetes (SMD ¼ 0.02, p ¼ 0.86) and PCOS þ MS (SMD ¼ 0.26, p ¼ 0.10) was observed (Sup Fig. 18, Table 5).

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

25

%

Study ID

SMD (95% CI)

Weight

Ahmadian, (2017)

0.49 (-0.03, 1.01)

5.33

Mohamadshahi, (2014)

-1.13 (-1.79, -0.48)

4.99

Hove (2015)

-0.37 (-0.99, 0.26)

5.07

Abbaszadeh (2016)

-1.33 (-2.00, -0.66)

4.95

Xavier-Santos, (2018)

0.70 (0.10, 1.31)

5.12

Eslamparast (2014)

-0.78 (-1.35, -0.22)

5.22

Ghanei (2018)

0.00 (-0.51, 0.51)

5.36

Sherf-Dagan (2018)

-0.36 (-0.80, 0.09)

5.51

Sato (2017)

0.00 (-0.48, 0.48)

5.43

Mofidi (2017)

-0.34 (-0.89, 0.22)

5.23

Karlsson (2010)

0.22 (-0.77, 1.21)

4.08

Kooshki (2015)

-0.45 (-1.04, 0.15)

5.13

Ekhlasi (2017)

-2.37 (-3.31, -1.42)

4.20

Ekhlasi (2017)

-0.28 (-1.00, 0.43)

4.82

Kobyliak (2018)

1.20 (0.64, 1.76)

5.23

Aller (2011)

0.44 (-0.31, 1.19)

4.73

Barreto (2013)

0.85 (0.01, 1.69)

4.49

Malaguarnera (2012)

-1.81 (-2.38, -1.23)

5.19

Tonucci (2015)

-0.42 (-1.01, 0.17)

5.15

Tripolt (2013)

-0.33 (-1.08, 0.42)

4.74

Overall (I-squared = 84.8%, p = 0.000)

-0.29 (-0.65, 0.06)

100.00

NOTE: Weights are from random effects analysis -3.31

0

3.31

Fig. 19. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on TNF-a in patients with metabolic disorders. Study

%

ID

SMD (95% CI)

Weight

Smecuol (2013)

-1.07 (-2.10, -0.03)

7.64

Shadnoush (2013)

-1.54 (-1.88, -1.20)

17.00

Zhou (2017)

-0.51 (-1.00, -0.02)

14.58

Federico (2009)

0.02 (-0.91, 0.94)

8.76

Groeger (2016)

-1.02 (-1.62, -0.41)

12.88

Groeger (2016)

-0.62 (-1.14, -0.10)

14.25

Groeger (2016)

-0.71 (-1.32, -0.10)

12.79

Liu (2014)

-1.17 (-1.83, -0.51)

12.11

Overall (I-squared = 67.5%, p = 0.003)

-0.87 (-1.23, -0.50)

100.00

NOTE: Weights are from random effects analysis -2.1

0

2.1

Fig. 20. Forest plot displaying standard mean difference and 95% confidence intervals for the impact of probiotic administration on TNF-a in patients with inflammatory bowel disease (IBD).

3.10.5. Arthritis From four clinical trials in patients with arthritis, 142 participants were included (Table 5). In the pooled analysis of studies, no significant effect of probiotic on TNF-a reduction (SMD ¼ 0.23, 95% CI -1.18 to 0.71, p ¼ 0.63) was observed with a heterogeneity of 85.0% (p ¼ <0.001).

4. Discussion Probiotics and synbiotics are used to treat chronic diseases, principally due to their role in immune system modulation and the anti-inflammatory response [20]. Our study was designed to provide a strong combination of evidence that demonstrates the direct

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

26

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

and biological effects of probiotics on inflammatory markers in health and disease condition. Our study indicated that probiotic/synbiotic supplementation decreased serum levels of CRP in healthy subjects, patients with metabolic disorders, IBD, arthritis and critically ill patients but it made no change in CRF patients. The intervention was most effective in IBD with the effect size of 1.2 that is considered as a large effect. In arthritis and critically ill patients, a moderate effect was observed. The effect in patients with metabolic disorders and healthy individuals was small. This result may suggest that the more inflammation involved in the pathogenesis of the disease, the more effective was the probiotic/synbiotic supplementation. The decrease in CRP in most of the disease conditions may be due to the larger amount of serum CRP compared to the cytokines, which could better reflect the change in systemic inflammation. The main proinflammatory cytokine inducers of CRP in hepatic cells are the IL-1 and IL-6, and recently found IL-17 [42]. The significant reduction in CRP despite no change in IL-6 may be induced by IL-1 and IL17. Probiotic/symbiotic supplementation in healthy subjects had no significant effect on IL-1B level in total; however, it decreased IL-1B measured in PBMC. It may be due to the larger amount of IL-1B in PBMC than serum. Also in arthritis, no significant change was observed. Probiotic/synbiotic decreased TNF-a in healthy subjects and patients with, NAFLD, IBD and hepatic cirrhosis. The most reduction was seen in IBD with the effect size of 0.87 which is considered as a large effect, and after that, cirrhosis and healthy status. It was not changed in diabetes, MS þ PCOS and arthritis. Probiotic/synbiotic supplementation was not effective in reducing IL-6 in healthy subjects (no matter how it was measured in serum, PBMC or secreted from PBMC), metabolic disorders and arthritis, whereas it led to an increase in cirrhosis and CRF and a decrease in PCOS þ MS and in patients who underwent surgery. IL-10 was not change in healthy subjects overall; however, analysis according to the method of measurement indicated an increase in PBMC level of IL-10, a decrease in serum level and no change in its secretion from mitogen activated PBMC. In IBD and metabolic disorders, no change was observed whereas in arthritis, a moderate increase was demonstrated. Probiotic/synbiotic didn't make a significant change in IL-4, IL-8, IL-12 and TGF-b in healthy subjects, no matter how these factors were measured in PBMC, serum or secreted from stimulated PBMC. IFN-g did not change significantly overall; however, probiotic intake led to an increase in serum IFN-g and while no change in PBMC levels of IFN-g and IFN-g secreted from stimulated PBMC was observed. The roles of probiotics/synbiotics in inflammation have been a popular area of study. Several meta-analyses have been conducted in this regard. They have been mostly conducted in a particular disease state. A meta-analysis which investigated the effect of probiotic on CRP and TNF-a in patients at risk for CVD included only two studies for these outcomes [43]. The results of this study indicated a decrease in CRP but not TNF-a. Three meta-analyses investigated the effect of probiotic on inflammation in type 2 diabetes. Each meta-analyses included four studies. Two studies indicated a decrease in CRP [8,26], while the other one could not find significant effects of probiotic on CRP and IL-6 [27]. Three meta-analyses were conducted on the effects of probiotic intervention in RA (one in adult and two in both adults and children). Results of these meta-analyses were as follows: one meta-analysis in adults and children included five studies for CRP and three or four for the other outcomes indicated a significant decrease only in IL-6 [28]. CRP, IL-1B, IL-10, IL-12 and TNF-a didn't change significantly. The second one included four studies in adults and children

for CRP and three studies for IL-1B, IL-6, IL-10 and TNF-a. The results of this study demonstrated a significant decrease in CRP, TNFa and IL-1B and no change in IL-6 and IL-10 [29] and the third study which was conducted in adults included four studies for CRP and three for the other outcomes. It could not find a significant change in any of the inflammatory factors [13]. A meta-analysis of four clinical trials on the effect of synbiotic (but not probiotic) in NAFLD indicated a significant reduction in CRP and TNF-a. Two meta-analyses investigated the effects of probiotic and synbiotic intervention in both health and disease conditions. One of them explored the effect of prebiotic and synbiotic on IL-6, TNF and CRP while effect of probiotic was not explored in this study [44]. The other one investigated the effect of probiotic supplementation on only CRP [45] and our study used more comprehensive databases coverage with no language limitation compared to this study. There were several interesting findings from our subgroup analyses: It doesn't seems that the small effect of the probiotic on TNF-a, IL-6, IL-1b, IL-4, IL-10 and IFN-g in healthy individuals and patients with metabolic disorders, be related to pooling of data from trials receiving different probiotic strains since subgroup analysis indicated that in most of the subgroups no significant change was seen. Probiotic may be more effective in decreasing inflammation in obese and overweight than normal subjects since higher reduction of CRP was seen in subjects with BMI>25 (kg/m2) than BMI25 (kg/ m2); moreover, an inverse association between IL-8 and BMI and a direct association between IL-10 and BMI was observed. Regarding the age, the results were inconsistent. Higher reduction in IL-6 was observed in subjects with age <49 than >49. Moreover, an inverse association between IL-10 and age, and also a direct association between IL-12 and age after adjusting for BMI was seen. On the other hand, an inverse association was seen between CRP and age after adjusting for BMI. The reduction in pro-inflammatory cytokines IL-1B, IL-8, TNF-a, and the increase in anti-inflammatory cytokines IL-10 and IL-4 was higher when these cytokines were measured in PBMC than serum or secreted from stimulated PBMC. Release of inflammatory markers from stimulated PBMC indicates the effect of probiotic on modulating the immune system whenever is facing to an invading pathogen; while circulating (serum and PBMC) levels of inflammatory cytokines demonstrate the effect of probiotic on basal production of inflammatory cytokines in non-stimulated status. This finding suggests that measuring of the inflammatory markers in PBMC may be more appropriate than serum. This may be attributed to the larger amount of cytokines in PBMC than serum, which could better reflect the change in systemic inflammation. Moreover, it was found that synbiotic decreased CRP, IL-6 and IL-8 more effectively than probiotic. Sub-group analysis by the bacterial strains indicated that L. rhamnosus and two multiple strains formula were highly effective in decreasing of CRP, while L. casei increased it. Subgroup analysis by bacterial strains for IL-1b, IL-6, IL-10 and TNF-a indicated that small effect of probiotic on reduction of these markers does not seem to be related to strain variability since in most of the subgroup small insignificant effect was observed. Finally, the probiotic was most effective at the highest tertile of dose (>5  1010). Sub-group analysis by single vs. multiple strains was not significant. 4.1. Limitation and strength of the study The included studies in our meta-analysis did not analyse gut microbiome. Since the gut microbiota of humans is highly variable, this may affect the response of subjects to the probiotic. Moreover, different strains of probiotics were used. We tried to take in account this problem using subgroup analysis by the strains of probiotics.

Please cite this article as: Kazemi A et al., Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.04.004

A. Kazemi et al. / Clinical Nutrition xxx (xxxx) xxx

The strength of our study was a large number of included studies, which provided a strong combination of evidence on the effect of probiotic on inflammatory markers. 4.2. Recommendations for research It is recommended for the future clinical trials to analyse gut microbiome, use the strains that are exclusive for the intended outcome and to investigate the inflammatory markers in PBMC rather than serum. 5. Conclusion In healthy subjects we found a small significant reduction only in CRP and TNF-a, which suggest that probiotic supplementation might be useless for inflammation reduction in healthy subjects. In disease states such as arthritis a moderate reduction in CRP and TNF and a moderate increase in IL-10, in IBD a large decrease in CRP and TNF, and in NAFLD a moderate reduction in CRP and TNF was seen which suggests more beneficial effect of probiotic in theses disease state rather than healthy. More trials analysing gut microbiota are needed to determine whether our results could be generalized to all individuals or not. Financial support This study was supported by Vice Chancellor of Research, Shiraz University of Medical Sciences [grant number 97-01-106-17875]. Author contribution AK, SSM, AK and SS designed the research. AK, SS, SG and SMM assessed study eligibility and conducted quality assessments. AK, SS, SG performed data synthesis; AK, SMM, AK analysed the data; AK, SMM, AK: wrote the article; All authors read and approved the final manuscript; AK and SMM are the guarantors for the study. Conflict of interest None. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.clnu.2019.04.004. References [1] Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document: the international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506e14. [2] Rastall RA, Gibson GR, Gill HS, Guarner F, Klaenhammer TR, Pot B, et al. Modulation of the microbial ecology of the human colon by probiotics, prebiotics and synbiotics to enhance human health: an overview of enabling science and potential applications. FEMS Microbiol Ecol 2005;52:145e52. [3] Zhang Y, Li L, Guo C, Mu D, Feng B, Zuo X, et al. Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC Gastroenterol 2016;16. [4] Miller LE, Ouwehand AC, Ibarra A. Effects of probiotic-containing products on stool frequency and intestinal transit in constipated adults: systematic review and meta-analysis of randomized controlled trials. Ann Gastroenterol 2017;30:629e39. [5] Kang EJ, Kim SY, Hwang IH, Ji YJ. The effect of probiotics on prevention of common cold: a meta-analysis of randomized controlled trial studies. Korean J Family Med 2013;34:2e10. [6] Lü M, Yu S, Deng J, Yan Q, Yang C, Xia G, et al. Efficacy of probiotic supplementation therapy for Helicobacter pylori eradication: a meta-analysis of randomized controlled trials. PLoS One 2016;11.

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