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The Efficacy of Probiotics Supplementation on the Quality of Life of Patients with Gastrointestinal Disease: A Systematic Review of Clinical Studies
1Department of Nutritional Sciences, School of Nutritional Sciences and Food Technology and 3Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6719851552, Iran
2Social Determinants of Health Research Center (SDHRC), School of Health, Birjand University of Medical Sciences, Birjand 32048321, Iran
4Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd 8915173160, Iran
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Prev Nutr Food Sci 2024; 29(3): 237-255
Published September 30, 2024 https://doi.org/10.3746/pnf.2024.29.3.237
Copyright © The Korean Society of Food Science and Nutrition.
Abstract
Keywords
INTRODUCTION
Functional gastrointestinal disorders (FGIDs) are characterized by a combination of motility issues; visceral hypersensitivity; and changes in mucosal and immune function, gut microbiota, and central nervous system (CNS) processing (Drossman, 2016). Despite being poorly understood because of their complex pathophysiology, FGIDs [including irritable bowel syndrome (IBS), functional dyspepsia, and functional constipation (FC)] account for approximately 33% of all appointments at gastroenterology clinics (Shivaji and Ford, 2014). According to previous studies, more than 66% of individuals suffering from FGIDs have consulted a healthcare professional within the past year, 40% rely on medications regularly, and 33% have undergone unwarranted abdominal surgeries including hysterectomies or cholecystectomies to relieve their symptoms (Jafari et al., 2018). Aside from being costly to manage, these conditions also affect patients’ quality of life (QoL), which emphasize their fundamental importance to healthcare systems and society (Jafari et al., 2018). According to previous studies, pathogenic gut microbiota may be responsible for various chronic GI disorders, including cancer and diseases involving inflammation, metabolic, cardiovascular, autoimmune, neurologic, and psychiatric components (Kataoka, 2016; Lynch and Pedersen, 2016; Cani, 2017). The human body harbors the most abundant microorganisms in the GI tract. Therefore, intestinal microflora changes have been observed as a leading mechanism in the occurrence of some GI diseases (Aziz et al., 2013; Guinane and Cotter, 2013).
Probiotics are live microorganisms found in food and dietary supplements that, when consumed, can enhance the host’s health and provide nutritional value (Fuller and Gibson, 1998). These microorganisms mostly comprise bacteria and yeasts and naturally exist in fermented foods or some functional food products (Lin, 2003). The most well-known genera of probiotics belong to
In this regard, using some probiotic species can lead to a QoL improvement (Hungin et al., 2013). Research conducted in laboratory and live animal settings has demonstrated that probiotics can effectively diminish bloating, pain, and abdominal symptoms in individuals suffering from IBS (Kim et al., 2003; Aragon et al., 2010; Wong et al., 2015; Staudacher et al., 2017). In addition, studies on adults and children demonstrate the favorable effect of probiotic treatment on stool frequency, stool consistency, and constipation (Chmielewska and Szajewska, 2010). In another study, the administration of probiotics and synbiotics after surgery decreased the incidence of complications and enhanced the QoL and longevity of patients with colorectal cancer (Amitay et al., 2020). While many studies have investigated how probiotics can affect the QoL of individuals with GI diseases, no comprehensive systematic review has been conducted to reveal the potential complementary role of probiotics in patients with GI diseases and to identify existing scientific gaps. Therefore, based on available evidence, the present study investigated whether probiotic supplementation can improve the QoL of most GI patients by improving symptoms.
METHODS
This systematic review was designed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Furthermore, the study protocol was registered in the International Prospective Register of Systematic Reviews hosted by the Center for Reviews and Dissemination (PROSPERO) (CRD42022382414).
Search strategy
Two researchers conducted a thorough systematic search in five online databases (i.e., PubMed, Scopus, Embase, ProQuest, and Google Scholar) to identify relevant studies. The keywords were carefully selected, and pre-established criteria were used for included studies. The following Medical Subject Headings (MeSH) were applied in certain combinations: “probiotics,” “quality of life,” “probiotics and quality of life,” “probiotics and GI microbiome,” “probiotics and GI disease,” “probiotics and irritable bowel syndrome,” “probiotics and health-related outcomes,” and Medical Outcomes Study Short Form 36-Item questionnaire (SF-36).
Inclusion and exclusion criteria
Two researchers independently screened the titles and abstracts in the online database based on the inclusion and exclusion criteria. Eligible studies were required to meet the following inclusion criteria: 1) English-language articles available online (up to September 2022); 2) primary research articles and studies conducted on human individuals; and 3) all clinical trial studies on the effect of probiotics on the QoL in GI patients. Meanwhile, letters, comments, short communications, abstracts, studies on pregnant and lactating women, and
Screening and data extraction
Two investigators independently reviewed eligible full text studies. Thereafter, data extraction was conducted using standardized forms and research questions. In case of disputes, a third researcher assessed the precision and quality of the inputted data. Next, variables including general manuscript details (author, country, location, and year), subject characteristics (age, clinical setting or population), study design and intervention characteristics (study quality, study design, sample size, QoL assessment method, probiotic strain, daily dosage, and treatment duration), and QoL summary statistics necessary for systematic review were recorded in a predetermined database. Initially, 94 studies were selected in the comprehensive search. The titles and abstracts of studies were reviewed to exclude papers published in non-English journals (six studies were excluded). Afterward, review articles, study protocols, commentaries, and case reports were removed (11 studies were excluded). Next, the full text of the remaining studies was examined and reviewed. Studies that failed to describe the QoL or those that were non-randomized, non-controlled, or otherwise irrelevant were further removed (four studies were excluded). Finally, studies on the population with GI diseases were isolated, and 36 studies were eligible for the final review (Fig. 1).
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Figure 1. Flow chart of the study selection process.
Quality assessment
The Cochrane Collaboration’s tools were used to identify potential sources of bias in the selected studies. Two authors independently assessed each included study using the Revised Cochrane Risk of Bias 2 (RoB2) tool and the Risk Of Bias In Non-randomized Studies of Intervention (ROBINS-I) tool (Higgins et al., 2011). The methodological domains assessed for parallel and cross-over randomized controlled trials (RCTs) included the randomization process, deviation from intended interventions, missing outcome data, outcome measurement, and selection of reported results. Bias was evaluated as judgment for every criterion (indicated as “high risk of bias,” “low risk of bias,” or “some concerns”). Meanwhile, the methodological domains assessed for non-randomized clinical trials included bias from confounding, bias in participant selection, bias in intervention classification, bias from deviations in interventions, bias from missing data, bias in outcome measurement, and bias in the selection of reported results. Differences between these procedures were settled via agreement or seeking input from a third party, following communication with the authors of the original study for further explanation. If the trials did not provide sufficient information for assessment, we contacted the authors via email and allowed them a period of at least four weeks to reply.
RESULTS
Study selection
After applying all exclusion criteria, the final review was limited to 36 studies. Sixteen studies were related to IBS (Drisko et al., 2006; Choi et al., 2011; Dapoigny et al., 2012; Cappello et al., 2013; Abbas et al., 2014; Lorenzo-Zúñiga et al., 2014; Choi et al., 2015; Šmid et al., 2016; Giannetti et al., 2017; Nobutani et al., 2017; Pinto-Sanchez et al., 2017; Preston et al., 2018; Aroniadis et al., 2019; Catinean et al., 2019; Francavilla et al., 2019; El-Salhy et al., 2020). Eight studies were related to constipation (Ding et al., 2016; Cudmore et al., 2017; Ibarra et al., 2018; Xinias et al., 2018; Dimidi et al., 2019; Kommers et al., 2019; Riezzo et al., 2019; Olgac et al., 2020). Five studies were related to rectal cancer (Ohigashi et al., 2011; Lee et al., 2014; Theodoropoulos et al., 2016; Golkhalkhali et al., 2018; Radvar et al., 2020). One study was related to cirrhosis (Macnaughtan et al., 2020). One study was related to non-celiac gluten sensitivity disease (Di Pierro et al., 2020). One study was related to infant colic (Ahmadipour et al., 2020). One study was related to gastric bypass surgery (Chen et al., 2016). Two studies were related to FGIDs (Ringel-Kulka et al., 2011; Gomi et al., 2018). One study was related to ulcerative colitis (Fujimori et al., 2009). The details of each study are summarized in Tables 1-5.
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Table 1 . IBS-related disease: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes El-Salhy et al., 2020 (Norway) RCT IBS 165 39.9±9.0 30 g FMT or 60 g FMT at a ratio of 1:1:1 The material for FMT FMT 3 months IBS-QoL Positive effect Catinean et al., 2019 (Romania) RCT IBS 90 18-75
G1=38.77±10.96
G2=39.07±16.00
G3=40.37±11.95G2=7 days: 1 cap
27 days: 2 capG1= Bifidobacterium longum W11
G2=fiveBacillus spp.34 days
G1 and G3=10+24
G2=34IBS-QoL (SF-36) Positive effect Preston et al., 2018 (USA) RCT IBS 86 Plac: 39.9
Int: 40.62 capsules
50×109 CFULactobacillus acidophilus CL1285,L. casei LBC80R, andL. rhamnosus CLR212 weeks IBS-QoL Positive effect Giannetti et al., 2017 (Italy) RCT Children with IBS and functional dyspepsia 73 8.0-17.9 3 billion (3×109) of Bifidobacterium longum BB536, 1 billion (1×109) ofB. infantis M-63, 1 billion (1×109) of B. breve M-16V3 Bifidobacteria :M-63breve M-16Vlongum BB53616 weeks:
2-week run-in phase
6 weeks Int
2-week “washout”
Afterward, each patient was switched to the other group
6 weeks IntFDI Positive effect Pinto-Sanchez et al., 2017 (Canada) RCT IBS 44 Int: 46.5 (30-58)
Plac: 40.0 (26-57)1.0E+10 Bifidobacterium longum NCC3001 (BL)6-week treatment
10 week follow-upSF-36 Positive effect Nobutani et al., 2017 (Japan) RCT IBS 30 Int: 52.6±20.1
Plac: 45.9±19.513×108 CFU Lactobacillus gasseri CP23054 weeks IBS-QoL and PSQI-J Positive effect Choi et al., 2015 (Korea) RCT Non-diarrheal-type IBS 285 20-73 (47) Group 1: 1.0×1010
CFU
Groups 2 and 3: 1.5×1010
Group 4: 3×1010Bacillus subtilis andStreptococcus faecium 4 weeks IBS-QoL Positive effect Abbas et al., 2014 (Pakistan) RCT IBS-D 72
64
(completed)18-60
Int:
37.7±11.6
Plac:
33.0±12.0750 mg/d Saccharomyces boulardii 2-week run-in
6 weeks IntIBS-QoL Positive effect Lorenzo-Zúñiga et al., 2014 (Spain) RCT IBS 73 20-70
Int: 47.5±13.1
46.3±11.6
Plac: 46.5±13.11-3×1010 CFU or 3-6×109 Two Lactobacillus plantarum (CECT7484 and CECT7485) and onePediococcus acidilactici (CECT7483)6 weeks IBS-QoL Positive effect Cappello et al., 2013 (Italy) RCT IBS 64 38.7±12.6 5×109 Lactobacillus plantarum , 2×109L. casei subp.rhamnosus and 2×109L. gasseri , 1×109Bifidobacterium infantis and 1×109B. longum , 1×109L. acidophilus , 1×109L. salivarius and 1×109L. sporogenes and 5×109Streptococcus thermophilus
Prebiotic inulin 2.2 gLyophilized bacteria: L. plantarumL. casei subp.rhamnosusL. gasseriBifidobacterium infantisL. acidophilusL. salivariusL. sporogenesStreptococcus thermophilus
Prebiotic inulin6 weeks
(2-week run-in and 4-week treatment)SF-36 Positive effect Choi et al., 2011 (Korea) RCT IBS 67 41±13 2×1011 Saccharomyces boulardii 4 weeks IBS-QoL Positive effect Drisko et al., 2006 (USA) Open-label pilot study
Prospective outcome studyIBS 20 24-81 10 billion CFU Lactobacillus acidophilus ,Bifidobacterium bifidum ,L. rhamnosus ,L. plantarum ,B. infantis ,L. salivarius ,L. bulgaricus ,L. casei ,L. brevis , andStreptococcus thermophilus 1 year IBS-QoL Positive effect RCT, randomized control trial; IBS, irritable bowel syndrome; FMT, fecal microbiota transplantation; QoL, quality of life; IBS-QoL, irritable bowel syndrome QoL; IBS-D, diarrhea-dominant irritable bowel syndrome; SF-36, 36-item short form survey; CFU, colony forming unit; FDI, Functional Disability Inventory; Int, intervention; Plac, placebo; PSQI-J, Pittsburgh Sleep Quality Index.
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Table 2 . Constipation-related disease: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age Daily dose Probiotic species Duration of intervention System Main outcomes Olgac et al., 2020 (Turkey) RCT Children with FC 49 4-16 years 1×108 CFU Lactobacillus reuteri DSM 17938 or lactulose4 weeks KINDLⓇ HRQOL Positive effect Kommers et al., 2019 (Brazil) RCT Female university students with intestinal constipation 63 20-40 years
Int: 27.15±5.52
Plac: 24.38±5.41109 CFU of each one Bifidobacterium lactis (BL04),B. bifidum (Bb-06),Lactobacillus acidophilus (La-14),L. casei (Lc-11),Lactococcus lactis (LL-23)45 days PAC-QoL Positive effect Xinias et al., 2018 (Greece) Non-randomized clinical trial Infants with FC 65 3-13 weeks
Int: 1.4±0.8
Plac: 1.7±0.9Not reported Bifidobacterium lactis BB121 month Not reported (parents completed a QoL) Positive effect Cudmore et al., 2017 (Ireland) RCT Chronic, FC 69 18-80 years 6×108 CFU twice daily Lactobacillus rhamnosus PXN 54 (NCIMB 30188),Bifidobacterium bifidum PXN 23 (NCIMB 30179),L. acidophilus PXN 35 (NCIMB 30184),L. plantarum PXN 47 (NCIMB 30187), andL. bulgaricus PXN 39 (NCIMB 30186)
Also psyllium and inulin4 weeks PAC-QoL Positive effect RCT, randomized control trial; FC, functional constipation; CFU, colony forming unit; QoL, quality of life; KINDLⓇ HRQOL, KINDLⓇ Health-Related QoL; PAC-QoL, Patient Assessment of Constipation QoL.
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Table 3 . Functional gastrointestinal disorders (FGIDs): characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention (weeks) System Main outcomes Ringel-Kulka et al., 2011 (USA) RCT Functional bowel disorders 60 18-65 Mean age Int: 36 Plac: 37 Twice a day (2×1011 CFU CFU/d) Lactobacillus acidophilus NCFM (L-NCFM) andBifidobacterium lactis Bi-07 (B-LBi07)8 IBS-QoL Positive effect RCT, randomized control trial; CFU, colony forming unit; IBS-QoL, irritable bowel syndrome-quality of life; Int, intervention; Plac, placebo.
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Table 4 . Colorectal cancer-related disease: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Radvar et al., 2020 (Iran) RCT Rectal cancer 38 Int: 57.58±12.78 Plac: 62.89±13.93 2 times a day 1×108 CFU/g Lactobacillus casei PXN 37,L. rhamnosus PXN 54,Streptococcus thermophilus 81 PXN 66,Bifidobacterium breve PXN 25,L. acidophilus PXN 35,B. longum PXN 30,L. bulgaricus PXN 39, FOS (fructooligosaccharide), magnesium stearate (source: mineral and vegetable), and vegetable capsule (hydroxypropyl methyl cellulose)6 weeks EORTC QLQ-C30 Positive effect Golkhalkhali et al., 2018 (Malaysia) RCT Colorectal cancer 140 <18 Two sachets daily 30 billion (CFUs) per sachet Lactobacillus acidophilus BCMCR 12130,L. casei BCMCR 12313,Lactobacillus lactis BCMCR 12451,Bifidobacterium bifidum BCMCR 02290,B. longum BCMCR 02120, andB. infantis BCMCR 021298 weeks EORTC QLQ-C30 Positive effect Lee et al., 2014 (Korea) RCT Colorectal cancer 60 56.18±8.86 Twice a day 2×109 CFU Lacidofil ( Lactobacillus rhamnosus R0011 andL. acidophilus R0052)12 weeks FACT Positive effect Ohigashi et al., 2011 (Japan) Questionnaire-based study Colorectal cancer 63 63±9 10 mg of Bacillus natto and 30 mg ofLactobacillus acidophilus B. natto andL. acidophilus 3 months SF-36 and EORTC QLQ-C30 Positive effect RCT, randomized control trial; Int, intervention; Plac, placebo; CFU, colony forming unit; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30; FACT, Functional Assessment of Cancer Therapy; SF-36, 36-item short form survey.
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Table 5 . Other diseases: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Di Pierro et al., 2020 (Italy) Non-randomized clinical trial Non-celiac gluten sensitivity 30 Int: 46.87±17.06 Plac: 43.53±18.94 1 dose/day 1×109 CFU (1 billion) Bifidobacterium longum ES1 or GFD 3 months Document of scientific support to the protocol for the diagnosis and follow-up of celiac disease Positive effect Chen et al., 2016 (Taiwan) RCT Gastric bypass surgery 53 18-60 35.1±8.3 Twice daily A: 5×109 CFU (5 billion) B: 8×109 CFU (8 billion) A: 1 g Clostridium butyricum MIYAIRI B: 300 mgBifidobacterium longum BB5362 weeks mGIQL Positive effect Fujimori et al., 2009 (Japan) RCT Ulcerative colitis 83 Pro=36±16 Pre=37±13 Syn=35±10 2×109 CFU Bifidobacterium longum Also prebiotic (psyllium) and synbiotic4 weeks IBDQ Positive effect RCT, randomized control trial; Int, intervention; Plac, placebo; Pro, probiotics; Pre, prebiotics; Syn, symbiotic; CFU, colony forming unit; GFD, gluten-free diet; mGIQL, modified Gastrointestinal QoL Index; IBDQ, Inflammatory Bowel Disease Questionnaire.
Quality assessment
The risk of bias of included studies is presented in Table 6 and 7. Out of the 32 parallel and cross-over double-blind RCTs that were included, only 14 studies had low risk of bias. The rest revealed some concerns and high risk in overall risk of bias (Table 7). Furthermore, each of the four non-randomized clinical trials showed a significant potential for bias. Confounding bias was the major concern in non-randomized clinical trials (Table 8).
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Table 6 . Characteristics of included studies that did not find any effect
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Francavilla et al., 2019 (Italy) RCT Patients with celiac disease and IBS 109 Age 18 years and above
Int: 43.3 (18.8-62.2)
Plac: 44.6 (19.3-63.4)5×109 CFU/sachet+5×109 CFU/sachet+10×109 CFU/sachet+10×109 CFU/sachet+10×109 CFU/sachet Lactobacillus casei LMG 101/37 P-17504 (5×109 CFU/sachet),L. plantarum CECT 4528 (5×109 CFU/sachet),Bifidobacterium animalis subsp.lactis Bi1 LMG P-17502 (10×109 CFU/sachet),B. breve Bbr8 LMG P-17501 (10×109 CFU/sachet),B. breve Bl10 LMG P-17500 (10×109 CFU/sachet)14 weeks IBS–QoL Without effect Aroniadis et al., 2019 (USA) RCT IBS 45 18-65
Int: 33 (27-48)
Plac: 42 (28-48)25 capsules perday
0.38 g minimallyProcessed donor whole stool per capsule 12 weeks IBS–QoL Without effect Šmid et al., 2016 (Slovenia–Croatia) RCT IBS 76 18-65 (1.8×107 CFU/g) and
(2.5×107 CFU/g)Lactobacillus acidophilus La-5Ⓡ (1.8×107 CFU/g) andBifidobacterium animalis ssp.lactis BB-12Ⓡ (2.5×107 CFU/g)Streptococcus thermophilus 4 weeks IBS–QoL Without effect Dapoigny et al., 2012 (France) Randomized double-blind pilot study IBS 47 Int: 46.1±11.3
Plac: 48.0±10.86×108 CFU Lactobacillus casei varietyrhamnosus LCR354 weeks GIQLI Without effect Riezzo et al., 2019 (Italy) RCT FC 56 19-65
42.4±13.815 days: four tablets daily
Then: two tablets daily
One tablet=1×108 CFULactobacillus reuteri (LR) DSM 17938105 days PAC–QoL Without effect Dimidi et al., 2019 (UK) RCT Constipation 75 18-65
Int: 35 (12)
Plac: 31 (10)1.5×1010 CFU/day Bifidobacterium lactis NCC28184 weeks PAC–QoL Without effect Ibarra et al., 2018 (France) RCT Adults with functional constipation 224 18-70 1×109 or 1×1010 CFU Bifidobacterium animalis subsp.lactis HN01928 days PAC-QoL Without effect Ding et al., 2016 (China) RCT (prospective) Slow transit constipation 93 Plac: 48.3±11.3
Int: 47.2±10.70.63 g Bifid triple viable capsules (BIFICO) and 8 g of soluble dietary fiber 12 weeks GIQLI Positive effect Gomi et al., 2018 (Japan) RCT Patients with functional GI disorders 79 20-64
Int: 41.1±10.1
Plac: 41.6±9.9YIT 10347=3×107 CFU/mL Streptococcus thermophilus YIT 2021=1×107Bifidobacterium bifidum YIT 10347Streptococcus thermophilus YIT 2021 (in both Plac and Int groups)4 weeks SF-36 v2 Without effect Theodoropoulos et al., 2016 (Netherlands) RCT Colectomy for cancer 67 Int: 66.8±2.17
Plac: 69±1.37Sachets
12 gPediococcus pentosaceus 5-33:3,Leuconostoc mesenteroides 32-77:1,Lactobacillus paracasei ssp.paracasei 19, andL. plantarum 2362 and 2.5 g of each of the four fermentable fibers (prebiotics): b-glucan, inulin, pectin, and resistant starch15 days GIQLI and EORTC QLQ-C30 Without effect Macnaughtan et al., 2020 (UK) RCT Cirrhosis 92 (68) 18-78 6.5×109 CFU Lactobacillus casei Shirota (LcS)3 times per day for 6 months SF-36 Without effect Ahmadipour et al., 2020 (Iran) RCT Infant colic 72 21-90 days old
Int: 52.20±41.885 days
Plac: 49.36±23.321 days5 drops of Pedilact
109 CFULactobacillus rhamnosus ,L. reuteri ,Bifidobacterium infantis probiotics and fructooligosaccharide28 days Not reported Without effect RCT, randomized control trial; IBS, irritable bowel syndrome; FC, functional constipation; Int, intervention; Plac, placebo; CFU, colony forming unit; IBS-QoL, irritable bowel syndrome QoL; GIQLI, Gastrointestinal Quality of Life Index; PAC-QoL, Patient Assessment of Constipation QoL; SF-36, 36-item short form survey; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30.
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Table 7 . Assessment of risk of bias for randomized and cross-over clinical trials using the Cochrane Risk of Bias 2 tool
Reference Risk domain Bias arising from the randomization process Bias because of deviations from the intended intervention Missing outcome data Bias in outcome measurement Bias in the selection of reported results Overall risk of bias Fujimori et al., 2009 Low High High Low Some concerns High Chen et al., 2016 Some concerns Low High Low Some concerns High Ahmadipour et al., 2020 Some concerns Low Low Low Low Some concerns Macnaughtan et al., 2020 Low Low Low Low Low Low Lee et al., 2014 Low Low High Low Low High Theodoropoulos et al., 2016 Low Low Low Low Low Low Golkhalkhali et al., 2018 Low Low Low Low Low Low Radvar et al., 2020 Low Low Low Low Low Low Ringel-Kulka et al., 2011 Low Low Low Low Low Low Gomi et al., 2018 Low Low Low Low Low Low Ding et al., 2016 Low Low Some concerns Low Low Some concerns Cudmore et al., 2017 Low Low Low Low Low Low Ibarra et al., 2018 Low Low High Low Low High Dimidi et al., 2019 Low Low Low Low Low Low Kommers et al., 2019 Low Low High Low Low High Riezzo et al., 2019 Some concerns Some concerns Some concerns Low Low Some concerns Olgac et al., 2020 Some concerns High Some concerns Low Some concerns High Choi et al., 2011 Low Low High Low Low High Dapoigny et al., 2012 Low Low Some concerns Low Some concerns Some concerns Cappello et al., 2013 Low Low Some concerns Low Some concerns Some concerns Lorenzo-Zúñiga et al., 2014 Low Low Some concerns Low Some concerns Some concerns Abbas et al., 2014 Low Low Some concerns Low Some concerns Some concerns Choi et al., 2015 Low Low Low Low Low Low Šmid et al., 2016 Low Low Low Low Low Low Nobutani et al., 2017 Some concerns Some concerns Low Low Some concerns Some concerns Pinto-Sanchez et al., 2017 Low Low Low Low Low Low Giannetti et al., 2017 Low Low Low Low Low Low Preston et al., 2018 Some concerns Low Low Low Low Some concerns Aroniadis et al., 2019 Low Low High Low Low High Francavilla et al., 2019 Low Low Low Low Low Low Catinean et al., 2019 Some concerns Some concerns Low Low Some concerns Some concerns El-Salhy et al., 2020 Low Low Low Low Low Low
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Table 8 . Assessment of risk of bias for non-randomized clinical trials using the Cochrane Risk of Bias 2 tool
Reference Risk domain Bias because of confounding Bias because of the selection of participants Bias in the classification of intervention Bias because of deviations from the intended intervention Bias because of missing outcome data Bias in outcome measurement Bias in the selection of reported results Overall risk of bias Drisko et al., 2006 High Low Some concerns Low Some concerns Low Low High Xinias et al., 2018 High Low Low Low Low Low Low High Ohigashi et al., 2011 High Low Some concerns Low Some concerns Low Some concerns High Di Pierro et al., 2020 High Low Low Low Low Low Low High
Characteristics of included studies
The median age of participants across studies was 18-81 years, and the duration of probiotic supplementation ranged from 15 days to 16 weeks. In 36 studies, 2,942 patients with GI disease were supplemented with probiotics, and the QoL of individuals was assessed using a questionnaire. All studies were randomized trials that were published from 2006 to 2020. Five studies were conducted in Italy (Cappello et al., 2013; Giannetti et al., 2017; Francavilla et al., 2019; Riezzo et al., 2019; Di Pierro et al., 2020). Four studies were conducted in Japan (Fujimori et al., 2009; Ohigashi et al., 2011; Nobutani et al., 2017; Gomi et al., 2018). Four studies were conducted in the USA (Drisko et al., 2006; Ringel-Kulka et al., 2011; Preston et al., 2018; Aroniadis et al., 2019). Three studies were conducted in Korea (Choi et al., 2011; Lee et al., 2014; Choi et al., 2015). Two studies were conducted in France (Dapoigny et al., 2012; Ibarra et al., 2018). Two studies were conducted in the UK (Dimidi et al., 2019; Macnaughtan et al., 2020). Two studies were conducted in Iran (Ahmadipour et al., 2020; Radvar et al., 2020). One study was conducted in Norway (El-Salhy et al., 2020). One study was conducted in Canada (Pinto-Sanchez et al., 2017). One study was conducted in Romania (Catinean et al., 2019). One study was conducted in Pakistan (Abbas et al., 2014). One study was conducted in Spain (Lorenzo-Zúñiga et al., 2014). One study was conducted in Turkey (Olgac et al., 2020). One study was conducted in Brazil (Kommers et al., 2019). One study was conducted in Greece (Xinias et al., 2018). One study was conducted in Ireland (Cudmore et al., 2017). One study was conducted in China (Ding et al., 2016). One study was conducted in the Netherlands (Theodoropoulos et al., 2016). One study was conducted in Malaysia (Golkhalkhali et al., 2018). One study was conducted in Taiwan (Chen et al., 2016). One study was conducted in Slovenia-Croatia (Šmid et al., 2016).
Health-related quality of life (HRQOL) instruments
The HRQOL instruments used in the included studies were either generic or GI-specific measures. Five studies used SF-36. Thirteen studies used the IBS-QoL questionnaire (Drisko et al., 2006; Choi et al., 2011; Ringel-Kulka et al., 2011; Abbas et al., 2014; Lorenzo-Zúñiga et al., 2014; Choi et al., 2015; Šmid et al., 2016; Nobutani et al., 2017; Preston et al., 2018; Aroniadis et al., 2019; Catinean et al., 2019; Francavilla et al., 2019; El-Salhy et al., 2020). Three studies used the Gastrointestinal Quality of Life Index (GIQLI) (Chen et al., 2016; Ding et al., 2016; Theodoropoulos et al., 2016). Four studies used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) (Ohigashi et al., 2011; Theodoropoulos et al., 2016; Golkhalkhali et al., 2018; Radvar et al., 2020). One study used the Functional Disability Inventory (FDI) (Giannetti et al., 2017). One study used the Pittsburgh Sleep Quality Index-Japanese version (PSQI-J) (Nobutani et al., 2017). One study used the Functional Assessment of Cancer Therapy (FACT) (Lee et al., 2014). One study used the modified Gastrointestinal QoL (mGIQL). One study used the Inflammatory Bowel Disease Questionnaire (IBDQ) (Fujimori et al., 2009). One study used the KINDLⓇ Health-Related Quality of Life (KINDLⓇ HRQOL) (Olgac et al., 2020). One study used the “Document of scientific support to the protocol for the diagnosis and follow-up of celiac disease” (Di Pierro et al., 2020). Two studies did not report the method used to measure the QoL (Xinias et al., 2018; Ahmadipour et al., 2020).
Probiotics
Among the 36 studies, eight different bacterial genera were used as probiotic supplements: a)
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Table 9 . Genus and species of probiotic supplementation in the included studies
1)
Lactobacillus andBifidobacterium were the most common genera of probiotics that were used to study the effects of probiotic supplementation in clinical gastrointestinal investigations.-, not available.
Overall, the investigation of the effect of different types of probiotic supplementation on the QoL of GI patients in RCT studies showed that 23 studies reported improvement in the QoL of patients (Drisko et al., 2006; Fujimori et al., 2009; Choi et al., 2011; Ringel-Kulka et al., 2011; Ohigashi et al., 2011; Cappello et al., 2013; Abbas et al., 2014; Lee et al., 2014; Lorenzo-Zúñiga et al., 2014; Choi et al., 2015; Chen et al., 2016; Cudmore et al., 2017; Giannetti et al., 2017; Nobutani et al., 2017; Pinto-Sanchez et al., 2017; Golkhalkhali et al., 2018; Preston et al., 2018; Ringel-Kulka et al., 2011; Xinias et al., 2018; Kommers et al., 2019; Di Pierro et al., 2020; El-Salhy et al., 2020; Olgac et al., 2020; Radvar et al., 2020), whereas 12 studies reported no improvement in the QoL of patients after probiotic supplementation (Dapoigny et al., 2012; Ding et al., 2016; Šmid et al., 2016; Theodoropoulos et al., 2016; Gomi et al., 2018; Ibarra et al., 2018; Aroniadis et al., 2019; Dimidi et al., 2019; Riezzo et al., 2019; Ahmadipour et al., 2020; Francavilla et al., 2019; Macnaughtan et al., 2020) (Table 6).
Irritable bowel syndrome (IBS)
Based on evidence provided by the included studies, supplementation with the following probiotic species has been reported to be effective in IBS:
Rectal cancer
Based on evidence provided by the included studies, the following probiotic species have been demonstrated to improve overall health status and QoL and minimize certain side effects of chemotherapy in patients with cancer:
Functional gastrointestinal disorders (FGIDs)
According to several studies, probiotic supplementation with the following species had no effect on the QoL of patients with FGIDs:
Functional constipation (FC)
Based on evidence provided by the included studies, supplementation with the following probiotic species could improve FC and the QoL of patients:
-
Table 10 . Notable outcomes of selected RCT studies assessing the effects of probiotics on GI diseases
Reference Gut microbiota assessment Outcomes of GI symptoms Macnaughtan et al., 2020, UK - - Giannetti et al., 2017, Italy - In IBS, Bifidobacteria supplementation resulted in a complete resolution of abdominal pain in a significantly higher proportion of childrenCappello et al., 2013
Italy (Rome)- - Cudmore et al., 2017, Ireland - Symptoms of constipation improved Fujimori et al., 2009, Japan - Emotional function increased in the probiotic and synbiotic groups Gomi et al., 2018, Japan - The YIT10347 group had significantly higher relief rates of overall gastrointestinal symptoms, upper gastrointestinal symptoms, flatus, and diarrhea than the placebo group Francavilla et al., 2019, Italy ·Using plate counts and 16S rRNA gene-based analysis
·Fecal samples (5 g) were mixed with 45 mL of sterilized physiological solution and homogenized. Viable bacterial cells were counted as described by De Angelis et al.
·To determine the identities of bacteria, sequences were first queried using a distributed BLASTn.NET algorithm24 against 16S bacterial sequences derived from NCBI.- Radvar et al., 2020, Iran - Body weight decreased in the synbiotic and placebo groups Aroniadis et al., 2019, USA 16S rRNA sequencing - Chen et al., 2016, Taiwan - Complaints of abdominal pain, abdominal bloating, excessive passage of gas, foul smell of flatulence, belching, abdominal noises, and heartburn were significantly improved in the entire sample Dapoigny et al., 2012, France Extraction of total bacterial DNA (QIAamp Fast DNA Stool Mini Kit, QIAGEN), the presence of Lactobacillus casei varietyrhamnosus was specifically determined by qualitative polymerase chain reaction (PCR - primer pairs hyb-21) – cycles of amplification.A decrease in the abdominal pain severity score was observed with LCR35 Choi et al., 2015, Korea - The abdominal pain/discomfort score in treatment group 4 was more prominently improved compared with that of the placebo group
In patients with constipation-predominant IBS, the improvements in stool frequency and consistency were significantly higher in treatment groups 4 and 1, respectively, than those in the placebo group
There were more favorable tendencies of effects on bloating in all treatment groups than in the placebo groupEl-Salhy et al., 2020, Norway 16S rRNA gene sequencing - Ding et al., 2016, China - During the intervention period, patients who were treated with the synbiotic exhibited increased stool frequency, improved stool consistency, decreased colonic transit time, and improved constipation-related symptoms Ohigashi et al., 2011, Japan - Defecation frequency, anal pain, and Wexner score were significantly poorer in the rectal group than in the colonic group Ringel-Kulka et al., 2011, USA Quantitative real-time polymerase chain reaction of fecal samples Abdominal bloating improved in the probiotic group compared with the placebo group at 4 and 8 weeks Dimidi et al., 2019, UK Quantitative polymerase chain reaction - Šmid et al., 2016, Slovenia & Croatia - Significant improvements in bloating severity, satisfaction with bowel movements Golkhalkhali et al., 2018, Malaysia - Nausea, vomiting, and diarrhea significantly improved in the treatment group Theodoropoulos et al., 2016, Netherlands - Differences in the EORTC QLQ-C30 “diarrhea” domain score from baseline were better after synbiotic administration after 3 ( P =0.04) and 6 months (P =0.003)Nobutani et al., 2017, Japan ·Purified DNA was used as a template for the following two-step polymerase chain reaction.
·Fecal microbiota was measured using fecal bacterial 16S rDNA V4-V6 region-targeted pyrosequencing.CP2305 favorably changed the fecal characteristics compared with placebo among patients with IBS with either diarrhea or constipation subtypes Drisko et al., 2006, USA - Significant improvements in pain were observed ( P =0.05)RCT, randomized controlled trial; GI, gastrointestinal; IBS, irritable bowel syndrome; NCBI, National Center for Biotechnology Information; QoL, quality of life; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30; -, not available.
DISCUSSION
To the best of our knowledge, this study is the first systematic evaluation examining how different probiotic species affect the QoL of patients with GI disorders. According to the 10 different QoL assessment systems used in recent clinical studies (SF-36, IBS-QoL, GIQLI, EORTC QLQ-C30, FDI, PSQI-J, FACT, mGIQL, IBDQ, and KINDLⓇ HRQOL), different probiotic species (especially
Probiotic supplementation and IBS
After the idea linking the gut microbiome with human illnesses was put forward, researchers have investigated whether microbiome changes could be found in GI diseases (Pimentel and Lembo, 2020). Several studies have identified less microbial diversity or richness in individuals with IBS than in those without (Codling et al., 2010; Carroll et al., 2012; Jeffery et al., 2012; Ng et al., 2013; Giamarellos-Bourboulis et al., 2015; Maharshak et al., 2018). However, one study did not (Ponnusamy et al., 2011). The majority of trials have assessed how well probiotics work in patients with IBS, many of whom have significant cognitive impairments (Quigley, 2009). The results from a meta-analysis of 15 controlled studies discovered that probiotics decreased pain levels and symptom severity in IBS (Didari et al., 2015). However, the best strain, dose, formulation, and length of treatment remain unknown (Pimentel and Lembo, 2020).
When probiotics were utilized for treating IBS,
Probiotic supplementation and cancer
Cancer and its treatments are commonly accompanied by fatigue. Several studies have demonstrated intestinal microbiome changes in patients with cancer, chronic fatigue syndrome, and other neuropsychiatric disorders (Hajjar et al., 2021). Hajjar et al., revealed that cancer patients with varying levels of fatigue may exhibit diverse gut microbiome compositions. Because of the significance of the microbiome in mucosal immunity and the growing understanding of the link between the gut-brain axis and fatigue and other symptoms, disruption in intestinal microbiota may play a key role in these conditions. On the other hand, improving the microbiome can reduce fatigue severity in patients with cancer and improve their QoL. This research indicates the necessity for further studies on how adjusting the gut microbiome can affect fatigue and enhance QoL in individuals with cancer (Hajjar et al., 2021).
To date, the exact mechanisms behind the effect of gut microbiota on cancer remain unknown. Nevertheless, the gut microbiome could have a significant impact on cancer development through various mechanisms (Grivennikov et al., 2012). First, there are differences in the gut microbial content between individuals with cancer and those without, which may have carcinogenesis effects and contribute to cancer development. For instance, research on the human microbiome revealed notable variations in the prevalence of certain microbes in the cancer group compared with the control group (Bultman, 2014). The second mechanism is the well-known link between inflammation and intestinal microbiota and metabolism, which are cancer characteristics (Tlaskalova-Hogenova et al., 2014). In the metabolic pathway, plant-derived foods are metabolized by intestinal microbiota to biologically active compounds that may be carcinogenic (Tlaskalova-Hogenova et al., 2014). Some studies suggested that the perioperative administration of probiotics/synbiotics reduces the prevalence of side effects and improves the QoL and survival of patients with colorectal cancer (Amitay et al., 2020).
Probiotic supplementation and FC
The prevalence of FC is high in the elderly and is associated with poor QoL. According to previous studies, the most common symptoms of FC that significantly affect the health-related QoL of adults include stool stiffness, squeezing, and feeling of anal obstruction (Norton, 2006; Arco et al., 2022), wherein patients with FC scored lower in all dimensions of the EQ5D3L than those without. European Quality of Life 5 Dimensions 3 Level Version (EQ5D3L) is recognized as an effective and useful assessment tool for comparing QoL in different conditions. However, some researchers also recommend the use of FC-specific QoL measurements, such as assessing a patient’s QoL in constipation (Marquis et al., 2005). Moreover, FC has been reported to be associated with serious mental illness (Merkel et al., 1993; Towers et al., 1994). One study showed that patients with FC are more likely to experience depression and anxiety, according to the corresponding EQ5D3L subscale. Thus, primary care teams and specialists should take into account the impact of FC on the QoL of the elderly, considering the wide range of factors to enhance the overall health of this group (Arco et al., 2022). Additionally, evidence indicated that probiotic therapy has a positive impact on defecation frequency, stool consistency, and constipation condition in adults and children (Chmielewska and Szajewska, 2010).
Mechanism of action of probiotics in improving the QoL of GI patients
Age, health conditions, and food choices play a significant role in shaping the microbiota composition. A previous study showed that the microorganisms found in individuals between the ages of 65 and 96 years are distinct from those in younger adults, showing elevated levels of cluster IV of
With regard to nutrition, the impact of eating on the microbiome has been thoroughly researched. A habitual long-term diet is strongly associated with enterotypes. Animal fat/protein is linked to enterotype 1, whereas carbohydrates are linked to enterotype 2. On the other hand, acute feeding with diets containing different fats and non-starch polysaccharides alters the human microbial phase, indicating that the manipulation of major dietary nutrients is responsible for most changes in microbiota (Faith et al., 2011; Wu et al., 2011). Some approaches for regulating GI flora, especially the use of probiotic organisms, have been sought as ways to promote health and, in some cases, treatment of diseases (Whelan and Quigley, 2013).
In addition, the gut microbiota is associated with many GI-related syndromes, including IBS. Hence, there is an increasing focus on controlling the microbiota as a treatment alternative. Since microbial flora is connected to the CNS via the cerebrointestinal axis, additional changes in this relationship have been identified as the mechanisms of IBS, which function in the intestines through central and peripheral pathways and microbial metabolites (Distrutti et al., 2004; Parkes et al., 2008; Bhattarai et al., 2017).
Limitations and future directions
This review has some limitations. First, there may be language bias as our search only used English sources. Second, the evidence level of the systematic review is restricted by included studies’ evidence level. Third, we did not exclude studies that used unreliable HRQOL tools. Finally, systematic studies on probiotic formulations did not find enough evidence to explain how each species in the combination works. In future studies, the effects of supplementation with different types of probiotics in combination and alone need to be studied to determine the exact mechanisms of each probiotic species.
This systematic review provides a new overview of how probiotic supplementation affects QoL in patients with GI diseases and outlines potential areas for future research. Based on our review of available clinical trial studies, we found that patients with GI diseases reported significant improvement in HRQOL after probiotic supplementation. However, more
ACKNOWLEDGEMENTS
We hereby acknowledge the student research committee of Kermanshah University of Medical Sciences for the financial support of this project.
FUNDING
This study was supported by Kermanshah University of Medical Science (No. 4020345).
AUTHOR DISCLOSURE STATEMENT
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
Concept and design: JM, AS. Analysis and interpretation: MAZ. Data collection: MAZ. Validation: YA, SM, SH. Writing the article: YA, JM, SM, SH. Critical revision of the article: YP, SM, FM. Statistical analysis: FM, YA. Obtained funding: FM, YA, SH, MAZ. Final approval of the article: all authors. Overall responsibility: AS.
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Article
Review
Prev Nutr Food Sci 2024; 29(3): 237-255
Published online September 30, 2024 https://doi.org/10.3746/pnf.2024.29.3.237
Copyright © The Korean Society of Food Science and Nutrition.
The Efficacy of Probiotics Supplementation on the Quality of Life of Patients with Gastrointestinal Disease: A Systematic Review of Clinical Studies
Jalal Moludi1,3 , Amir Saber1,3
, Morteza Arab Zozani2
, Shima Moradi3
, Yasaman Azamian3
, Salimeh Hajiahmadi4
, Yahya Pasdar1
, Fardin Moradi3
1Department of Nutritional Sciences, School of Nutritional Sciences and Food Technology and 3Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6719851552, Iran
2Social Determinants of Health Research Center (SDHRC), School of Health, Birjand University of Medical Sciences, Birjand 32048321, Iran
4Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd 8915173160, Iran
Correspondence to:Amir Saber, E-mail: dr.saber61@gmail.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Patients with gastrointestinal (GI) disorders might benefit from probiotic supplementation to resolve their bowel symptoms and enhance their quality of life (QoL). This systematic review aimed to evaluate the effects of oral probiotic supplementation on improving QoL. Relevant studies were systematically searched in online databases, including PubMed, Scopus, Embase, ProQuest, and Google Scholar up to September 2022 using relevant keywords. Studies that were conducted on GI patients and presented QoL outcomes were included. The Revised Cochrane Risk of Bias 2 tool and the Risk Of Bias In Non-randomized Studies of Intervention tool were used to assess the risk of bias. Of the 4,555 results found in the systematic search of databases, only 36 studies were eligible for evaluation. According to this systematic review, 24 studies reported improvements, whereas 12 studies reported no improvements on QoL in GI patients supplemented with probiotics. We found that probiotics may improve the QoL of patients with GI diseases and related metabolic complications. Therefore, probiotics can be a useful supportive treatment strategy in these patients.
Keywords: gastrointestinal diseases, probiotics, quality of life
INTRODUCTION
Functional gastrointestinal disorders (FGIDs) are characterized by a combination of motility issues; visceral hypersensitivity; and changes in mucosal and immune function, gut microbiota, and central nervous system (CNS) processing (Drossman, 2016). Despite being poorly understood because of their complex pathophysiology, FGIDs [including irritable bowel syndrome (IBS), functional dyspepsia, and functional constipation (FC)] account for approximately 33% of all appointments at gastroenterology clinics (Shivaji and Ford, 2014). According to previous studies, more than 66% of individuals suffering from FGIDs have consulted a healthcare professional within the past year, 40% rely on medications regularly, and 33% have undergone unwarranted abdominal surgeries including hysterectomies or cholecystectomies to relieve their symptoms (Jafari et al., 2018). Aside from being costly to manage, these conditions also affect patients’ quality of life (QoL), which emphasize their fundamental importance to healthcare systems and society (Jafari et al., 2018). According to previous studies, pathogenic gut microbiota may be responsible for various chronic GI disorders, including cancer and diseases involving inflammation, metabolic, cardiovascular, autoimmune, neurologic, and psychiatric components (Kataoka, 2016; Lynch and Pedersen, 2016; Cani, 2017). The human body harbors the most abundant microorganisms in the GI tract. Therefore, intestinal microflora changes have been observed as a leading mechanism in the occurrence of some GI diseases (Aziz et al., 2013; Guinane and Cotter, 2013).
Probiotics are live microorganisms found in food and dietary supplements that, when consumed, can enhance the host’s health and provide nutritional value (Fuller and Gibson, 1998). These microorganisms mostly comprise bacteria and yeasts and naturally exist in fermented foods or some functional food products (Lin, 2003). The most well-known genera of probiotics belong to
In this regard, using some probiotic species can lead to a QoL improvement (Hungin et al., 2013). Research conducted in laboratory and live animal settings has demonstrated that probiotics can effectively diminish bloating, pain, and abdominal symptoms in individuals suffering from IBS (Kim et al., 2003; Aragon et al., 2010; Wong et al., 2015; Staudacher et al., 2017). In addition, studies on adults and children demonstrate the favorable effect of probiotic treatment on stool frequency, stool consistency, and constipation (Chmielewska and Szajewska, 2010). In another study, the administration of probiotics and synbiotics after surgery decreased the incidence of complications and enhanced the QoL and longevity of patients with colorectal cancer (Amitay et al., 2020). While many studies have investigated how probiotics can affect the QoL of individuals with GI diseases, no comprehensive systematic review has been conducted to reveal the potential complementary role of probiotics in patients with GI diseases and to identify existing scientific gaps. Therefore, based on available evidence, the present study investigated whether probiotic supplementation can improve the QoL of most GI patients by improving symptoms.
METHODS
This systematic review was designed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Furthermore, the study protocol was registered in the International Prospective Register of Systematic Reviews hosted by the Center for Reviews and Dissemination (PROSPERO) (CRD42022382414).
Search strategy
Two researchers conducted a thorough systematic search in five online databases (i.e., PubMed, Scopus, Embase, ProQuest, and Google Scholar) to identify relevant studies. The keywords were carefully selected, and pre-established criteria were used for included studies. The following Medical Subject Headings (MeSH) were applied in certain combinations: “probiotics,” “quality of life,” “probiotics and quality of life,” “probiotics and GI microbiome,” “probiotics and GI disease,” “probiotics and irritable bowel syndrome,” “probiotics and health-related outcomes,” and Medical Outcomes Study Short Form 36-Item questionnaire (SF-36).
Inclusion and exclusion criteria
Two researchers independently screened the titles and abstracts in the online database based on the inclusion and exclusion criteria. Eligible studies were required to meet the following inclusion criteria: 1) English-language articles available online (up to September 2022); 2) primary research articles and studies conducted on human individuals; and 3) all clinical trial studies on the effect of probiotics on the QoL in GI patients. Meanwhile, letters, comments, short communications, abstracts, studies on pregnant and lactating women, and
Screening and data extraction
Two investigators independently reviewed eligible full text studies. Thereafter, data extraction was conducted using standardized forms and research questions. In case of disputes, a third researcher assessed the precision and quality of the inputted data. Next, variables including general manuscript details (author, country, location, and year), subject characteristics (age, clinical setting or population), study design and intervention characteristics (study quality, study design, sample size, QoL assessment method, probiotic strain, daily dosage, and treatment duration), and QoL summary statistics necessary for systematic review were recorded in a predetermined database. Initially, 94 studies were selected in the comprehensive search. The titles and abstracts of studies were reviewed to exclude papers published in non-English journals (six studies were excluded). Afterward, review articles, study protocols, commentaries, and case reports were removed (11 studies were excluded). Next, the full text of the remaining studies was examined and reviewed. Studies that failed to describe the QoL or those that were non-randomized, non-controlled, or otherwise irrelevant were further removed (four studies were excluded). Finally, studies on the population with GI diseases were isolated, and 36 studies were eligible for the final review (Fig. 1).
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Figure 1. Flow chart of the study selection process.
Quality assessment
The Cochrane Collaboration’s tools were used to identify potential sources of bias in the selected studies. Two authors independently assessed each included study using the Revised Cochrane Risk of Bias 2 (RoB2) tool and the Risk Of Bias In Non-randomized Studies of Intervention (ROBINS-I) tool (Higgins et al., 2011). The methodological domains assessed for parallel and cross-over randomized controlled trials (RCTs) included the randomization process, deviation from intended interventions, missing outcome data, outcome measurement, and selection of reported results. Bias was evaluated as judgment for every criterion (indicated as “high risk of bias,” “low risk of bias,” or “some concerns”). Meanwhile, the methodological domains assessed for non-randomized clinical trials included bias from confounding, bias in participant selection, bias in intervention classification, bias from deviations in interventions, bias from missing data, bias in outcome measurement, and bias in the selection of reported results. Differences between these procedures were settled via agreement or seeking input from a third party, following communication with the authors of the original study for further explanation. If the trials did not provide sufficient information for assessment, we contacted the authors via email and allowed them a period of at least four weeks to reply.
RESULTS
Study selection
After applying all exclusion criteria, the final review was limited to 36 studies. Sixteen studies were related to IBS (Drisko et al., 2006; Choi et al., 2011; Dapoigny et al., 2012; Cappello et al., 2013; Abbas et al., 2014; Lorenzo-Zúñiga et al., 2014; Choi et al., 2015; Šmid et al., 2016; Giannetti et al., 2017; Nobutani et al., 2017; Pinto-Sanchez et al., 2017; Preston et al., 2018; Aroniadis et al., 2019; Catinean et al., 2019; Francavilla et al., 2019; El-Salhy et al., 2020). Eight studies were related to constipation (Ding et al., 2016; Cudmore et al., 2017; Ibarra et al., 2018; Xinias et al., 2018; Dimidi et al., 2019; Kommers et al., 2019; Riezzo et al., 2019; Olgac et al., 2020). Five studies were related to rectal cancer (Ohigashi et al., 2011; Lee et al., 2014; Theodoropoulos et al., 2016; Golkhalkhali et al., 2018; Radvar et al., 2020). One study was related to cirrhosis (Macnaughtan et al., 2020). One study was related to non-celiac gluten sensitivity disease (Di Pierro et al., 2020). One study was related to infant colic (Ahmadipour et al., 2020). One study was related to gastric bypass surgery (Chen et al., 2016). Two studies were related to FGIDs (Ringel-Kulka et al., 2011; Gomi et al., 2018). One study was related to ulcerative colitis (Fujimori et al., 2009). The details of each study are summarized in Tables 1-5.
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Table 1 . IBS-related disease: characteristics of selected clinical trials included in the review.
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes El-Salhy et al., 2020 (Norway) RCT IBS 165 39.9±9.0 30 g FMT or 60 g FMT at a ratio of 1:1:1 The material for FMT FMT 3 months IBS-QoL Positive effect Catinean et al., 2019 (Romania) RCT IBS 90 18-75
G1=38.77±10.96
G2=39.07±16.00
G3=40.37±11.95G2=7 days: 1 cap
27 days: 2 capG1= Bifidobacterium longum W11
G2=fiveBacillus spp.34 days
G1 and G3=10+24
G2=34IBS-QoL (SF-36) Positive effect Preston et al., 2018 (USA) RCT IBS 86 Plac: 39.9
Int: 40.62 capsules
50×109 CFULactobacillus acidophilus CL1285,L. casei LBC80R, andL. rhamnosus CLR212 weeks IBS-QoL Positive effect Giannetti et al., 2017 (Italy) RCT Children with IBS and functional dyspepsia 73 8.0-17.9 3 billion (3×109) of Bifidobacterium longum BB536, 1 billion (1×109) ofB. infantis M-63, 1 billion (1×109) of B. breve M-16V3 Bifidobacteria :M-63breve M-16Vlongum BB53616 weeks:
2-week run-in phase
6 weeks Int
2-week “washout”
Afterward, each patient was switched to the other group
6 weeks IntFDI Positive effect Pinto-Sanchez et al., 2017 (Canada) RCT IBS 44 Int: 46.5 (30-58)
Plac: 40.0 (26-57)1.0E+10 Bifidobacterium longum NCC3001 (BL)6-week treatment
10 week follow-upSF-36 Positive effect Nobutani et al., 2017 (Japan) RCT IBS 30 Int: 52.6±20.1
Plac: 45.9±19.513×108 CFU Lactobacillus gasseri CP23054 weeks IBS-QoL and PSQI-J Positive effect Choi et al., 2015 (Korea) RCT Non-diarrheal-type IBS 285 20-73 (47) Group 1: 1.0×1010
CFU
Groups 2 and 3: 1.5×1010
Group 4: 3×1010Bacillus subtilis andStreptococcus faecium 4 weeks IBS-QoL Positive effect Abbas et al., 2014 (Pakistan) RCT IBS-D 72
64
(completed)18-60
Int:
37.7±11.6
Plac:
33.0±12.0750 mg/d Saccharomyces boulardii 2-week run-in
6 weeks IntIBS-QoL Positive effect Lorenzo-Zúñiga et al., 2014 (Spain) RCT IBS 73 20-70
Int: 47.5±13.1
46.3±11.6
Plac: 46.5±13.11-3×1010 CFU or 3-6×109 Two Lactobacillus plantarum (CECT7484 and CECT7485) and onePediococcus acidilactici (CECT7483)6 weeks IBS-QoL Positive effect Cappello et al., 2013 (Italy) RCT IBS 64 38.7±12.6 5×109 Lactobacillus plantarum , 2×109L. casei subp.rhamnosus and 2×109L. gasseri , 1×109Bifidobacterium infantis and 1×109B. longum , 1×109L. acidophilus , 1×109L. salivarius and 1×109L. sporogenes and 5×109Streptococcus thermophilus
Prebiotic inulin 2.2 gLyophilized bacteria: L. plantarumL. casei subp.rhamnosusL. gasseriBifidobacterium infantisL. acidophilusL. salivariusL. sporogenesStreptococcus thermophilus
Prebiotic inulin6 weeks
(2-week run-in and 4-week treatment)SF-36 Positive effect Choi et al., 2011 (Korea) RCT IBS 67 41±13 2×1011 Saccharomyces boulardii 4 weeks IBS-QoL Positive effect Drisko et al., 2006 (USA) Open-label pilot study
Prospective outcome studyIBS 20 24-81 10 billion CFU Lactobacillus acidophilus ,Bifidobacterium bifidum ,L. rhamnosus ,L. plantarum ,B. infantis ,L. salivarius ,L. bulgaricus ,L. casei ,L. brevis , andStreptococcus thermophilus 1 year IBS-QoL Positive effect RCT, randomized control trial; IBS, irritable bowel syndrome; FMT, fecal microbiota transplantation; QoL, quality of life; IBS-QoL, irritable bowel syndrome QoL; IBS-D, diarrhea-dominant irritable bowel syndrome; SF-36, 36-item short form survey; CFU, colony forming unit; FDI, Functional Disability Inventory; Int, intervention; Plac, placebo; PSQI-J, Pittsburgh Sleep Quality Index..
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Table 2 . Constipation-related disease: characteristics of selected clinical trials included in the review.
Reference Type of study Clinical setting/population Sample size Age Daily dose Probiotic species Duration of intervention System Main outcomes Olgac et al., 2020 (Turkey) RCT Children with FC 49 4-16 years 1×108 CFU Lactobacillus reuteri DSM 17938 or lactulose4 weeks KINDLⓇ HRQOL Positive effect Kommers et al., 2019 (Brazil) RCT Female university students with intestinal constipation 63 20-40 years
Int: 27.15±5.52
Plac: 24.38±5.41109 CFU of each one Bifidobacterium lactis (BL04),B. bifidum (Bb-06),Lactobacillus acidophilus (La-14),L. casei (Lc-11),Lactococcus lactis (LL-23)45 days PAC-QoL Positive effect Xinias et al., 2018 (Greece) Non-randomized clinical trial Infants with FC 65 3-13 weeks
Int: 1.4±0.8
Plac: 1.7±0.9Not reported Bifidobacterium lactis BB121 month Not reported (parents completed a QoL) Positive effect Cudmore et al., 2017 (Ireland) RCT Chronic, FC 69 18-80 years 6×108 CFU twice daily Lactobacillus rhamnosus PXN 54 (NCIMB 30188),Bifidobacterium bifidum PXN 23 (NCIMB 30179),L. acidophilus PXN 35 (NCIMB 30184),L. plantarum PXN 47 (NCIMB 30187), andL. bulgaricus PXN 39 (NCIMB 30186)
Also psyllium and inulin4 weeks PAC-QoL Positive effect RCT, randomized control trial; FC, functional constipation; CFU, colony forming unit; QoL, quality of life; KINDLⓇ HRQOL, KINDLⓇ Health-Related QoL; PAC-QoL, Patient Assessment of Constipation QoL..
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Table 3 . Functional gastrointestinal disorders (FGIDs): characteristics of selected clinical trials included in the review.
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention (weeks) System Main outcomes Ringel-Kulka et al., 2011 (USA) RCT Functional bowel disorders 60 18-65 Mean age Int: 36 Plac: 37 Twice a day (2×1011 CFU CFU/d) Lactobacillus acidophilus NCFM (L-NCFM) andBifidobacterium lactis Bi-07 (B-LBi07)8 IBS-QoL Positive effect RCT, randomized control trial; CFU, colony forming unit; IBS-QoL, irritable bowel syndrome-quality of life; Int, intervention; Plac, placebo..
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Table 4 . Colorectal cancer-related disease: characteristics of selected clinical trials included in the review.
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Radvar et al., 2020 (Iran) RCT Rectal cancer 38 Int: 57.58±12.78 Plac: 62.89±13.93 2 times a day 1×108 CFU/g Lactobacillus casei PXN 37,L. rhamnosus PXN 54,Streptococcus thermophilus 81 PXN 66,Bifidobacterium breve PXN 25,L. acidophilus PXN 35,B. longum PXN 30,L. bulgaricus PXN 39, FOS (fructooligosaccharide), magnesium stearate (source: mineral and vegetable), and vegetable capsule (hydroxypropyl methyl cellulose)6 weeks EORTC QLQ-C30 Positive effect Golkhalkhali et al., 2018 (Malaysia) RCT Colorectal cancer 140 <18 Two sachets daily 30 billion (CFUs) per sachet Lactobacillus acidophilus BCMCR 12130,L. casei BCMCR 12313,Lactobacillus lactis BCMCR 12451,Bifidobacterium bifidum BCMCR 02290,B. longum BCMCR 02120, andB. infantis BCMCR 021298 weeks EORTC QLQ-C30 Positive effect Lee et al., 2014 (Korea) RCT Colorectal cancer 60 56.18±8.86 Twice a day 2×109 CFU Lacidofil ( Lactobacillus rhamnosus R0011 andL. acidophilus R0052)12 weeks FACT Positive effect Ohigashi et al., 2011 (Japan) Questionnaire-based study Colorectal cancer 63 63±9 10 mg of Bacillus natto and 30 mg ofLactobacillus acidophilus B. natto andL. acidophilus 3 months SF-36 and EORTC QLQ-C30 Positive effect RCT, randomized control trial; Int, intervention; Plac, placebo; CFU, colony forming unit; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30; FACT, Functional Assessment of Cancer Therapy; SF-36, 36-item short form survey..
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Table 5 . Other diseases: characteristics of selected clinical trials included in the review.
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Di Pierro et al., 2020 (Italy) Non-randomized clinical trial Non-celiac gluten sensitivity 30 Int: 46.87±17.06 Plac: 43.53±18.94 1 dose/day 1×109 CFU (1 billion) Bifidobacterium longum ES1 or GFD 3 months Document of scientific support to the protocol for the diagnosis and follow-up of celiac disease Positive effect Chen et al., 2016 (Taiwan) RCT Gastric bypass surgery 53 18-60 35.1±8.3 Twice daily A: 5×109 CFU (5 billion) B: 8×109 CFU (8 billion) A: 1 g Clostridium butyricum MIYAIRI B: 300 mgBifidobacterium longum BB5362 weeks mGIQL Positive effect Fujimori et al., 2009 (Japan) RCT Ulcerative colitis 83 Pro=36±16 Pre=37±13 Syn=35±10 2×109 CFU Bifidobacterium longum Also prebiotic (psyllium) and synbiotic4 weeks IBDQ Positive effect RCT, randomized control trial; Int, intervention; Plac, placebo; Pro, probiotics; Pre, prebiotics; Syn, symbiotic; CFU, colony forming unit; GFD, gluten-free diet; mGIQL, modified Gastrointestinal QoL Index; IBDQ, Inflammatory Bowel Disease Questionnaire..
Quality assessment
The risk of bias of included studies is presented in Table 6 and 7. Out of the 32 parallel and cross-over double-blind RCTs that were included, only 14 studies had low risk of bias. The rest revealed some concerns and high risk in overall risk of bias (Table 7). Furthermore, each of the four non-randomized clinical trials showed a significant potential for bias. Confounding bias was the major concern in non-randomized clinical trials (Table 8).
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Table 6 . Characteristics of included studies that did not find any effect.
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Francavilla et al., 2019 (Italy) RCT Patients with celiac disease and IBS 109 Age 18 years and above
Int: 43.3 (18.8-62.2)
Plac: 44.6 (19.3-63.4)5×109 CFU/sachet+5×109 CFU/sachet+10×109 CFU/sachet+10×109 CFU/sachet+10×109 CFU/sachet Lactobacillus casei LMG 101/37 P-17504 (5×109 CFU/sachet),L. plantarum CECT 4528 (5×109 CFU/sachet),Bifidobacterium animalis subsp.lactis Bi1 LMG P-17502 (10×109 CFU/sachet),B. breve Bbr8 LMG P-17501 (10×109 CFU/sachet),B. breve Bl10 LMG P-17500 (10×109 CFU/sachet)14 weeks IBS–QoL Without effect Aroniadis et al., 2019 (USA) RCT IBS 45 18-65
Int: 33 (27-48)
Plac: 42 (28-48)25 capsules perday
0.38 g minimallyProcessed donor whole stool per capsule 12 weeks IBS–QoL Without effect Šmid et al., 2016 (Slovenia–Croatia) RCT IBS 76 18-65 (1.8×107 CFU/g) and
(2.5×107 CFU/g)Lactobacillus acidophilus La-5Ⓡ (1.8×107 CFU/g) andBifidobacterium animalis ssp.lactis BB-12Ⓡ (2.5×107 CFU/g)Streptococcus thermophilus 4 weeks IBS–QoL Without effect Dapoigny et al., 2012 (France) Randomized double-blind pilot study IBS 47 Int: 46.1±11.3
Plac: 48.0±10.86×108 CFU Lactobacillus casei varietyrhamnosus LCR354 weeks GIQLI Without effect Riezzo et al., 2019 (Italy) RCT FC 56 19-65
42.4±13.815 days: four tablets daily
Then: two tablets daily
One tablet=1×108 CFULactobacillus reuteri (LR) DSM 17938105 days PAC–QoL Without effect Dimidi et al., 2019 (UK) RCT Constipation 75 18-65
Int: 35 (12)
Plac: 31 (10)1.5×1010 CFU/day Bifidobacterium lactis NCC28184 weeks PAC–QoL Without effect Ibarra et al., 2018 (France) RCT Adults with functional constipation 224 18-70 1×109 or 1×1010 CFU Bifidobacterium animalis subsp.lactis HN01928 days PAC-QoL Without effect Ding et al., 2016 (China) RCT (prospective) Slow transit constipation 93 Plac: 48.3±11.3
Int: 47.2±10.70.63 g Bifid triple viable capsules (BIFICO) and 8 g of soluble dietary fiber 12 weeks GIQLI Positive effect Gomi et al., 2018 (Japan) RCT Patients with functional GI disorders 79 20-64
Int: 41.1±10.1
Plac: 41.6±9.9YIT 10347=3×107 CFU/mL Streptococcus thermophilus YIT 2021=1×107Bifidobacterium bifidum YIT 10347Streptococcus thermophilus YIT 2021 (in both Plac and Int groups)4 weeks SF-36 v2 Without effect Theodoropoulos et al., 2016 (Netherlands) RCT Colectomy for cancer 67 Int: 66.8±2.17
Plac: 69±1.37Sachets
12 gPediococcus pentosaceus 5-33:3,Leuconostoc mesenteroides 32-77:1,Lactobacillus paracasei ssp.paracasei 19, andL. plantarum 2362 and 2.5 g of each of the four fermentable fibers (prebiotics): b-glucan, inulin, pectin, and resistant starch15 days GIQLI and EORTC QLQ-C30 Without effect Macnaughtan et al., 2020 (UK) RCT Cirrhosis 92 (68) 18-78 6.5×109 CFU Lactobacillus casei Shirota (LcS)3 times per day for 6 months SF-36 Without effect Ahmadipour et al., 2020 (Iran) RCT Infant colic 72 21-90 days old
Int: 52.20±41.885 days
Plac: 49.36±23.321 days5 drops of Pedilact
109 CFULactobacillus rhamnosus ,L. reuteri ,Bifidobacterium infantis probiotics and fructooligosaccharide28 days Not reported Without effect RCT, randomized control trial; IBS, irritable bowel syndrome; FC, functional constipation; Int, intervention; Plac, placebo; CFU, colony forming unit; IBS-QoL, irritable bowel syndrome QoL; GIQLI, Gastrointestinal Quality of Life Index; PAC-QoL, Patient Assessment of Constipation QoL; SF-36, 36-item short form survey; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30..
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Table 7 . Assessment of risk of bias for randomized and cross-over clinical trials using the Cochrane Risk of Bias 2 tool.
Reference Risk domain Bias arising from the randomization process Bias because of deviations from the intended intervention Missing outcome data Bias in outcome measurement Bias in the selection of reported results Overall risk of bias Fujimori et al., 2009 Low High High Low Some concerns High Chen et al., 2016 Some concerns Low High Low Some concerns High Ahmadipour et al., 2020 Some concerns Low Low Low Low Some concerns Macnaughtan et al., 2020 Low Low Low Low Low Low Lee et al., 2014 Low Low High Low Low High Theodoropoulos et al., 2016 Low Low Low Low Low Low Golkhalkhali et al., 2018 Low Low Low Low Low Low Radvar et al., 2020 Low Low Low Low Low Low Ringel-Kulka et al., 2011 Low Low Low Low Low Low Gomi et al., 2018 Low Low Low Low Low Low Ding et al., 2016 Low Low Some concerns Low Low Some concerns Cudmore et al., 2017 Low Low Low Low Low Low Ibarra et al., 2018 Low Low High Low Low High Dimidi et al., 2019 Low Low Low Low Low Low Kommers et al., 2019 Low Low High Low Low High Riezzo et al., 2019 Some concerns Some concerns Some concerns Low Low Some concerns Olgac et al., 2020 Some concerns High Some concerns Low Some concerns High Choi et al., 2011 Low Low High Low Low High Dapoigny et al., 2012 Low Low Some concerns Low Some concerns Some concerns Cappello et al., 2013 Low Low Some concerns Low Some concerns Some concerns Lorenzo-Zúñiga et al., 2014 Low Low Some concerns Low Some concerns Some concerns Abbas et al., 2014 Low Low Some concerns Low Some concerns Some concerns Choi et al., 2015 Low Low Low Low Low Low Šmid et al., 2016 Low Low Low Low Low Low Nobutani et al., 2017 Some concerns Some concerns Low Low Some concerns Some concerns Pinto-Sanchez et al., 2017 Low Low Low Low Low Low Giannetti et al., 2017 Low Low Low Low Low Low Preston et al., 2018 Some concerns Low Low Low Low Some concerns Aroniadis et al., 2019 Low Low High Low Low High Francavilla et al., 2019 Low Low Low Low Low Low Catinean et al., 2019 Some concerns Some concerns Low Low Some concerns Some concerns El-Salhy et al., 2020 Low Low Low Low Low Low
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Table 8 . Assessment of risk of bias for non-randomized clinical trials using the Cochrane Risk of Bias 2 tool.
Reference Risk domain Bias because of confounding Bias because of the selection of participants Bias in the classification of intervention Bias because of deviations from the intended intervention Bias because of missing outcome data Bias in outcome measurement Bias in the selection of reported results Overall risk of bias Drisko et al., 2006 High Low Some concerns Low Some concerns Low Low High Xinias et al., 2018 High Low Low Low Low Low Low High Ohigashi et al., 2011 High Low Some concerns Low Some concerns Low Some concerns High Di Pierro et al., 2020 High Low Low Low Low Low Low High
Characteristics of included studies
The median age of participants across studies was 18-81 years, and the duration of probiotic supplementation ranged from 15 days to 16 weeks. In 36 studies, 2,942 patients with GI disease were supplemented with probiotics, and the QoL of individuals was assessed using a questionnaire. All studies were randomized trials that were published from 2006 to 2020. Five studies were conducted in Italy (Cappello et al., 2013; Giannetti et al., 2017; Francavilla et al., 2019; Riezzo et al., 2019; Di Pierro et al., 2020). Four studies were conducted in Japan (Fujimori et al., 2009; Ohigashi et al., 2011; Nobutani et al., 2017; Gomi et al., 2018). Four studies were conducted in the USA (Drisko et al., 2006; Ringel-Kulka et al., 2011; Preston et al., 2018; Aroniadis et al., 2019). Three studies were conducted in Korea (Choi et al., 2011; Lee et al., 2014; Choi et al., 2015). Two studies were conducted in France (Dapoigny et al., 2012; Ibarra et al., 2018). Two studies were conducted in the UK (Dimidi et al., 2019; Macnaughtan et al., 2020). Two studies were conducted in Iran (Ahmadipour et al., 2020; Radvar et al., 2020). One study was conducted in Norway (El-Salhy et al., 2020). One study was conducted in Canada (Pinto-Sanchez et al., 2017). One study was conducted in Romania (Catinean et al., 2019). One study was conducted in Pakistan (Abbas et al., 2014). One study was conducted in Spain (Lorenzo-Zúñiga et al., 2014). One study was conducted in Turkey (Olgac et al., 2020). One study was conducted in Brazil (Kommers et al., 2019). One study was conducted in Greece (Xinias et al., 2018). One study was conducted in Ireland (Cudmore et al., 2017). One study was conducted in China (Ding et al., 2016). One study was conducted in the Netherlands (Theodoropoulos et al., 2016). One study was conducted in Malaysia (Golkhalkhali et al., 2018). One study was conducted in Taiwan (Chen et al., 2016). One study was conducted in Slovenia-Croatia (Šmid et al., 2016).
Health-related quality of life (HRQOL) instruments
The HRQOL instruments used in the included studies were either generic or GI-specific measures. Five studies used SF-36. Thirteen studies used the IBS-QoL questionnaire (Drisko et al., 2006; Choi et al., 2011; Ringel-Kulka et al., 2011; Abbas et al., 2014; Lorenzo-Zúñiga et al., 2014; Choi et al., 2015; Šmid et al., 2016; Nobutani et al., 2017; Preston et al., 2018; Aroniadis et al., 2019; Catinean et al., 2019; Francavilla et al., 2019; El-Salhy et al., 2020). Three studies used the Gastrointestinal Quality of Life Index (GIQLI) (Chen et al., 2016; Ding et al., 2016; Theodoropoulos et al., 2016). Four studies used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) (Ohigashi et al., 2011; Theodoropoulos et al., 2016; Golkhalkhali et al., 2018; Radvar et al., 2020). One study used the Functional Disability Inventory (FDI) (Giannetti et al., 2017). One study used the Pittsburgh Sleep Quality Index-Japanese version (PSQI-J) (Nobutani et al., 2017). One study used the Functional Assessment of Cancer Therapy (FACT) (Lee et al., 2014). One study used the modified Gastrointestinal QoL (mGIQL). One study used the Inflammatory Bowel Disease Questionnaire (IBDQ) (Fujimori et al., 2009). One study used the KINDLⓇ Health-Related Quality of Life (KINDLⓇ HRQOL) (Olgac et al., 2020). One study used the “Document of scientific support to the protocol for the diagnosis and follow-up of celiac disease” (Di Pierro et al., 2020). Two studies did not report the method used to measure the QoL (Xinias et al., 2018; Ahmadipour et al., 2020).
Probiotics
Among the 36 studies, eight different bacterial genera were used as probiotic supplements: a)
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Table 9 . Genus and species of probiotic supplementation in the included studies.
1)
Lactobacillus andBifidobacterium were the most common genera of probiotics that were used to study the effects of probiotic supplementation in clinical gastrointestinal investigations..-, not available..
Overall, the investigation of the effect of different types of probiotic supplementation on the QoL of GI patients in RCT studies showed that 23 studies reported improvement in the QoL of patients (Drisko et al., 2006; Fujimori et al., 2009; Choi et al., 2011; Ringel-Kulka et al., 2011; Ohigashi et al., 2011; Cappello et al., 2013; Abbas et al., 2014; Lee et al., 2014; Lorenzo-Zúñiga et al., 2014; Choi et al., 2015; Chen et al., 2016; Cudmore et al., 2017; Giannetti et al., 2017; Nobutani et al., 2017; Pinto-Sanchez et al., 2017; Golkhalkhali et al., 2018; Preston et al., 2018; Ringel-Kulka et al., 2011; Xinias et al., 2018; Kommers et al., 2019; Di Pierro et al., 2020; El-Salhy et al., 2020; Olgac et al., 2020; Radvar et al., 2020), whereas 12 studies reported no improvement in the QoL of patients after probiotic supplementation (Dapoigny et al., 2012; Ding et al., 2016; Šmid et al., 2016; Theodoropoulos et al., 2016; Gomi et al., 2018; Ibarra et al., 2018; Aroniadis et al., 2019; Dimidi et al., 2019; Riezzo et al., 2019; Ahmadipour et al., 2020; Francavilla et al., 2019; Macnaughtan et al., 2020) (Table 6).
Irritable bowel syndrome (IBS)
Based on evidence provided by the included studies, supplementation with the following probiotic species has been reported to be effective in IBS:
Rectal cancer
Based on evidence provided by the included studies, the following probiotic species have been demonstrated to improve overall health status and QoL and minimize certain side effects of chemotherapy in patients with cancer:
Functional gastrointestinal disorders (FGIDs)
According to several studies, probiotic supplementation with the following species had no effect on the QoL of patients with FGIDs:
Functional constipation (FC)
Based on evidence provided by the included studies, supplementation with the following probiotic species could improve FC and the QoL of patients:
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Table 10 . Notable outcomes of selected RCT studies assessing the effects of probiotics on GI diseases.
Reference Gut microbiota assessment Outcomes of GI symptoms Macnaughtan et al., 2020, UK - - Giannetti et al., 2017, Italy - In IBS, Bifidobacteria supplementation resulted in a complete resolution of abdominal pain in a significantly higher proportion of childrenCappello et al., 2013
Italy (Rome)- - Cudmore et al., 2017, Ireland - Symptoms of constipation improved Fujimori et al., 2009, Japan - Emotional function increased in the probiotic and synbiotic groups Gomi et al., 2018, Japan - The YIT10347 group had significantly higher relief rates of overall gastrointestinal symptoms, upper gastrointestinal symptoms, flatus, and diarrhea than the placebo group Francavilla et al., 2019, Italy ·Using plate counts and 16S rRNA gene-based analysis
·Fecal samples (5 g) were mixed with 45 mL of sterilized physiological solution and homogenized. Viable bacterial cells were counted as described by De Angelis et al.
·To determine the identities of bacteria, sequences were first queried using a distributed BLASTn.NET algorithm24 against 16S bacterial sequences derived from NCBI.- Radvar et al., 2020, Iran - Body weight decreased in the synbiotic and placebo groups Aroniadis et al., 2019, USA 16S rRNA sequencing - Chen et al., 2016, Taiwan - Complaints of abdominal pain, abdominal bloating, excessive passage of gas, foul smell of flatulence, belching, abdominal noises, and heartburn were significantly improved in the entire sample Dapoigny et al., 2012, France Extraction of total bacterial DNA (QIAamp Fast DNA Stool Mini Kit, QIAGEN), the presence of Lactobacillus casei varietyrhamnosus was specifically determined by qualitative polymerase chain reaction (PCR - primer pairs hyb-21) – cycles of amplification.A decrease in the abdominal pain severity score was observed with LCR35 Choi et al., 2015, Korea - The abdominal pain/discomfort score in treatment group 4 was more prominently improved compared with that of the placebo group
In patients with constipation-predominant IBS, the improvements in stool frequency and consistency were significantly higher in treatment groups 4 and 1, respectively, than those in the placebo group
There were more favorable tendencies of effects on bloating in all treatment groups than in the placebo groupEl-Salhy et al., 2020, Norway 16S rRNA gene sequencing - Ding et al., 2016, China - During the intervention period, patients who were treated with the synbiotic exhibited increased stool frequency, improved stool consistency, decreased colonic transit time, and improved constipation-related symptoms Ohigashi et al., 2011, Japan - Defecation frequency, anal pain, and Wexner score were significantly poorer in the rectal group than in the colonic group Ringel-Kulka et al., 2011, USA Quantitative real-time polymerase chain reaction of fecal samples Abdominal bloating improved in the probiotic group compared with the placebo group at 4 and 8 weeks Dimidi et al., 2019, UK Quantitative polymerase chain reaction - Šmid et al., 2016, Slovenia & Croatia - Significant improvements in bloating severity, satisfaction with bowel movements Golkhalkhali et al., 2018, Malaysia - Nausea, vomiting, and diarrhea significantly improved in the treatment group Theodoropoulos et al., 2016, Netherlands - Differences in the EORTC QLQ-C30 “diarrhea” domain score from baseline were better after synbiotic administration after 3 ( P =0.04) and 6 months (P =0.003)Nobutani et al., 2017, Japan ·Purified DNA was used as a template for the following two-step polymerase chain reaction.
·Fecal microbiota was measured using fecal bacterial 16S rDNA V4-V6 region-targeted pyrosequencing.CP2305 favorably changed the fecal characteristics compared with placebo among patients with IBS with either diarrhea or constipation subtypes Drisko et al., 2006, USA - Significant improvements in pain were observed ( P =0.05)RCT, randomized controlled trial; GI, gastrointestinal; IBS, irritable bowel syndrome; NCBI, National Center for Biotechnology Information; QoL, quality of life; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30; -, not available..
DISCUSSION
To the best of our knowledge, this study is the first systematic evaluation examining how different probiotic species affect the QoL of patients with GI disorders. According to the 10 different QoL assessment systems used in recent clinical studies (SF-36, IBS-QoL, GIQLI, EORTC QLQ-C30, FDI, PSQI-J, FACT, mGIQL, IBDQ, and KINDLⓇ HRQOL), different probiotic species (especially
Probiotic supplementation and IBS
After the idea linking the gut microbiome with human illnesses was put forward, researchers have investigated whether microbiome changes could be found in GI diseases (Pimentel and Lembo, 2020). Several studies have identified less microbial diversity or richness in individuals with IBS than in those without (Codling et al., 2010; Carroll et al., 2012; Jeffery et al., 2012; Ng et al., 2013; Giamarellos-Bourboulis et al., 2015; Maharshak et al., 2018). However, one study did not (Ponnusamy et al., 2011). The majority of trials have assessed how well probiotics work in patients with IBS, many of whom have significant cognitive impairments (Quigley, 2009). The results from a meta-analysis of 15 controlled studies discovered that probiotics decreased pain levels and symptom severity in IBS (Didari et al., 2015). However, the best strain, dose, formulation, and length of treatment remain unknown (Pimentel and Lembo, 2020).
When probiotics were utilized for treating IBS,
Probiotic supplementation and cancer
Cancer and its treatments are commonly accompanied by fatigue. Several studies have demonstrated intestinal microbiome changes in patients with cancer, chronic fatigue syndrome, and other neuropsychiatric disorders (Hajjar et al., 2021). Hajjar et al., revealed that cancer patients with varying levels of fatigue may exhibit diverse gut microbiome compositions. Because of the significance of the microbiome in mucosal immunity and the growing understanding of the link between the gut-brain axis and fatigue and other symptoms, disruption in intestinal microbiota may play a key role in these conditions. On the other hand, improving the microbiome can reduce fatigue severity in patients with cancer and improve their QoL. This research indicates the necessity for further studies on how adjusting the gut microbiome can affect fatigue and enhance QoL in individuals with cancer (Hajjar et al., 2021).
To date, the exact mechanisms behind the effect of gut microbiota on cancer remain unknown. Nevertheless, the gut microbiome could have a significant impact on cancer development through various mechanisms (Grivennikov et al., 2012). First, there are differences in the gut microbial content between individuals with cancer and those without, which may have carcinogenesis effects and contribute to cancer development. For instance, research on the human microbiome revealed notable variations in the prevalence of certain microbes in the cancer group compared with the control group (Bultman, 2014). The second mechanism is the well-known link between inflammation and intestinal microbiota and metabolism, which are cancer characteristics (Tlaskalova-Hogenova et al., 2014). In the metabolic pathway, plant-derived foods are metabolized by intestinal microbiota to biologically active compounds that may be carcinogenic (Tlaskalova-Hogenova et al., 2014). Some studies suggested that the perioperative administration of probiotics/synbiotics reduces the prevalence of side effects and improves the QoL and survival of patients with colorectal cancer (Amitay et al., 2020).
Probiotic supplementation and FC
The prevalence of FC is high in the elderly and is associated with poor QoL. According to previous studies, the most common symptoms of FC that significantly affect the health-related QoL of adults include stool stiffness, squeezing, and feeling of anal obstruction (Norton, 2006; Arco et al., 2022), wherein patients with FC scored lower in all dimensions of the EQ5D3L than those without. European Quality of Life 5 Dimensions 3 Level Version (EQ5D3L) is recognized as an effective and useful assessment tool for comparing QoL in different conditions. However, some researchers also recommend the use of FC-specific QoL measurements, such as assessing a patient’s QoL in constipation (Marquis et al., 2005). Moreover, FC has been reported to be associated with serious mental illness (Merkel et al., 1993; Towers et al., 1994). One study showed that patients with FC are more likely to experience depression and anxiety, according to the corresponding EQ5D3L subscale. Thus, primary care teams and specialists should take into account the impact of FC on the QoL of the elderly, considering the wide range of factors to enhance the overall health of this group (Arco et al., 2022). Additionally, evidence indicated that probiotic therapy has a positive impact on defecation frequency, stool consistency, and constipation condition in adults and children (Chmielewska and Szajewska, 2010).
Mechanism of action of probiotics in improving the QoL of GI patients
Age, health conditions, and food choices play a significant role in shaping the microbiota composition. A previous study showed that the microorganisms found in individuals between the ages of 65 and 96 years are distinct from those in younger adults, showing elevated levels of cluster IV of
With regard to nutrition, the impact of eating on the microbiome has been thoroughly researched. A habitual long-term diet is strongly associated with enterotypes. Animal fat/protein is linked to enterotype 1, whereas carbohydrates are linked to enterotype 2. On the other hand, acute feeding with diets containing different fats and non-starch polysaccharides alters the human microbial phase, indicating that the manipulation of major dietary nutrients is responsible for most changes in microbiota (Faith et al., 2011; Wu et al., 2011). Some approaches for regulating GI flora, especially the use of probiotic organisms, have been sought as ways to promote health and, in some cases, treatment of diseases (Whelan and Quigley, 2013).
In addition, the gut microbiota is associated with many GI-related syndromes, including IBS. Hence, there is an increasing focus on controlling the microbiota as a treatment alternative. Since microbial flora is connected to the CNS via the cerebrointestinal axis, additional changes in this relationship have been identified as the mechanisms of IBS, which function in the intestines through central and peripheral pathways and microbial metabolites (Distrutti et al., 2004; Parkes et al., 2008; Bhattarai et al., 2017).
Limitations and future directions
This review has some limitations. First, there may be language bias as our search only used English sources. Second, the evidence level of the systematic review is restricted by included studies’ evidence level. Third, we did not exclude studies that used unreliable HRQOL tools. Finally, systematic studies on probiotic formulations did not find enough evidence to explain how each species in the combination works. In future studies, the effects of supplementation with different types of probiotics in combination and alone need to be studied to determine the exact mechanisms of each probiotic species.
This systematic review provides a new overview of how probiotic supplementation affects QoL in patients with GI diseases and outlines potential areas for future research. Based on our review of available clinical trial studies, we found that patients with GI diseases reported significant improvement in HRQOL after probiotic supplementation. However, more
ACKNOWLEDGEMENTS
We hereby acknowledge the student research committee of Kermanshah University of Medical Sciences for the financial support of this project.
FUNDING
This study was supported by Kermanshah University of Medical Science (No. 4020345).
AUTHOR DISCLOSURE STATEMENT
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
Concept and design: JM, AS. Analysis and interpretation: MAZ. Data collection: MAZ. Validation: YA, SM, SH. Writing the article: YA, JM, SM, SH. Critical revision of the article: YP, SM, FM. Statistical analysis: FM, YA. Obtained funding: FM, YA, SH, MAZ. Final approval of the article: all authors. Overall responsibility: AS.
Fig 1.

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Table 1 . IBS-related disease: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes El-Salhy et al., 2020 (Norway) RCT IBS 165 39.9±9.0 30 g FMT or 60 g FMT at a ratio of 1:1:1 The material for FMT FMT 3 months IBS-QoL Positive effect Catinean et al., 2019 (Romania) RCT IBS 90 18-75
G1=38.77±10.96
G2=39.07±16.00
G3=40.37±11.95G2=7 days: 1 cap
27 days: 2 capG1= Bifidobacterium longum W11
G2=fiveBacillus spp.34 days
G1 and G3=10+24
G2=34IBS-QoL (SF-36) Positive effect Preston et al., 2018 (USA) RCT IBS 86 Plac: 39.9
Int: 40.62 capsules
50×109 CFULactobacillus acidophilus CL1285,L. casei LBC80R, andL. rhamnosus CLR212 weeks IBS-QoL Positive effect Giannetti et al., 2017 (Italy) RCT Children with IBS and functional dyspepsia 73 8.0-17.9 3 billion (3×109) of Bifidobacterium longum BB536, 1 billion (1×109) ofB. infantis M-63, 1 billion (1×109) of B. breve M-16V3 Bifidobacteria :M-63breve M-16Vlongum BB53616 weeks:
2-week run-in phase
6 weeks Int
2-week “washout”
Afterward, each patient was switched to the other group
6 weeks IntFDI Positive effect Pinto-Sanchez et al., 2017 (Canada) RCT IBS 44 Int: 46.5 (30-58)
Plac: 40.0 (26-57)1.0E+10 Bifidobacterium longum NCC3001 (BL)6-week treatment
10 week follow-upSF-36 Positive effect Nobutani et al., 2017 (Japan) RCT IBS 30 Int: 52.6±20.1
Plac: 45.9±19.513×108 CFU Lactobacillus gasseri CP23054 weeks IBS-QoL and PSQI-J Positive effect Choi et al., 2015 (Korea) RCT Non-diarrheal-type IBS 285 20-73 (47) Group 1: 1.0×1010
CFU
Groups 2 and 3: 1.5×1010
Group 4: 3×1010Bacillus subtilis andStreptococcus faecium 4 weeks IBS-QoL Positive effect Abbas et al., 2014 (Pakistan) RCT IBS-D 72
64
(completed)18-60
Int:
37.7±11.6
Plac:
33.0±12.0750 mg/d Saccharomyces boulardii 2-week run-in
6 weeks IntIBS-QoL Positive effect Lorenzo-Zúñiga et al., 2014 (Spain) RCT IBS 73 20-70
Int: 47.5±13.1
46.3±11.6
Plac: 46.5±13.11-3×1010 CFU or 3-6×109 Two Lactobacillus plantarum (CECT7484 and CECT7485) and onePediococcus acidilactici (CECT7483)6 weeks IBS-QoL Positive effect Cappello et al., 2013 (Italy) RCT IBS 64 38.7±12.6 5×109 Lactobacillus plantarum , 2×109L. casei subp.rhamnosus and 2×109L. gasseri , 1×109Bifidobacterium infantis and 1×109B. longum , 1×109L. acidophilus , 1×109L. salivarius and 1×109L. sporogenes and 5×109Streptococcus thermophilus
Prebiotic inulin 2.2 gLyophilized bacteria: L. plantarumL. casei subp.rhamnosusL. gasseriBifidobacterium infantisL. acidophilusL. salivariusL. sporogenesStreptococcus thermophilus
Prebiotic inulin6 weeks
(2-week run-in and 4-week treatment)SF-36 Positive effect Choi et al., 2011 (Korea) RCT IBS 67 41±13 2×1011 Saccharomyces boulardii 4 weeks IBS-QoL Positive effect Drisko et al., 2006 (USA) Open-label pilot study
Prospective outcome studyIBS 20 24-81 10 billion CFU Lactobacillus acidophilus ,Bifidobacterium bifidum ,L. rhamnosus ,L. plantarum ,B. infantis ,L. salivarius ,L. bulgaricus ,L. casei ,L. brevis , andStreptococcus thermophilus 1 year IBS-QoL Positive effect RCT, randomized control trial; IBS, irritable bowel syndrome; FMT, fecal microbiota transplantation; QoL, quality of life; IBS-QoL, irritable bowel syndrome QoL; IBS-D, diarrhea-dominant irritable bowel syndrome; SF-36, 36-item short form survey; CFU, colony forming unit; FDI, Functional Disability Inventory; Int, intervention; Plac, placebo; PSQI-J, Pittsburgh Sleep Quality Index.
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Table 2 . Constipation-related disease: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age Daily dose Probiotic species Duration of intervention System Main outcomes Olgac et al., 2020 (Turkey) RCT Children with FC 49 4-16 years 1×108 CFU Lactobacillus reuteri DSM 17938 or lactulose4 weeks KINDLⓇ HRQOL Positive effect Kommers et al., 2019 (Brazil) RCT Female university students with intestinal constipation 63 20-40 years
Int: 27.15±5.52
Plac: 24.38±5.41109 CFU of each one Bifidobacterium lactis (BL04),B. bifidum (Bb-06),Lactobacillus acidophilus (La-14),L. casei (Lc-11),Lactococcus lactis (LL-23)45 days PAC-QoL Positive effect Xinias et al., 2018 (Greece) Non-randomized clinical trial Infants with FC 65 3-13 weeks
Int: 1.4±0.8
Plac: 1.7±0.9Not reported Bifidobacterium lactis BB121 month Not reported (parents completed a QoL) Positive effect Cudmore et al., 2017 (Ireland) RCT Chronic, FC 69 18-80 years 6×108 CFU twice daily Lactobacillus rhamnosus PXN 54 (NCIMB 30188),Bifidobacterium bifidum PXN 23 (NCIMB 30179),L. acidophilus PXN 35 (NCIMB 30184),L. plantarum PXN 47 (NCIMB 30187), andL. bulgaricus PXN 39 (NCIMB 30186)
Also psyllium and inulin4 weeks PAC-QoL Positive effect RCT, randomized control trial; FC, functional constipation; CFU, colony forming unit; QoL, quality of life; KINDLⓇ HRQOL, KINDLⓇ Health-Related QoL; PAC-QoL, Patient Assessment of Constipation QoL.
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Table 3 . Functional gastrointestinal disorders (FGIDs): characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention (weeks) System Main outcomes Ringel-Kulka et al., 2011 (USA) RCT Functional bowel disorders 60 18-65 Mean age Int: 36 Plac: 37 Twice a day (2×1011 CFU CFU/d) Lactobacillus acidophilus NCFM (L-NCFM) andBifidobacterium lactis Bi-07 (B-LBi07)8 IBS-QoL Positive effect RCT, randomized control trial; CFU, colony forming unit; IBS-QoL, irritable bowel syndrome-quality of life; Int, intervention; Plac, placebo.
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Table 4 . Colorectal cancer-related disease: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Radvar et al., 2020 (Iran) RCT Rectal cancer 38 Int: 57.58±12.78 Plac: 62.89±13.93 2 times a day 1×108 CFU/g Lactobacillus casei PXN 37,L. rhamnosus PXN 54,Streptococcus thermophilus 81 PXN 66,Bifidobacterium breve PXN 25,L. acidophilus PXN 35,B. longum PXN 30,L. bulgaricus PXN 39, FOS (fructooligosaccharide), magnesium stearate (source: mineral and vegetable), and vegetable capsule (hydroxypropyl methyl cellulose)6 weeks EORTC QLQ-C30 Positive effect Golkhalkhali et al., 2018 (Malaysia) RCT Colorectal cancer 140 <18 Two sachets daily 30 billion (CFUs) per sachet Lactobacillus acidophilus BCMCR 12130,L. casei BCMCR 12313,Lactobacillus lactis BCMCR 12451,Bifidobacterium bifidum BCMCR 02290,B. longum BCMCR 02120, andB. infantis BCMCR 021298 weeks EORTC QLQ-C30 Positive effect Lee et al., 2014 (Korea) RCT Colorectal cancer 60 56.18±8.86 Twice a day 2×109 CFU Lacidofil ( Lactobacillus rhamnosus R0011 andL. acidophilus R0052)12 weeks FACT Positive effect Ohigashi et al., 2011 (Japan) Questionnaire-based study Colorectal cancer 63 63±9 10 mg of Bacillus natto and 30 mg ofLactobacillus acidophilus B. natto andL. acidophilus 3 months SF-36 and EORTC QLQ-C30 Positive effect RCT, randomized control trial; Int, intervention; Plac, placebo; CFU, colony forming unit; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30; FACT, Functional Assessment of Cancer Therapy; SF-36, 36-item short form survey.
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Table 5 . Other diseases: characteristics of selected clinical trials included in the review
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Di Pierro et al., 2020 (Italy) Non-randomized clinical trial Non-celiac gluten sensitivity 30 Int: 46.87±17.06 Plac: 43.53±18.94 1 dose/day 1×109 CFU (1 billion) Bifidobacterium longum ES1 or GFD 3 months Document of scientific support to the protocol for the diagnosis and follow-up of celiac disease Positive effect Chen et al., 2016 (Taiwan) RCT Gastric bypass surgery 53 18-60 35.1±8.3 Twice daily A: 5×109 CFU (5 billion) B: 8×109 CFU (8 billion) A: 1 g Clostridium butyricum MIYAIRI B: 300 mgBifidobacterium longum BB5362 weeks mGIQL Positive effect Fujimori et al., 2009 (Japan) RCT Ulcerative colitis 83 Pro=36±16 Pre=37±13 Syn=35±10 2×109 CFU Bifidobacterium longum Also prebiotic (psyllium) and synbiotic4 weeks IBDQ Positive effect RCT, randomized control trial; Int, intervention; Plac, placebo; Pro, probiotics; Pre, prebiotics; Syn, symbiotic; CFU, colony forming unit; GFD, gluten-free diet; mGIQL, modified Gastrointestinal QoL Index; IBDQ, Inflammatory Bowel Disease Questionnaire.
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Table 6 . Characteristics of included studies that did not find any effect
Reference Type of study Clinical setting/population Sample size Age (year) Daily dose Probiotic species Duration of intervention System Main outcomes Francavilla et al., 2019 (Italy) RCT Patients with celiac disease and IBS 109 Age 18 years and above
Int: 43.3 (18.8-62.2)
Plac: 44.6 (19.3-63.4)5×109 CFU/sachet+5×109 CFU/sachet+10×109 CFU/sachet+10×109 CFU/sachet+10×109 CFU/sachet Lactobacillus casei LMG 101/37 P-17504 (5×109 CFU/sachet),L. plantarum CECT 4528 (5×109 CFU/sachet),Bifidobacterium animalis subsp.lactis Bi1 LMG P-17502 (10×109 CFU/sachet),B. breve Bbr8 LMG P-17501 (10×109 CFU/sachet),B. breve Bl10 LMG P-17500 (10×109 CFU/sachet)14 weeks IBS–QoL Without effect Aroniadis et al., 2019 (USA) RCT IBS 45 18-65
Int: 33 (27-48)
Plac: 42 (28-48)25 capsules perday
0.38 g minimallyProcessed donor whole stool per capsule 12 weeks IBS–QoL Without effect Šmid et al., 2016 (Slovenia–Croatia) RCT IBS 76 18-65 (1.8×107 CFU/g) and
(2.5×107 CFU/g)Lactobacillus acidophilus La-5Ⓡ (1.8×107 CFU/g) andBifidobacterium animalis ssp.lactis BB-12Ⓡ (2.5×107 CFU/g)Streptococcus thermophilus 4 weeks IBS–QoL Without effect Dapoigny et al., 2012 (France) Randomized double-blind pilot study IBS 47 Int: 46.1±11.3
Plac: 48.0±10.86×108 CFU Lactobacillus casei varietyrhamnosus LCR354 weeks GIQLI Without effect Riezzo et al., 2019 (Italy) RCT FC 56 19-65
42.4±13.815 days: four tablets daily
Then: two tablets daily
One tablet=1×108 CFULactobacillus reuteri (LR) DSM 17938105 days PAC–QoL Without effect Dimidi et al., 2019 (UK) RCT Constipation 75 18-65
Int: 35 (12)
Plac: 31 (10)1.5×1010 CFU/day Bifidobacterium lactis NCC28184 weeks PAC–QoL Without effect Ibarra et al., 2018 (France) RCT Adults with functional constipation 224 18-70 1×109 or 1×1010 CFU Bifidobacterium animalis subsp.lactis HN01928 days PAC-QoL Without effect Ding et al., 2016 (China) RCT (prospective) Slow transit constipation 93 Plac: 48.3±11.3
Int: 47.2±10.70.63 g Bifid triple viable capsules (BIFICO) and 8 g of soluble dietary fiber 12 weeks GIQLI Positive effect Gomi et al., 2018 (Japan) RCT Patients with functional GI disorders 79 20-64
Int: 41.1±10.1
Plac: 41.6±9.9YIT 10347=3×107 CFU/mL Streptococcus thermophilus YIT 2021=1×107Bifidobacterium bifidum YIT 10347Streptococcus thermophilus YIT 2021 (in both Plac and Int groups)4 weeks SF-36 v2 Without effect Theodoropoulos et al., 2016 (Netherlands) RCT Colectomy for cancer 67 Int: 66.8±2.17
Plac: 69±1.37Sachets
12 gPediococcus pentosaceus 5-33:3,Leuconostoc mesenteroides 32-77:1,Lactobacillus paracasei ssp.paracasei 19, andL. plantarum 2362 and 2.5 g of each of the four fermentable fibers (prebiotics): b-glucan, inulin, pectin, and resistant starch15 days GIQLI and EORTC QLQ-C30 Without effect Macnaughtan et al., 2020 (UK) RCT Cirrhosis 92 (68) 18-78 6.5×109 CFU Lactobacillus casei Shirota (LcS)3 times per day for 6 months SF-36 Without effect Ahmadipour et al., 2020 (Iran) RCT Infant colic 72 21-90 days old
Int: 52.20±41.885 days
Plac: 49.36±23.321 days5 drops of Pedilact
109 CFULactobacillus rhamnosus ,L. reuteri ,Bifidobacterium infantis probiotics and fructooligosaccharide28 days Not reported Without effect RCT, randomized control trial; IBS, irritable bowel syndrome; FC, functional constipation; Int, intervention; Plac, placebo; CFU, colony forming unit; IBS-QoL, irritable bowel syndrome QoL; GIQLI, Gastrointestinal Quality of Life Index; PAC-QoL, Patient Assessment of Constipation QoL; SF-36, 36-item short form survey; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30.
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Table 7 . Assessment of risk of bias for randomized and cross-over clinical trials using the Cochrane Risk of Bias 2 tool
Reference Risk domain Bias arising from the randomization process Bias because of deviations from the intended intervention Missing outcome data Bias in outcome measurement Bias in the selection of reported results Overall risk of bias Fujimori et al., 2009 Low High High Low Some concerns High Chen et al., 2016 Some concerns Low High Low Some concerns High Ahmadipour et al., 2020 Some concerns Low Low Low Low Some concerns Macnaughtan et al., 2020 Low Low Low Low Low Low Lee et al., 2014 Low Low High Low Low High Theodoropoulos et al., 2016 Low Low Low Low Low Low Golkhalkhali et al., 2018 Low Low Low Low Low Low Radvar et al., 2020 Low Low Low Low Low Low Ringel-Kulka et al., 2011 Low Low Low Low Low Low Gomi et al., 2018 Low Low Low Low Low Low Ding et al., 2016 Low Low Some concerns Low Low Some concerns Cudmore et al., 2017 Low Low Low Low Low Low Ibarra et al., 2018 Low Low High Low Low High Dimidi et al., 2019 Low Low Low Low Low Low Kommers et al., 2019 Low Low High Low Low High Riezzo et al., 2019 Some concerns Some concerns Some concerns Low Low Some concerns Olgac et al., 2020 Some concerns High Some concerns Low Some concerns High Choi et al., 2011 Low Low High Low Low High Dapoigny et al., 2012 Low Low Some concerns Low Some concerns Some concerns Cappello et al., 2013 Low Low Some concerns Low Some concerns Some concerns Lorenzo-Zúñiga et al., 2014 Low Low Some concerns Low Some concerns Some concerns Abbas et al., 2014 Low Low Some concerns Low Some concerns Some concerns Choi et al., 2015 Low Low Low Low Low Low Šmid et al., 2016 Low Low Low Low Low Low Nobutani et al., 2017 Some concerns Some concerns Low Low Some concerns Some concerns Pinto-Sanchez et al., 2017 Low Low Low Low Low Low Giannetti et al., 2017 Low Low Low Low Low Low Preston et al., 2018 Some concerns Low Low Low Low Some concerns Aroniadis et al., 2019 Low Low High Low Low High Francavilla et al., 2019 Low Low Low Low Low Low Catinean et al., 2019 Some concerns Some concerns Low Low Some concerns Some concerns El-Salhy et al., 2020 Low Low Low Low Low Low
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Table 8 . Assessment of risk of bias for non-randomized clinical trials using the Cochrane Risk of Bias 2 tool
Reference Risk domain Bias because of confounding Bias because of the selection of participants Bias in the classification of intervention Bias because of deviations from the intended intervention Bias because of missing outcome data Bias in outcome measurement Bias in the selection of reported results Overall risk of bias Drisko et al., 2006 High Low Some concerns Low Some concerns Low Low High Xinias et al., 2018 High Low Low Low Low Low Low High Ohigashi et al., 2011 High Low Some concerns Low Some concerns Low Some concerns High Di Pierro et al., 2020 High Low Low Low Low Low Low High
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Table 9 . Genus and species of probiotic supplementation in the included studies
1)
Lactobacillus andBifidobacterium were the most common genera of probiotics that were used to study the effects of probiotic supplementation in clinical gastrointestinal investigations.-, not available.
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Table 10 . Notable outcomes of selected RCT studies assessing the effects of probiotics on GI diseases
Reference Gut microbiota assessment Outcomes of GI symptoms Macnaughtan et al., 2020, UK - - Giannetti et al., 2017, Italy - In IBS, Bifidobacteria supplementation resulted in a complete resolution of abdominal pain in a significantly higher proportion of childrenCappello et al., 2013
Italy (Rome)- - Cudmore et al., 2017, Ireland - Symptoms of constipation improved Fujimori et al., 2009, Japan - Emotional function increased in the probiotic and synbiotic groups Gomi et al., 2018, Japan - The YIT10347 group had significantly higher relief rates of overall gastrointestinal symptoms, upper gastrointestinal symptoms, flatus, and diarrhea than the placebo group Francavilla et al., 2019, Italy ·Using plate counts and 16S rRNA gene-based analysis
·Fecal samples (5 g) were mixed with 45 mL of sterilized physiological solution and homogenized. Viable bacterial cells were counted as described by De Angelis et al.
·To determine the identities of bacteria, sequences were first queried using a distributed BLASTn.NET algorithm24 against 16S bacterial sequences derived from NCBI.- Radvar et al., 2020, Iran - Body weight decreased in the synbiotic and placebo groups Aroniadis et al., 2019, USA 16S rRNA sequencing - Chen et al., 2016, Taiwan - Complaints of abdominal pain, abdominal bloating, excessive passage of gas, foul smell of flatulence, belching, abdominal noises, and heartburn were significantly improved in the entire sample Dapoigny et al., 2012, France Extraction of total bacterial DNA (QIAamp Fast DNA Stool Mini Kit, QIAGEN), the presence of Lactobacillus casei varietyrhamnosus was specifically determined by qualitative polymerase chain reaction (PCR - primer pairs hyb-21) – cycles of amplification.A decrease in the abdominal pain severity score was observed with LCR35 Choi et al., 2015, Korea - The abdominal pain/discomfort score in treatment group 4 was more prominently improved compared with that of the placebo group
In patients with constipation-predominant IBS, the improvements in stool frequency and consistency were significantly higher in treatment groups 4 and 1, respectively, than those in the placebo group
There were more favorable tendencies of effects on bloating in all treatment groups than in the placebo groupEl-Salhy et al., 2020, Norway 16S rRNA gene sequencing - Ding et al., 2016, China - During the intervention period, patients who were treated with the synbiotic exhibited increased stool frequency, improved stool consistency, decreased colonic transit time, and improved constipation-related symptoms Ohigashi et al., 2011, Japan - Defecation frequency, anal pain, and Wexner score were significantly poorer in the rectal group than in the colonic group Ringel-Kulka et al., 2011, USA Quantitative real-time polymerase chain reaction of fecal samples Abdominal bloating improved in the probiotic group compared with the placebo group at 4 and 8 weeks Dimidi et al., 2019, UK Quantitative polymerase chain reaction - Šmid et al., 2016, Slovenia & Croatia - Significant improvements in bloating severity, satisfaction with bowel movements Golkhalkhali et al., 2018, Malaysia - Nausea, vomiting, and diarrhea significantly improved in the treatment group Theodoropoulos et al., 2016, Netherlands - Differences in the EORTC QLQ-C30 “diarrhea” domain score from baseline were better after synbiotic administration after 3 ( P =0.04) and 6 months (P =0.003)Nobutani et al., 2017, Japan ·Purified DNA was used as a template for the following two-step polymerase chain reaction.
·Fecal microbiota was measured using fecal bacterial 16S rDNA V4-V6 region-targeted pyrosequencing.CP2305 favorably changed the fecal characteristics compared with placebo among patients with IBS with either diarrhea or constipation subtypes Drisko et al., 2006, USA - Significant improvements in pain were observed ( P =0.05)RCT, randomized controlled trial; GI, gastrointestinal; IBS, irritable bowel syndrome; NCBI, National Center for Biotechnology Information; QoL, quality of life; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer’s 30-item QoL questionnaire version 30; -, not available.
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