1.
The Role of Genetically Engineered Probiotics for Treatment of Inflammatory Bowel Disease: A Systematic Review.
Zhang, T, Zhang, J, Duan, L
Nutrients. 2023;15(7)
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Plain language summary
Inflammatory bowel disease (IBD), largely classified as Crohn’s disease (CD) or ulcerative colitis (UC), is a chronic intestinal inflammatory disorder mediated by genetic, immune, microbial, and environmental factors. The aim of this study was to summarise the efficacy of different genetically modified probiotics compared to wild-type probiotics in the treatment of IBD in animal models and patients and to investigate the specific effects and main mechanisms involved. This study was a systematic review of forty-five preclinical studies and one clinical study. Results showed a protective effect of genetically modified organisms (gm) probiotics in colitis. Several protective mechanisms have been identified: reduction of the pro- to anti-inflammatory cytokine ratio in colonic tissue and plasma, modulation of the activity of oxidative stress in the colon, improvement of intestinal barrier integrity, modulation of the diversity and composition of gut microbiota, and production of favourable metabolites, including short-chain fatty acids, by beneficial bacteria. Authors concluded that gm probiotics are more effective and safer than wild-type probiotics, to facilitate clinical translation.
Expert Review
Conflicts of interest:
None
Take Home Message:
Conclusions of this review were largely based on mouse models and although treatment using probiotics is generally considered safe in humans, with only minor side-effects (flatulence), practitioners need to be aware that in an IBD population the use of GM formulations might not be completely without risk.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This paper summarises the efficacy of specific genetically modified (GM) probiotic formulations for Inflammatory Bowel Disease (IBD) when compared to wild type probiotics. The aim was to ascertain what specific effects and mechanisms such probiotics have on IBD symptomatology.
Methods
- A total of 46 published articles were included; 45 mouse experimental models (induced acute or chronic colitis) (n=15-130) and 1 human IBD population clinical trial (n=10)
- The effect of GM probiotics were compared to placebo and wild-type probiotics in trials including preclinical studies, randomised controlled trials and cohort studies
- Animals received probiotics via gastric gavage (105 - 4 x 1012 CFU) for 3-6 weeks
- The human placebo-uncontrolled trial lasted 7 days and patients received 10 GM capsules of L.lactis (1 x 1010 CFU) twice daily.
Results
- GM probiotics that secrete immunoregulatory cytokines such as IL-10 appear to reduce intestinal damage
- The human trial using GM L.lactis resulted in 5 patients who went into complete clinical remission (CDAI, <150) with 3 patients exhibiting a clinical response (decrease in CDAI, >70). with only minor adverse events (flatulence)
- However, human cytokines that promote intestinal barrier function and epithelial restitution were not enhanced with oral administration of probiotics
- Two studies concluded that GM L.lactis and S.boulardii, that secrete atrial natriuretic peptide, might be the most effective options in supporting colitis
- GM L.casei resulted in faster recovery from weight loss in acute colitis models
- Superoxide dismutase (SOD) producing GM L.fermentum increased SOD activity by almost eightfold compared to the wild type
- GM Lact. fermentum furthermore showed a higher survival rate and lower disease activity index (P <0·05) in colitis models
- GM L.lactis improved gut microbial composition and GM S.cerevisiae improved microbial diversity whilst reducing the Firmicutes to Bacteroides ratio
- GM E.coli significantly reduced weight loss, colon shortening plus lower disease activity and histological changes (P < 0.05).
Conclusion
Despite the heterogeneity of the trials, GM probiotics appear to play a notable part in ameliorating IBD symptomatology and disease severity when compared to wild-type probiotics. Human efficacy and potential adverse effects require more in-depth trials to ascertain safety and optimal dosages.
Clinical practice applications:
- Probiotics species used in the trials included S.thermophilus, E.coli, L.lactis, B.ovatus, S.boulardii, L.fermentum, B.longhum, L.casei, L.plantarum, and S.cerevisiae. Wild-types of some of these are already available to use in clinical practice
- Note that oral administration in the human trial showed no significant health outcome, therefore efficacy and safety need to be ascertained on an individual patient level
- Colonisation of beneficial bacteria in the gut of IBD patients might be difficult and any form of supplementation therefore needs to be closely monitored.
Considerations for future research:
- More evidence is needed to demonstrate that GM probiotic formulations result in significantly improved outcomes when compared to wild-types
- Future randomised placebo-controlled trials need to include larger cohorts to determine supplement efficacy
- Longer periods of intervention are needed to confirm efficacy, safety, and tolerance for both Crohn’s Disease and Colitis
- Optimal GM probiotic formulation, doses, and means of application need to be identified.
Abstract
BACKGROUND Many preclinical studies have demonstrated the effectiveness of genetically modified probiotics (gm probiotics) in animal models of inflammatory bowel disease (IBD). OBJECTIVE This systematic review was performed to investigate the role of gm probiotics in treating IBD and to clarify the involved mechanisms. METHODS PubMed, Web of Science, Cochrane Library, and Medline were searched from their inception to 18 September 2022 to identify preclinical and clinical studies exploring the efficacy of gm probiotics in IBD animal models or IBD patients. Two independent researchers extracted data from the included studies, and the data were pooled by the type of study; that is, preclinical or clinical. RESULTS Forty-five preclinical studies were included. In these studies, sodium dextran sulfate and trinitrobenzene sulfonic acid were used to induce colitis. Eleven probiotic species have been genetically modified to produce therapeutic substances, including IL-10, antimicrobial peptides, antioxidant enzymes, and short-chain fatty acids, with potential therapeutic properties against colitis. The results showed generally positive effects of gm probiotics in reducing disease activity and ameliorating intestinal damage in IBD models; however, the efficacy of gm probiotics compared to that of wild-type probiotics in many studies was unclear. The main mechanisms identified include modulation of the diversity and composition of the gut microbiota, production of regulatory metabolites by beneficial bacteria, reduction of the pro- to anti-inflammatory cytokine ratio in colonic tissue and plasma, modulation of oxidative stress activity in the colon, and improvement of intestinal barrier integrity. Moreover, only one clinical trial with 10 patients with Crohn's disease was included, which showed that L. lactis producing IL-10 was safe, and a decrease in disease activity was observed in these patients. CONCLUSIONS Gm probiotics have a certain efficacy in colitis models through several mechanisms. However, given the scarcity of clinical trials, it is important for researchers to pay more attention to gm probiotics that are more effective and safer than wild-type probiotics to facilitate further clinical translation.
2.
Comparative analysis of the efficacies of probiotic supplementation and glucose-lowering drugs for the treatment of type 2 diabetes: A systematic review and meta-analysis.
Liang, T, Xie, X, Wu, L, Li, L, Yang, L, Gao, H, Deng, Z, Zhang, X, Chen, X, Zhang, J, et al
Frontiers in nutrition. 2022;9:825897
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Type 2 diabetes (T2D) is a serious medical condition often requiring antidiabetic drug management. Although commonly used antidiabetic drugs effectively control glucose levels, their tolerability profiles differ, causing various side effects. Probiotics can be used as single or multi strains to reduce glycaemic and lipid indicators and avoid the negative effects of antidiabetic medications. The study included twenty-five randomised controlled trials, of which fourteen studies assessed the effectiveness of probiotics (single probiotics, multi-strain probiotics, and probiotics with co-supplements), and eleven studies included different antidiabetic drugs such as Thiazolidinedione (TZD), Glucagon-like peptide-1 receptor agonists (GLP-1 RA), Dipeptidyl peptidase IV inhibitors (DPP-4i), and Sodium-glucose co-transporter 2 inhibitors (SGLT-2i). This systematic review and meta-analysis compared the effectiveness of probiotic and antidiabetic drugs on glycaemia, lipid profile and blood pressure in T2D patients. Probiotics were less effective than specific antidiabetic drugs in reducing fasting blood sugar levels (FBS), HbA1c levels, and triglycerides. Different probiotic formulations were effective in reducing the HOMA-IR index, total cholesterol (TC), triglycerides (TG), and systolic and diastolic pressure (SBP and DBP). A subgroup analysis showed a greater reduction in FBS, HbA1c, TC, TG, and SBP in obese and elderly participants, those who participated for a longer duration, and those from Eastern origins. Considering the high heterogeneity in baseline study characteristics among the studies included in this systematic review and meta-analysis, further studies are required to evaluate the effects of probiotics and antidiabetic drugs. However, healthcare professionals can use the study to understand the effect of probiotics and antidiabetic drugs in reducing glycaemic, lipid and hypertension profiles.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Glucose-lowering drugs, except for DPP-4i, reduced FBS and HbA1c more than probiotics; and SGLT-2i induced the greatest decrease in HbA1c
- A BMI ≥ 30 kg/m2 showed a significant decrease in FBS and the HOMA-IR index compared with those with lower BMI
- Weight loss induced by glucose-lowering drugs and probiotic supplementation plays an important role in glycaemic control in obese patients with type 2 diabetes.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This meta-analysis compared the effects of probiotics and glucose-lowering drugs thiazolidinedione [TZD], glucagon-like pep-tide-1 receptor agonists [GLP-1 RA], dipeptidyl peptidase IV inhibitors, and sodium glucose co-transporter 2 inhibitors [SGLT-2i]) on various outcome measures in patients with type 2 diabetes (T2D).
Methods
A search was performed on PubMed, Web of science, Embase, and Cochrane Library between January 2015 - April 2021.
Results
25 randomised controlled trials (RCT) were included (2843 participants). 14 RCTs (842 participants) involved the administration of single probiotics, multi-strain probiotics, and probiotics with co-supplements, and 11 RCTs (2001 participants) involved TZD, GLP-1 RA, SGLT-2i, and DPP-4i. Participants in 7 of the studies had T2D, aged ≤ 55 years old. 8 RCTs included participants with a mean BMI ≥ 30 kg/m2, and 11 RCTs participants had a mean BMI < 30 kg/m2.
Effects of probiotics:
- Fasting Blood Sugar (FBS): A reduction (−1.42, −0.32 mg/dL, p=0.000)
- Glycated hemaglobin (HbA1c): No reduction (p = 0.000)
- Insulin Resistance (HOMA-IR): A decrease (−0.64, −0.31; p = 0.780), regardless of probiotic strain or with a co-supplement
- Insulin: Not significant (p = 0.000). Subgroup analysis: no reduction
- Total Cholesterol (TC): No difference (p = 0.941). Subgroup analysis: reduction from multi-species probiotics (−0.36, −0.01 mg/dL, p = 0.871)
- Triglycerides: Difference (−0.25 mg/dL, p = 0.958)
- LDL-C: No changes (p = 0.189)
- HDL-C: No increase (p = 0.014)
- Systolic Blood Pressure (SBP): A decrease (−6.44, −0.08 mmHg, p = 0.044)
- Diastolic Blood Pressure (DBP): A reduction (−4.53, −0.80 mmHg, p = 0.206).
Effects of glucose-lowering drugs:
- FBS: A decrease (−4.22 mg/dL, −1.24 mg/dL, p = 0.000)
- HbA1c: A decrease (−2.51%, −0.52%, p = 0.000) with TZD, GLP-1 RA, SGLT-2i, and DPP- 4i; a reduction with SGLT-2i (p = 0.003)
- TC: No difference (p = 0.000). Subgroup: no decrease with single species probiotics and probiotics with co-supplements, TZD, GLP-1 RA, and DPP-4i)
- TG: No difference (p = 0.000)
- . HDL-C: No increase (p = 0.000). Subgroup: a decrease with TZDs (−2.37, −0.72 mg/dL). No difference with probiotic strains, or probiotics with co-supplements, GLP-1 RA, and DPP-4i
- LDL-C: No changes (p = 0.000), Subgroups: no difference with probiotic strains, probiotics with co-supplements, TZD, GLP-1 RA, and DPP-4i).
Limitations
Limited number of studies for TZD and SGLT-2i, making results potentially unreliable.
Conclusions
Multi species probiotics are worth considering as an adjunct to glucose-lowering drugs, and for improving lipid profiles and hypertension.
Clinical practice applications:
- Probiotic supplementation reduced the HOMA-IR index
- Multi-species probiotics were associated with reduction in TC and TG levels
- DPP-4i only decreased TG levels
- TZD was associated with decrease in HDL-C, whereas probiotic supplementation was associated with higher decrease in SBP and DBP and that GLP-1 RA increases the risk of hypoglycaemia.
Considerations for future research:
- Semaglutide was associated with an increased risk for hypoglycaemia compared with a placebo, indicating that the safety of semaglutide needs further study
- Dietary and physical activity should be considered in future studies
- Heterogeneity in some indicators may be due to differences in study baseline characteristics,Larger trials needed to support the results of this meta-analysis.
Abstract
The aim of this systematic review and meta-analysis was to evaluate the effects of probiotics and glucose-lowering drugs (thiazolidinedione [TZD], glucagon-like pep-tide-1 receptor agonists [GLP-1 RA], dipeptidyl peptidase IV inhibitors, and sodium glucose co-transporter 2 inhibitors [SGLT-2i]) in patients with type 2 diabetes from randomized con-trolled trials (RCTs). The PubMed, Web of science, Embase, and Cochrane Library databases were searched on the treatment effects of probiotics and glucose-lowering drugs on glycemia, lipids, and blood pressure metabolism published between Jan 2015 and April 2021. We performed meta-analyses using the random-effects model. We included 25 RCTs (2,843 participants). Overall, GLP-1RA, SGLT-2i, and TZD significantly reduce fasting blood sugar (FBS) and glycated hemoglobin (HbA1c), whereas GLP-1 RA increased the risk of hypoglycaemia. Multispecies probiotics decrease FBS, total cholesterol (TC), and systolic and diastolic blood pressure (SBP, DBP). Moreover, subgroup analyses indicated that participants aged >55 years, BMI ≥30 kg/m2, longer duration of intervention, and subjects from Eastern countries, showed significantly higher reduction in FBS and HbA1c, TC, TG and SBP. This meta-analysis revealed that including multiple probiotic rather than glucose-lowering drugs might be more beneficial regarding T2D prevention who suffering from simultaneously hyperglycemia, hypercholesterolemia, and hypertension.
3.
Probiotics for the Treatment of Atopic Dermatitis in Children: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Huang, R, Ning, H, Shen, M, Li, J, Zhang, J, Chen, X
Frontiers in cellular and infection microbiology. 2017;7:392
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It is estimated that atopic dermatitis (AD) affects around 10-20% of children. This systematic review and meta-analysis evaluates the evidence for using probiotics for the treatment of AD in children. 13 randomised controlled trials (RCT) were included in the review, all but one were of a double-blind design. They included a total of 1070 children, 553 receiving probiotics and 517 controls. Overall, a beneficial effect of probiotics in AD was observed. Subgroup analysis showed a) positive results in children aged 1-18 years, but probiotics being ineffective in infants younger than 1 year; b) probiotics reduced AD in Asian, but not European studies, and c) certain strains proved beneficial (Lactobacillus salivarius, Lactobacillus fermentum and a multi-strain probiotic), whilst Lactobacillus rhamnosus GG and Lactobacillus plantarum showed no effect. The authors discuss that their meta-analysis is limited by the heterogeneity among the trials and inclusion of studies with small sample sizes. They conclude that probiotics may be of benefit in children with AD but that more adequately powered trials assessing specific probiotics and dosages are needed, to inform the best treatment protocols.
Abstract
Objective: Atopic dermatitis (AD) is a prevalent, burdensome, and psychologically important pediatric concern. Probiotics have been suggested as a treatment for AD. Some reports have explored this topic; however, the utility of probiotics for AD remains to be firmly established. Methods: To assess the effects of probiotics on AD in children, the PubMed/Medline, Cochrane Library Scopus, and OVID databases were searched for reports published in the English language. Results: Thirteen studies were identified. Significantly higher SCORAD values favoring probiotics over controls were observed (mean difference [MD], -3.07; 95% confidence interval [CI], -6.12 to -0.03; P < 0.001). The reported efficacy of probiotics in children < 1 year old was -1.03 (95%CI, -7.05 to 4.99) and that in children 1-18 years old was -4.50 (95%CI, -7.45 to -1.54; P < 0.001). Subgroup analyses showed that in Europe, SCORAD revealed no effect of probiotics, whereas significantly lower SCORAD values were reported in Asia (MD, -5.39; 95%CI, -8.91 to -1.87). Lactobacillus rhamnosus GG (MD, 3.29; 95%CI, -0.30 to 6.88; P = 0.07) and Lactobacillus plantarum (MD, -0.70; 95%CI, -2.30 to 0.90; P = 0.39) showed no significant effect on SCORAD values in children with AD. However, Lactobacillus fermentum (MD, -11.42; 95%CI, -13.81 to -9.04), Lactobacillus salivarius (MD, -7.21; 95%CI, -9.63 to -4.78), and a mixture of different strains (MD, -3.52; 95%CI, -5.61 to -1.44) showed significant effects on SCORAD values in children with AD. Conclusions: Our meta-analysis indicated that the research to date has not robustly shown that probiotics are beneficial for children with AD. However, caution is needed when generalizing our results, as the populations evaluated were heterogeneous. Randomized controlled trials with larger samples and greater power are necessary to identify the species, dose, and treatment duration of probiotics that are most efficacious for treating AD in children.