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The role of the microbiota-gut-brain axis in neuropsychiatric disorders.
Generoso, JS, Giridharan, VV, Lee, J, Macedo, D, Barichello, T
Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2021;43(3):293-305
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Metabolites produced by the gut microbiota have been shown to influence mood and behaviour via the microbiota-gut-brain axis, and there is increased interest in better understanding this interaction in the context of mental health. This review summarises the evidence around the influence of gut microbiota in various neuropsychiatric disorders, primarily focusing on the metabolic pathways that originate in the gut microbiota. Current research highlights an association between gut microbiota metabolites with neuropsychiatric disorders and that probiotics demonstrate a significant therapeutic role in many of these disorders. Based on the current literature, the authors conclude it is crucial to better understand the complex microbiota-host interaction in health and disease, leading to more targeted and improved therapeutic interventions.
Abstract
The microbiota-gut-brain axis is a bidirectional signaling mechanism between the gastrointestinal tract and the central nervous system. The complexity of the intestinal ecosystem is extraordinary; it comprises more than 100 trillion microbial cells that inhabit the small and large intestine, and this interaction between microbiota and intestinal epithelium can cause physiological changes in the brain and influence mood and behavior. Currently, there has been an emphasis on how such interactions affect mental health. Evidence indicates that intestinal microbiota are involved in neurological and psychiatric disorders. This review covers evidence for the influence of gut microbiota on the brain and behavior in Alzheimer disease, dementia, anxiety, autism spectrum disorder, bipolar disorder, major depressive disorder, Parkinson's disease, and schizophrenia. The primary focus is on the pathways involved in intestinal metabolites of microbial origin, including short-chain fatty acids, tryptophan metabolites, and bacterial components that can activate the host's immune system. We also list clinical evidence regarding prebiotics, probiotics, and fecal microbiota transplantation as adjuvant therapies for neuropsychiatric disorders.
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Gut Microbiota and Pathophysiology of Depressive Disorder.
Kunugi, H
Annals of nutrition & metabolism. 2021;77 Suppl 2:11-20
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Bidirectional communication between the brain and gastrointestinal tract has been established and evidence suggests the microbiota-gut-brain axis may play a role in many psychiatric diseases, including major depression disorder (MDD). Although there is currently no established biochemical marker used in the clinical setting, recent findings have identified four potential mechanisms underlying MDD. The aim of this review is to outline these mechanisms and summarise the current evidence related to the pathophysiology of MDD. The literature suggests the gut microbiota impacts each of the potential mechanisms in the pathophysiology of MDD, and recent clinical trials on probiotics indicate beneficial effects on depression symptoms. Based on these results, the author concludes that practices leading to a healthier gut microbiota may aid in the reduction of depression symptoms. Future research on the microbiota-gut-brain axis in MDD is a promising avenue for better understanding the pathophysiology of disease and developing improved treatments for MDD.
Abstract
BACKGROUND Accumulating evidence has suggested that the bi-directional communication pathway, the microbiota-gut-brain axis, plays an important role in the pathophysiology of many neuropsychiatric diseases including major depressive disorder (MDD). This review outlines current evidence and promising findings related to the pathophysiology and treatment of MDD. SUMMARY There are at least 4 key biological molecules/systems underlying the pathophysiology of MDD: central dopamine, stress responses by the hypothalamic-pituitary-adrenal axis and autonomic nervous system, inflammation, and brain-derived neurotrophic factor. Animal experiments in several depression models have clearly indicated that gut microbiota is closely related to these molecules/systems and administration of probiotics and prebitotics may have beneficial effects on them. Although the results of microbiota profile of MDD patients varied from a study to another, multiple studies reported that bacteria which produce short-chain fatty acids such as butyrate and those protective against metabolic diseases (e.g., Bacteroidetes) were reduced. Clinical trials of probiotics have emerged, and the majority of the studies have reported beneficial effects on depression symptoms and related biological markers. Key Messages: The accumulating evidence suggests that research on the microbiota-gut-brain axis in major depressive disorder (MDD) is promising to elucidate the pathophysiology and to develop novel treatment of MDD, although there is still a long distance yet to reach the goals.
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Mining microbes for mental health: Determining the role of microbial metabolic pathways in human brain health and disease.
Spichak, S, Bastiaanssen, TFS, Berding, K, Vlckova, K, Clarke, G, Dinan, TG, Cryan, JF
Neuroscience and biobehavioral reviews. 2021;125:698-761
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The microbiota-gut-brain axis is an emerging area of focus for mental health and disease. Metabolic products from gut microbiota exert direct and indirect effects on the brain through various body systems. The aim of this study was to review the evidence on these metabolic pathways and utilise new predictive tools to assess metabolic signatures of various disease states. This review included 278 studies and, despite the weak evidence, identified new links between gut microbial metabolic pathways in schizophrenia, Alzheimer’s disease, and anxiety and depression. The authors conclude this review provides a novel approach for understanding the mechanisms behind the bidirectional communication between the gut and brain. They also suggest guidelines for analysing and interpreting metadata of human-microbiome-brain studies and provide a framework for better understanding these metabolic pathways in relation to the brain.
Abstract
There is increasing knowledge regarding the role of the microbiome in modulating the brain and behaviour. Indeed, the actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids, tryptophan, and bile acid metabolites/pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour. With the identification of neuroactive gut-brain modules, new predictive tools can be applied to existing datasets. We identified 278 studies relating to the human microbiota-gut-brain axis which included sequencing data. This spanned across psychiatric and neurological disorders with a small number also focused on normal behavioural development. With a consistent bioinformatics pipeline, thirty-five of these datasets were reanalysed from publicly available raw sequencing files and the remainder summarised and collated. Among the reanalysed studies, we uncovered evidence of disease-related alterations in microbial metabolic pathways in Alzheimer's Disease, schizophrenia, anxiety and depression. Amongst studies that could not be reanalysed, many sequencing and technical limitations hindered the discovery of specific biomarkers of microbes or metabolites conserved across studies. Future studies are warranted to confirm our findings. We also propose guidelines for future human microbiome analysis to increase reproducibility and consistency within the field.
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Altered Composition of Gut Microbiota in Depression: A Systematic Review.
Barandouzi, ZA, Starkweather, AR, Henderson, WA, Gyamfi, A, Cong, XS
Frontiers in psychiatry. 2020;11:541
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The brain-gut microbiome axis has emerged to be a link between gut microbiota pattern and depression, however the mechanism by which gut microbiota modulate depression-like behaviors remains inconclusive. While studies have observed differences in the diversity and abundance of different bacteria taxa, no definitive classifications have been confirmed. The aim of this systematic review was to identify gut microbiota patterns in people with depression compared with healthy controls. According to the nine articles included in this review, conflicting results were found on characteristics of gut microbiota in people with depression compared to healthy controls. Based on these findings, the authors conclude the role of the microbiota in the development or maintenance of depression remains limited, suggesting the likelihood of confounding factors. Further research is recommended to better understand the relationship between gut microbiota pattern and treatment outcomes for people with depression.
Abstract
Cumulative evidence shows a linkage between gut microbiota pattern and depression through the brain-gut microbiome axis. The aim of this systematic review was to identify the alterations of the gut microbiota patterns in people with depression compared to healthy controls. A comprehensive literature search of human studies, published between January 2000 and June 2019, was reviewed. The key words included gastrointestinal microbiome, gut microbiome, microbiota, depression, depressive symptoms, and depressive disorder. The systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Nine articles met the eligibility criteria. Disparities in α-diversity and β-diversity of the microbiota existed in people with depression compared to healthy controls. At the phylum level, there were inconsistencies in the abundance of Firmicutes, Bacteroidetes, and Proteobacteria. However, high abundance in Actinobacteria and Fusobacteria phyla were observed in people with depression. On the family level, high abundance of Actinomycineae, Coriobacterineae, Bifidobacteriaceae, Clostridiales incertae sedis XI, Porphyromonadaceae, Clostridiaceae, Lactobacillaceae, Streptococcaceae, Eubacteriaceae, Thermoanaerobacteriaceae, Fusobacteriaceae, Nocardiaceae, Streptomycetaceae, and low abundance of Veillonellaceae, Prevotellaceae, Bacteroidaceae, Sutterellaceae, Oscillospiraceae, Marniabilaceae, and Chitinophagaceae were observed in people with depression. On the genus level, high abundance of Oscillibacter, Blautia, Holdemania, Clostridium XIX, Anaerostipes, Anaerofilum, Streptococcus, Gelria, Turicibacter, Parabacteroides, Eggerthella, Klebsiella, Paraprevotella, Veillonella, Clostridium IV, Erysipelotrichaceae incertae sedis, Eubacterium, Parvimonas, Desulfovibrio, Parasutterella, Actinomyces, Asaccharobacter, Atopobium, Olsenella and low abundance of Coprococcus, Lactobacillus, Escherichia/Shigella, Clostridium XlVa, Dialister, Howardella, Pyramidobacter, and Sutterella were found in people with depression. Alteration of gut microbiome patterns was evident in people with depression. Further evidence is warranted to allow for the translation of microbiome findings toward innovative clinical strategies that may improve treatment outcomes in people with depression.
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Prevention of Recurrent Acute Otitis Media in Children Through the Use of Lactobacillus salivarius PS7, a Target-Specific Probiotic Strain.
Cárdenas, N, Martín, V, Arroyo, R, López, M, Carrera, M, Badiola, C, Jiménez, E, Rodríguez, JM
Nutrients. 2019;11(2)
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20–30% of infants suffer from recurrent acute otitis media (rAOM) which is usually treated with antibiotics, leading to increasing antimicrobial resistance rates. A bacterial strain, Lactobacillus salivarius PS7, was identified and characterised by in vitro studies which showed antimicrobial activity against most of otitis-related organisms. It was shown to be safe in rat toxicity studies. The investigators then carried out this prospective pilot study to test the efficacy and safety of L. Salivarius PS7 in infants and children with rAOM. 61 subjects completed the study and received the probiotic for the duration of 6 months. Oral intakes of L. salivarius PS7 over 6 months led to a statistically significant reduction (84%) in the number of episodes of AOM in comparison to those observed in the same children during the 6 months preceding probiotic intake. When AOM occurred, the duration of AOM episodes was shorter than in control children not receiving the probiotic. Ear samples showed that the probiotic treatment led to a statistically significant decrease in potential otopathogens. Limitations of this preliminary “proof of concept” trial were lack of placebo group and randomisation.
Abstract
Acute otitis media (AOM) is one of the most common bacterial infections in children. Empiric antibiotherapy leads to increasing antimicrobial resistance rates among otopathogens and may impair the correct development of the microbiota in early life. In this context, probiotics seem to be an attractive approach for preventing recurrent AOM (rAOM) through the restoration of the middle ear and nasopharyngeal microbiota. The aim of this study was the selection of a probiotic strain (Lactobacillus salivarius PS7), specifically tailored for its antagonism against otopathogens. Since L. salivarius PS7 was safe and displayed a strong antimicrobial activity against otopathogens, its efficacy in preventing rAOM was assessed in a trial involving 61 children suffering from rAOM. Children consumed daily ~1 × 10⁸ CFU of L. salivarius PS7, and the number of AOM episodes were registered and compared with that observed in the previous 6 and 12 months. The microbiota of samples collected from the external auditory canal samples was quantitatively and qualitatively assessed. The number of AOM episodes during the intervention period decreased significantly (84%) when compared to that reported during the 6 months period before the probiotic intervention. In conclusion, L. salivarius PS7 is a promising strain for the prevention of rAOM in infants and children.
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Current Understanding of Gut Microbiota in Mood Disorders: An Update of Human Studies.
Huang, TT, Lai, JB, Du, YL, Xu, Y, Ruan, LM, Hu, SH
Frontiers in genetics. 2019;10:98
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The bidirectional communication between the brain and gastrointestinal tract has been established, and evidence suggests the gut microbiota can influence brain function. While the underlying cause of mood disorders is multifactorial and complex, the gut microbiota may play a role in the pathogenesis of disease. The aim of this review is to summarize the human studies of gut microbiota in mood disorders and discuss the cause-effect relationship between microbiota composition and mood disorders. Twelve studies were included and showed the microbiome diversity and composition of those experiencing mood disorders were significantly different compared with healthy individuals. They found an increase in the abundance of Actinobacteria, Enterobacteriaceae and a decrease in Faecalibacterium, suggesting a pro-inflammatory state. Based on these results, the authors conclude the gut microbiota plays an important role in mood disorders through the brain-gut-microbiota axis, and suggests it to be a target for improved diagnosis and therapeutic interventions.
Abstract
Gut microbiota plays an important role in the bidirectional communication between the gut and the central nervous system. Mounting evidence suggests that gut microbiota can influence the brain function via neuroimmune and neuroendocrine pathways as well as the nervous system. Advances in gene sequencing techniques further facilitate investigating the underlying relationship between gut microbiota and psychiatric disorders. In recent years, researchers have preliminarily explored the gut microbiota in patients with mood disorders. The current review aims to summarize the published human studies of gut microbiota in mood disorders. The findings showed that microbial diversity and taxonomic compositions were significantly changed compared with healthy individuals. Most of these findings revealed that short-chain fatty acids-producing bacterial genera were decreased, while pro-inflammatory genera and those involved in lipid metabolism were increased in patients with depressive episodes. Interestingly, the abundance of Actinobacteria, Enterobacteriaceae was increased and Faecalibacterium was decreased consistently in patients with either bipolar disorder or major depressive disorder. Some studies further indicated that specific bacteria were associated with clinical characteristics, inflammatory profiles, metabolic markers, and pharmacological treatment. These studies present preliminary evidence of the important role of gut microbiota in mood disorders, through the brain-gut-microbiota axis, which emerges as a promising target for disease diagnosis and therapeutic interventions in the future.
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Comparison of Oropharyngeal Microbiota from Children with Asthma and Cystic Fibrosis.
Boutin, S, Depner, M, Stahl, M, Graeber, SY, Dittrich, SA, Legatzki, A, von Mutius, E, Mall, M, Dalpke, AH
Mediators of inflammation. 2017;2017:5047403
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The lungs are under constant exposure to microorganisms contained in inhaled air and the upper respiratory tract. In healthy subjects, the lower airways are colonized by bacteria. Changes in the microbiome are found in several lung diseases associated with chronic airway inflammation including chronic obstructive pulmonary disease, asthma and cystic fibrosis. The aim of the study was to find out whether the throat microbiota of children with asthma and cystic fibrosis differ from healthy children. Another aim was to find out whether the throat microbiota of children with asthma differ from those with cystic fibrosis. The study compared the throat microbiota of healthy school-aged children with that of age-matched children with asthma and cystic fibrosis. Results indicate that the microbiota of cystic fibrosis, asthmatic, and healthy children show high levels of similarities with a strong core microbiota. The cystic fibrosis group show a decrease in both diversity and total bacterial load in the throat in comparison to asthmatic and control children. The cystic fibrosis group also showed a significant increase in typical pathogens in the throat. Based on the results, the authors conclude that the three patient groups had a core microbiome and a host regulation that favours the growth of commensals.
Abstract
A genuine microbiota resides in the lungs which emanates from the colonization by the oropharyngeal microbiota. Changes in the oropharyngeal microbiota might be the source of dysbiosis observed in the lower airways in patients suffering from asthma or cystic fibrosis (CF). To examine this hypothesis, we compared the throat microbiota from healthy children (n = 62) and that from children with asthma (n = 27) and CF (n = 57) aged 6 to 12 years using 16S rRNA amplicon sequencing. Our results show high levels of similarities between healthy controls and children with asthma and CF revealing the existence of a core microbiome represented by Prevotella, Streptococcus, Neisseria, Veillonella, and Haemophilus. However, in CF, the global diversity, the bacterial load, and abundances of 53 OTUs were significantly reduced, whereas abundances of 6 OTUs representing opportunistic pathogens such as Pseudomonas, Staphylococcus, and Streptococcus were increased compared to those in healthy controls controls and asthmatics. Our data reveal a core microbiome in the throat of healthy children that persists in asthma and CF indicating shared host regulation favoring growth of commensals. Furthermore, we provide evidence for dysbiosis with a decrease in diversity and biomass associated with the presence of known pathogens consistent with impaired host defense in children with CF.
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Systematic review: probiotics for functional constipation in children.
Wojtyniak, K, Szajewska, H
European journal of pediatrics. 2017;176(9):1155-1162
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Functional constipation is common in children with a prevalence ranging between 0.7 to 29.6%. Data have shown that 10% of children with functional constipation take laxatives for longer than 12months, and 40% are still symptomatic despite use of laxatives. The aim of the study is to find out the efficacy and safety of probiotics use in the management of functional constipation in children. The study is a systemic review and meta-analysis of seven double-blind randomized control trials (515 participants) that examined the effects of probiotics in patients aged 0 – 18 years with functional constipation. The study shows that probiotics are ineffective for the management of functional constipation in children in terms of treatment success, defecation frequency, frequency of faecal incontinence, and frequency of abdominal pain. Authors conclude that current evidence does not support the use of probiotics in the treatment of functional constipation in children.
Abstract
We updated our 2010 systematic review on the efficacy of probiotics in the treatment of constipation in children. The MEDLINE, EMBASE, and Cochrane Library databases; clinical trial registries; and reference lists of included studies were searched to February 2017 for randomized controlled trials (RCTs) performed in children, with no language restriction. The primary outcome measure was treatment success, as defined by the investigators. We included seven RCTs with a total of 515 participants. Included trials were heterogeneous with respect to study population, probiotic strains, dosages, study duration, and follow-up. Pooled results of two RCTs showed no significant difference between the Lactobacillus rhamnosus casei Lcr35 and placebo groups with respect to treatment success. Other probiotics were studied in single trials only. There was no significant difference between the probiotic and control groups with respect to treatment success. While some probiotic strains showed some effects on defecation frequency, none of the probiotics had beneficial effects on frequency of fecal incontinence or frequency of abdominal pain. Adverse events were rare and not serious. CONCLUSION Limited evidence does not support the use of any of currently evaluated probiotics in the treatment of functional constipation in children. What is Known: • Conventional treatment for functional constipation in children does not always provide satisfying improvement. • Probiotics have been suggested as potential treatment modalities for this condition. What is New: • Probiotics are ineffective for the management of functional constipation in children in terms of treatment success, frequency of fecal incontinence, and frequency of abdominal pain.
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Positive Effect of Probiotics on Constipation in Children: A Systematic Review and Meta-Analysis of Six Randomized Controlled Trials.
Huang, R, Hu, J
Frontiers in cellular and infection microbiology. 2017;7:153
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Constipation is the primary complaint in 3-5% of children who present to paediatric physicians. Constipation is characterised by infrequent and painful evacuation, abdominal pain, and faecal incontinence. Technological developments have shown that the gut microbiota is essential for human health and a wide variety of childhood diseases are associated with the condition of the gut microbiota. The aim of this study was to summarize the evidence of the relationship between probiotics and constipation in children and to identify heterogeneity among the RCT findings. The study is a systemic review of six RCTs involving 498 children. The outcomes of this study show that probiotic supplementation significantly increased stool frequency, particularly in Asian children, but had no significant effect on improving stool consistency in children. Authors conclude that probiotics are an alternative approach for parents with respect to the management of constipation in their children.
Abstract
Context: Constipation in children is a prevalent, burdensome, and psychologically important pediatric issue, the treatment of which remains a global challenge. The use of probiotics has been reported for management of the gastrointestinal microbiota. Objective: This study reviewed the existing literatures of 6 Randomized Control Trials (RCTs) to ascertain some baseline understanding and available information for the effects of probiotics on stool frequency and consistency in children with constipation. Data Sources: PubMed, Springer, Elsevier Science, Cochrane Library, Scopus, Ovid (Medline, EMBASE, PsycINFO), Orbis, and Web of Science from the earliest record in each database to 15 September, 2016. Study selection: Eligible studies were randomized controlled trials that compared the effect of probiotics interventions to any control intervention on stool frequency and consistency. Data Extraction: Studies were identified by searching electronic databases. The meta-analysis was performed by Review Manager 5.3 software using a randomized model. Results: Six studies were identified. The use of probiotics significantly increased the stool frequency [mean difference (MD), 0.73; 95% confidence interval (CI), 0.14-1.31; P = 0.02]. Subgroup assessment showed a significantly increased stool frequency in Asian patients (MD, 1.18; 95% CI, 0.33-2.02; P = 0.006), but no significant difference in stool consistency (MD, -0.07; 95% CI, -0.21-0.06; P = 0.27). Limitations: Only six RCTs met the criteria and were included. Each RCT in this study was performed in a different country, and some of the included studies had a small sample size, which might have influenced the reliability and validity of the conclusions. Conclusion: The present study shows that probiotics increase stool frequency and have beneficial effects in Asian children. However, caution is needed when interpreting these outcomes because of the existence of heterogeneity. Evidence from larger samples and more adequately powered RCTs with results obtained by standardized measurements are necessary to determine which species and dosage of probiotics and what length of treatment are most efficacious for constipation in children.
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Effect of Probiotics on Metabolic Outcomes in Pregnant Women with Gestational Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Taylor, BL, Woodfall, GE, Sheedy, KE, O'Riley, ML, Rainbow, KA, Bramwell, EL, Kellow, NJ
Nutrients. 2017;9(5)
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The gut microbiota is an important ecosystem consisting of both residential and pathogenic bacteria. The microbiota produce bioactive compounds shown to benefit host metabolism. A variety of factors influence the gut microbiome, including host genetics, illness, antibiotic use, dietary patterns, weight loss and pregnancy. Throughout pregnancy the gut microbiota undergoes significant changes. The aim of this study is to determine the effect of 6-8-week probiotic supplementation versus placebo on glucose homeostasis, lipid levels and gestational weight gain in pregnant women diagnosed with gestational diabetes mellitus. This study is a systemic review based on four randomised controlled trials involving 288 participants. All studies included healthy pregnant women, age range between 18 – 40 years, who were diagnosed with gestational diabetes mellitus at 24 – 30 weeks gestation by oral glucose tolerance test. The study found that a 6 – 8-week probiotic intervention did not improve fasting blood glucose or LDL-cholesterol levels. However, probiotic supplementation in women with gestational diabetes mellitus was associated with significant reductions in insulin resistance. Authors conclude that while probiotic supplementation resulted in a significant reduction in insulin resistance in pregnant women with gestational diabetes mellitus, there was no significant effect on fasting blood glucose or LDL-cholesterol.
Abstract
The metabolic effects of probiotic administration in women with gestational diabetes mellitus (GDM) is unknown. The objective of this review was to investigate the effect of probiotics on fasting plasma glucose (FPG), insulin resistance (HOMA-IR) and LDL-cholesterol levels in pregnant women diagnosed with GDM. Seven electronic databases were searched for RCTs published in English between 2001 and 2017 investigating the metabolic effects of a 6-8 week dietary probiotic intervention in pregnant women following diagnosis with GDM. Eligible studies were assessed for risk of bias and subjected to qualitative and quantitative synthesis using a random effects model meta-analyses. Four high quality RCTs involving 288 participants were included in the review. Probiotic supplementation was not effective in decreasing FBG (Mean Difference = -0.13; 95% CI -0.32, 0.06, p = 0.18) or LDL-cholesterol (-0.16; 95% CI -0.45, 0.13, p = 0.67) in women with GDM. However, a significant reduction in HOMA-IR was observed following probiotic supplementation (-0.69; 95% CI -1.24, -0.14, p = 0.01). There were no significant differences in gestational weight gain, delivery method or neonatal outcomes between experimental and control groups, and no adverse effects of the probiotics were reported. Probiotic supplementation for 6-8 weeks resulted in a significant reduction in insulin resistance in pregnant women diagnosed with GDM. The use of probiotic supplementation is promising as a potential therapy to assist in the metabolic management of GDM. Further high quality studies of longer duration are required to determine the safety, optimal dose and ideal bacterial composition of probiotics before their routine use can be recommended in this patient group.