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1.
Efficacy of a Synbiotic Containing Lactobacillus paracasei DKGF1 and Opuntia humifusa in Elderly Patients with Irritable Bowel Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.
Oh, JH, Jang, YS, Kang, D, Kim, HS, Kim, EJ, Park, SY, Kim, CH, Min, YW, Chang, DK
Gut and liver. 2023;17(1):100-107
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Irritable bowel syndrome (IBS) affects 1 in 10 people globally and is a common health problem for the elderly. Recent studies have shown that changes in the gut microbiome may play an important part in IBS and there is evidence that using pre and pro biotics have positive effects on IBS. The aim of this randomized, double-blind, placebo-controlled trial was to determine the effects of a new synbiotic formulation (L. paracasei DKGF1 and prebiotics extracted from O. humifusa) on GI symptoms in elderly patients with IBS. 67 participants were randomly divided into 2 groups. For 4 weeks one group took the synbiotic and the other group took a placebo. Symptoms were recorded via questionnaires. The consumption of the synbiotic combination was associated with overall relief of IBS symptoms in elderly patients. In particular, abdominal pain and psychological well-being noticeably improved. In conclusion this synbiotic is effective and safe to use in elderly patients with global IBS symptoms.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The management of IBS in elderly people is more complicated than in younger populations.
- Synbiotic formulations containing both probiotics and prebiotics have reported gastrointestinal health benefits.
- This randomized controlled trial indicated that the synbiotic containing L. paracasei DKGF1 and Optuntia humifusa extracts might be effective and safe for treating IBS symptoms in elderly patients.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
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:
This study involved a randomized, double-blind, placebo-controlled trial to investigate the impact of a synbiotic combination, comprising of L. paracasei DKGF1 and prebiotics extracted from Optuntia humifusa, on Irritable Bowel Syndrome (IBS) in elderly patients.
Method
Sixty-seven IBS patients (mean age: 64 years) were randomly assigned to either a synbiotic group (n=33) or a placebo group (n=34) for a 4-week intervention. The synbiotic group received a daily sachet containing one billion colony-forming units of L. paracasei DKGF1, 0.2g of O. humifusa extract and 1.59 grams of maltodextrin, while the placebo group received an identical sachet containing only maltodextrin.
During the study period
- Participants recorded the degree of symptom improvement using a Subject Global Assessment (SGA) scale.
- IBS symptoms, abdominal pain, gas, bloating, and psychological well-being were recorded using a Visual Analogue Scale (VAS).
- Stool form and consistency were assessed using a Bristol Stool Chart (BSC).
Results
The primary findings from the study were as follows:
- There was significant improvement in IBS symptoms as measured by the SGA score, in the synbiotic group versus the placebo group (+50.5% vs +23.5%, p=0.017). The synbiotic group consistently demonstrated improved response rates.
The secondary findings were as follows:
- Participants also reported an improvement in psychological well-being in the synbiotic group (from 1.3 to 1.0) compared to the placebo group (from 3.0 to 2.0) (p=0.003).
- Responders reported a significant improvement in stool form and consistency in the synbiotic group (+85.7%) compared to the placebo group (+22.2%) (p=0.04).
- Among the patients with IBS constipation, patients in the synbiotic group reported a positive response compared to the placebo group (0% and +100%, p=0.029).
- . However, there was no significant improvement among the patients with IBS diarrhoea in the synbiotic group compared to the placebo group (+33.3% and +66.6%,, p=0.52).
Conclusion:
This randomized, double-blind, placebo-controlled trial, reported that the synbiotic combination of L. paracasei DKGF1 and Optuntia humifusa, may be associated with the relief of IBS symptoms in elderly patients, particularly in terms of abdominal pain and psychological well-being.
Clinical practice applications:
- The human microbiota undergoes changes in diversity and variation with age, emphasising the importance of understanding age-specific interventions.
- Managing IBS in the elderly is challenging, and synbiotics, containing both probiotics and prebiotics, have reported gastrointestinal health benefits.
- Most clinical trials have excluded elderly patients, and there has been uncertainty about whether synbiotic use is safe for the elderly.
- This study focused exclusively on elderly patients with IBS, indicating the potential safety and effective use of a synbiotic containing L. paracasei DKGF1 and Optuntia humifusa in improving IBS symptoms.
Considerations for future research:
- Only elderly patients were included in this study, therefore further investigation is needed to explore the effects of synbiotics on participants of different age groups.
- Microbial analysis was not done in this study. It would be useful to include this in future research to gain more insight into the microbiome’s diversity in elderly patients with IBS.
- The study did not quantify food intake or variety which might have impacted the results, therefore future research needs to consider the impact diet has on the microbiome and IBS.
- Since patient reports are subjective, future research should consider involving researchers during patient-reported assessments to enhance the accuracy and reliability of the data.
Abstract
BACKGROUND/AIMS: There is increasing evidence that supplementation with pre- and probiotics appears to have positive effects on irritable bowel syndrome (IBS). The aim of this study was to determine the effects of a new synbiotic formulation on gastrointestinal symptoms in elderly patients with IBS. METHODS Sixty-seven IBS patients aged ≥60 years were randomly assigned to either a placebo group (n=34) or a synbiotic group (n=33). During a 4-week intervention, subjects used a placebo or a synbiotic containing Lactobacillus paracasei DKGF1 and extracts of Opuntia humifusa once a day. Patients were evaluated with the subject global assessment, visual analog scale, and Bristol stool chart. The primary outcome was the overall responder rate and the secondary outcome was the responder rates for abdominal symptom reduction at week 4. RESULTS Overall, responder rates were significantly higher in the synbiotic group (51.5%) than in the placebo group (23.5%) (p=0.017). Abdominal pain (58.8% vs 81.8%) and psychological well-being (26.4% vs 60.6%) were noticeably improved in the synbiotic group (p=0.038 and p=0.004, respectively). However, there were no significant differences in gas and bloating symptoms (p=0.88 and p=0.88, respectively). In patients with constipation-dominant and diarrhea-dominant IBS (n=16), the synbiotic significantly improved abdominal pain and defecation symptoms (responder rates for the placebo vs the synbiotic: 22.2% vs 85.7%, p=0.04). There were no adverse events in either group. CONCLUSIONS The results indicate that this new synbiotic supplement can potentially relieve abdominal symptoms in elderly IBS patients.
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2.
Diet as an Optional Treatment in Adults With Inflammatory Bowel Disease: A Systematic Review of the Literature.
Jaramillo, AP, Abaza, A, Sid Idris, F, Anis, H, Vahora, I, Moparthi, KP, Al Rushaidi, MT, Muddam, M, Obajeun, OA
Cureus. 2023;15(7):e42057
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Crohn's disease (CD) and ulcerative colitis (UC) are linked with significant morbidity and higher healthcare costs. The current model of CD pathogenesis implies that environmental variables and the gut microbiota interact in those who are genetically predisposed to the condition. The aim of this study was to investigate a treatment based on the diet of IBD patients. This study was a systematic review of nine studies. Results showed that following a diet that reduces inflammation may prevent its recurrence in UC patients in clinical remission. In fact, there were significant systemic changes in the intestinal microbiota of anti-inflammatory diet patients. Authors concluded that a four-week FODMAP diet combined with professional counseling and regular follow-up will be helpful in the therapy of persistent gastrointestinal symptoms in quiescent IBD, although care should be used in the long run.
Expert Review
Conflicts of interest:
None
Take Home Message:
Whilst concise, this limited review highlights the current lack of evidence supporting stand alone dietary strategies in preventing relapse for IBD patients. At the very least an anti-inflammatory diet should ideally be implemented alongside specific medical care and counselling to minimise risk of disease relapses.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
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 systematic review evaluated the efficacy of diet as a preventative therapeutic treatment for Inflammatory Bowel Disease (IBD).
Methods
A total of 9 studies (published in the last 5 years) were chosen. The articles included 6 randomised controlled trials (RCT), one systematic literature review (SLR) and two SLR and meta-analysis. The authors used the Assessment Systematic Reviews (AMSTAR) approach and an unspecified Cochrane Risk of Bias assessment tool.
Results
(The following refers to the original RCT articles as the review article data was sparse).
- A 6-month, open-label, randomised, placebo-controlled trial of 53 adult Ulcerative Colitis (UC) patients compared response to an Anti-inflammatory Diet (AID) with Canada’s Food Guide (CFG). The outcome showed that the faecal calprotectin value (<150 µg/g at the endpoint) was significantly higher in the AID group (69.2 vs. 37.0%, p = 0.02) (Keshteli et al., 2022).
- The Specific Carbohydrate Diet (SCD) was not superior to the Mediterranean Diet (MD) in terms of achieved symptomatic remission at 6 weeks (SCD 46.5%, MD 43.5%; p = .77) (Lewis et al., 2022).
- A single-blind, 4-week trial concluded significant relief from gut symptoms was achieved when comparing a low FODMAP diet (14/27, 52% of positive patient feedback) to a control diet (4/25, 16%, p=.007) (Cox et al., 2020).
- A 7-day trial of 28 volunteers compared individualised food-based diet (CD-TREAT), with similar composition to Exclusive Enteral Nutrition (EEN) and found a change in relative abundance in faecal microbiome genera of 58 (49.3%) and 38 (32.3%) following both feeding practices respectively (Svolos et al., 2019).
- Substantial reduction in red and processed meat was not significant in reducing time to symptomatic relapse in Crohn’s Disease (CD) patients when comparing 115 high red meat consumers with 87 low red meat CD patients (p = 0.61 any relapse and p = 0.50 for moderate to severe relapse) (Aldenberg et al., 2019).
Conclusion
An anti-inflammatory diet may prolong clinical remission for UC patients. CD patients, with mild to severe symptoms, may tolerate both the MD and SCD equally well. The authors advise a low FODMAP diet for a 4-week period combined with professional counselling and regular follow-up sessions to delay flare-up episodes. However the findings were based on a very limited number of scientific material that requires extensive further assessment prior to deriving any firm conclusions.
Clinical practice applications:
- In order to delay relapse in IBD it is imperative that foods that support anti-inflammatory mechanisms are incorporated and maintained
- Whilst limited, the papers reviewed highlight potential for an initial low FODMAP diet followed by a longer term MD or SCD combined with constant monitoring
- From one study, red meat consumption did not appear to exacerbate symptoms.
Considerations for future research:
- Future studies need to include larger cohorts to ascertain the efficacy of dietary interventions as a stand alone treatment option for IBD
- Longer periods of intervention are needed to confirm dietary intervention efficacy and safety in this population.
Abstract
While the exact cause of IBD is unknown, there are a number of factors that are thought to contribute to its development, including environmental and genetic factors. While exclusive enteral nutrition (EEN) is a promising therapy for Crohn's disease (CD), it is not yet considered a first-line treatment. Additionally, the efficacy of EEN compared to corticosteroid treatment is still being investigated. EEN is suggested as a first-line therapy by which guidelines and in which age groups, as it may differ in pediatric and adult recommendations. Another finding was that dietary changes involving an increase in anti-inflammatory foods and decreased intake of foods high in inflammatory compounds are linked to a beneficial outcome both metabolically and microbiologically in patients with ulcerative colitis (UC) in remission. For relevant medical literature, we examined PubMed/Medline, the Cochrane Library, and Google Scholar as examples of medical databases. The articles were identified, evaluated, and eligibility applied, and nine publications were found. The finished articles investigated the role of several diet alternatives for patients with IBD. Some others have shown that following a normal low-fat diet may be effective in reducing the occurrence of subclinical colitis. The EEN and partial enteral nutrition (PEN) indicated no significant differences between both regimens, but both had good outcomes during active IBD. Other strict diets, such as the specific carbohydrate diet (SCD) versus the Mediterranean diet (MD), demonstrate excellent outcomes in patients with IBD. Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) dietary counseling improves gastrointestinal symptoms and quality of life in IBD patients. Based on the above, we concluded that more studies determining which component of the diet is not clear (proteins, carbs balanced) or diet types are required to establish a particular diet employed as a treatment intervention in these individuals.
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3.
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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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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X
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.
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4.
Gut Microbiota-Derived Metabolites and Cardiovascular Disease Risk: A Systematic Review of Prospective Cohort Studies.
Sanchez-Gimenez, R, Ahmed-Khodja, W, Molina, Y, Peiró, OM, Bonet, G, Carrasquer, A, Fragkiadakis, GA, Bulló, M, Bardaji, A, Papandreou, C
Nutrients. 2022;14(13)
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Cardiovascular disease (CVD) remains a major public health issue. Identification of circulating biomarkers with prognostic value may help to both identify pathophysiological processes relevant to CVD development and improve preventive cardiovascular risk reduction efforts. The aim of this study was to identify the association of circulating levels of microbial metabolites with CVD incidence. This study is a systematic review of twenty-one studies of which 19 were prospective cohort studies, one study included one nested case-control study and one study included two nested case–control studies. Results show that: - associations of trimethylamine N-oxide (TMAO) [molecular metabolite derived from the gut flora] and subsequent risk of CV outcomes were supported by some but not all prospective studies. - inconsistent results were also obtained for secondary bile acids in relation to CVD and related outcomes, and CVD/all-cause mortality. - with regards to branched-chain amino acids (BCAAs), their associations with CV outcomes were robust amongst most of the studies. Authors conclude that their findings show inconsistent results for TMAO and bile acids but robust ones for the relationships between BCAAs and CVD. Thus, further studies are needed to investigate whether circulating microbial metabolites could be an intervention target for CVD.
Abstract
Gut microbiota-derived metabolites have recently attracted considerable attention due to their role in host-microbial crosstalk and their link with cardiovascular health. The MEDLINE-PubMed and Elsevier's Scopus databases were searched up to June 2022 for studies evaluating the association of baseline circulating levels of trimethylamine N-oxide (TMAO), secondary bile acids, short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), tryptophan and indole derivatives, with risk of cardiovascular disease (CVD). A total of twenty-one studies were included in the systematic review after evaluating 1210 non-duplicate records. There were nineteen of the twenty-one studies that were cohort studies and two studies had a nested case-control design. All of the included studies were of high quality according to the "Newcastle-Ottawa Scale". TMAO was positively associated with adverse cardiovascular events and CVD/all-cause mortality in some, but not all of the included studies. Bile acids were associated with atrial fibrillation and CVD/all-cause mortality, but not with CVD. Positive associations were found between BCAAs and CVD, and between indole derivatives and major adverse cardiovascular events, while a negative association was reported between tryptophan and all-cause mortality. No studies examining the relationship between SCFAs and CVD risk were identified. Evidence from prospective studies included in the systematic review supports a role of microbial metabolites in CVD.
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5.
Dietary macronutrients and the gut microbiome: a precision nutrition approach to improve cardiometabolic health.
Jardon, KM, Canfora, EE, Goossens, GH, Blaak, EE
Gut. 2022;71(6):1214-1226
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The global rise in the prevalence of obesity is strongly associated with an increase in the incidence and prevalence of cardiometabolic diseases, including insulin resistance (IR) and type 2 diabetes mellitus. In recent years, advancements have been made in understanding the involvement of the gut microbiome in obesity and related cardiometabolic complications as regulator of host energy and substrate metabolism. This study is a review that discusses the latest research describing interactions between dietary composition, the gut microbiome and host metabolism. Results show that current evidence for developing optimal dietary interventions targeting bodyweight control and IR via the gut microbiota is still in its infancy and does not capture the complexity of the integration of a whole-diet approach, the microbial and the host’s metabolic phenotype. Furthermore, implementation of targeted, precision nutrition intervention strategies or dietary guidelines for individuals or subgroups in public health requires further insight in the mechanisms involved in (non-)response to dietary intervention. Authors conclude that future studies are needed and these should focus on assessing detailed individual phenotyping and gaining insight into the balance between carbohydrate and protein fermentation by the gut microbiota as well as the site of fermentation in the colon.
Abstract
Accumulating evidence indicates that the gut microbiome is an important regulator of body weight, glucose and lipid metabolism, and inflammatory processes, and may thereby play a key role in the aetiology of obesity, insulin resistance and type 2 diabetes. Interindividual responsiveness to specific dietary interventions may be partially determined by differences in baseline gut microbiota composition and functionality between individuals with distinct metabolic phenotypes. However, the relationship between an individual's diet, gut microbiome and host metabolic phenotype is multidirectional and complex, yielding a challenge for practical implementation of targeted dietary guidelines. In this review, we discuss the latest research describing interactions between dietary composition, the gut microbiome and host metabolism. Furthermore, we describe how this knowledge can be integrated to develop precision-based nutritional strategies to improve bodyweight control and metabolic health in humans. Specifically, we will address that (1) insight in the role of the baseline gut microbial and metabolic phenotype in dietary intervention response may provide leads for precision-based nutritional strategies; that (2) the balance between carbohydrate and protein fermentation by the gut microbiota, as well as the site of fermentation in the colon, seems important determinants of host metabolism; and that (3) 'big data', including multiple omics and advanced modelling, are of undeniable importance in predicting (non-)response to dietary interventions. Clearly, detailed metabolic and microbial phenotyping in humans is necessary to better understand the link between diet, the gut microbiome and host metabolism, which is required to develop targeted dietary strategies and guidelines for different subgroups of the population.
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The vaginal microbiome and the risk of preterm birth: a systematic review and network meta-analysis.
Gudnadottir, U, Debelius, JW, Du, J, Hugerth, LW, Danielsson, H, Schuppe-Koistinen, I, Fransson, E, Brusselaers, N
Scientific reports. 2022;12(1):7926
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Preterm birth is a major cause of neonatal mortality and morbidity. Many factors can trigger premature labour onset, including preterm premature rupture of membranes, infections and microbial invasion of the amniotic cavity. The vaginal microbiome is thought to protect from such infections. The aim of this study was to assess the association between the vaginal microbiome and the risk of preterm birth. This study is a systematic review and meta-analysis of 17 cohort studies. The number of pregnancies per study ranged between 38 and 539, with 8 and 107 preterm births. Results show that women with a “low-lactobacilli” vaginal microbiome composition were at higher risk of preterm birth (spontaneous and overall) compared to women with L. crispatus (microbiome) dominant microbiome compositions. Authors conclude that the diversity of the vaginal microbiome seems to play a part in the risk of preterm birth.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The diversity of the vaginal microbiome is reported to play a part in the risk of preterm births.
- Practitioners could consider testing the virginal microbiome for low Lactobacilli or the dominance of Gardnerella and Prevotella and then recommending a probiotic supplement to pregnant patients who have low Lactobacilli vaginal microbiome.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
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
A systematic review and network meta-analysis was conducted to investigate the association between vaginal microbiome and risk of preterm births.
Methodology
- Seventeen longitudinal cohort studies were included. Seven originated from North America, three from Europe, two from South America, three from Asia, and two from Africa. The number of pregnancies per study ranged between 38 and 539, with 8 and 107 preterm births. 16S Sequencing techniques were used to identify the microbial species. Preterm birth was defined as birth before 37 weeks of gestation.
- Microbiome community state types (CSTs) were grouped into five categories based on dominating species: L. crispatus, L. gasseri, L. iners,“low-lactobacilli” and L. jensenii. “Low-lactobacilli” was defined as an increased diversity of anaerobic or mixture of aerobe and facultative anaerobe bacteria (such as Gardnerella and Prevotella) based on the cut-offs and categorization used in the individual studies.
Results
Primary clinical outcomes were:
- Among women who delivered preterm, the pooled proportion with “low-lactobacilli” was 0.41 (95% CI 0.30-0.53) compared to 0.29 (95% CI 0.20-0.38) of women with full-term deliveries.
- The risk of preterm births was higher among women with “low-lactobacilli” compared to L. crispatus (OR 1.69, 95%CI 1.15 -2.49).”Low-lactobacilli” included Garnerella and Provotella, both of which are known to promote inflammatory cytokines and are commonly found in vaginal microbiome just before preterm premature rupture of membranes (PPROM).
Clinical practice applications:
- The diversity of the vaginal microbiome is reported to play an important role in the risk of preterm births.
- Women with low Lactobacilli seem to be at a greater risk of delivering preterm compared to women with L. crispatus dominant microbiome.
- Based on this study, practitioners could therefore consider testing the vaginal microbiome of their patients for low Lactobacilli and/or the dominance of Gardnerella and Prevotella.
- Practitioners may also consider recommending specific probiotic supplementation during pregnancy to increase the dominance of Lactobacilli and L. crispatus vaginal microbiome.
Considerations for future research:
- In the past, researchers have grouped the microbiome into categories based on dominating species, which is not ideal. Therefore, further studies are needed where individual microbiome sequencing data is used to make comparisons.
- Additionally, longitudinal studies are needed with higher sample sizes to investigate the natural changes of the vaginal microbiome during pregnancy and the physiological mechanisms underlying these apparent different risk profiles.
- Furthermore, randomized-controlled trials are needed to establish if pregnant women could benefit from specific probiotic supplementation during pregnancy.
Abstract
Preterm birth is a major cause of neonatal morbidity and mortality worldwide. Increasing evidence links the vaginal microbiome to the risk of spontaneous preterm labour that leads to preterm birth. The aim of this systematic review and network meta-analysis was to investigate the association between the vaginal microbiome, defined as community state types (CSTs, i.e. dominance of specific lactobacilli spp, or not (low-lactobacilli)), and the risk of preterm birth. Systematic review using PubMed, Web of Science, Embase and Cochrane library was performed. Longitudinal studies using culture-independent methods categorizing the vaginal microbiome in at least three different CSTs to assess the risk of preterm birth were included. A (network) meta-analysis was conducted, presenting pooled odds ratios (OR) and 95% confidence intervals (CI); and weighted proportions and 95% CI. All 17 studies were published between 2014 and 2021 and included 38-539 pregnancies and 8-107 preterm births. Women presenting with "low-lactobacilli" vaginal microbiome were at increased risk (OR 1.69, 95% CI 1.15-2.49) for delivering preterm compared to Lactobacillus crispatus dominant women. Our network meta-analysis supports the microbiome being predictive of preterm birth, where low abundance of lactobacilli is associated with the highest risk, and L. crispatus dominance the lowest.
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7.
Adverse pregnancy and birth outcomes associated with Mycoplasma hominis, Ureaplasma urealyticum and Ureaplasma parvum: a systematic review and meta-analysis.
Jonduo, ME, Vallely, LM, Wand, H, Sweeney, EL, Egli-Gany, D, Kaldor, J, Vallely, AJ, Low, N
BMJ open. 2022;12(8):e062990
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Mycoplasma hominis, Ureaplasma parvum and Ureaplasma urealyticum, referred to together as genital mycoplasmas, commonly colonise the urogenital tract in women, and are often found together. These species do not appear to cause symptoms or harmful effects in non-pregnant women. However, studies have reported that colonisation with a genital mycoplasma has been associated with several adverse pregnancy outcomes. The main objective of this study was to investigate the associations between M. hominis, U. urealyticum and/or U. parvum and the risk of pre-term birth, alone and in combination with bacterial vaginosis (BV). This study is a systematic review and meta-analysis of fifty-seven studies. Results show that genital mycoplasmas are associated with several different adverse pregnancy outcomes in univariable analysis only. Authors conclude that since only six of the fifty-seven studies reported multivariable analysis, the current available literature does not allow conclusions about the role of mycoplasmas in adverse pregnancy and birth outcomes, alone or with coexisting BV.
Abstract
OBJECTIVES Mycoplasma hominis, Ureaplasma urealyticum and Ureaplasma parvum (genital mycoplasmas) commonly colonise the urogenital tract in pregnant women. This systematic review aims to investigate their role in adverse pregnancy and birth outcomes, alone or in combination with bacterial vaginosis (BV). METHODS We searched Embase, Medline and CINAHL databases from January 1971 to February 2021. Eligible studies tested for any of the three genital mycoplasmas during pregnancy and reported on the primary outcome, preterm birth (PTB) and/or secondary outcomes low birth weight (LBW), premature rupture of membranes (PROM), spontaneous abortion (SA) and/or perinatal or neonatal death (PND).Two reviewers independently screened titles and abstracts, read potentially eligible full texts and extracted data. Two reviewers independently assessed risks of bias using published checklists. Random effects meta-analysis was used to estimate summary ORs (with 95% CIs and prediction intervals). Multivariable and stratified analyses were synthesised descriptively. RESULTS Of 57/1194 included studies, 39 were from high-income countries. In meta-analysis of unadjusted ORs, M. hominis was associated with PTB (OR 1.87, 95% CI 1.49 to 2.34), PROM, LBW and PND but not SA. U. urealyticum was associated with PTB (OR 1.84, 95% CI 1.34 to 2.55), PROM, LBW, SA and PND. U. parvum was associated with PTB (1.60, 95% CI 1.12 to 2.30), PROM and SA. Nine of 57 studies reported any multivariable analysis. In two studies, analyses stratified by BV status showed that M. hominis and U. parvum were more strongly associated with PTB in the presence than in the absence of BV. The most frequent source of bias was a failure to control for confounding. CONCLUSIONS The currently available literature does not allow conclusions about the role of mycoplasmas in adverse pregnancy and birth outcomes, alone or with coexisting BV. Future studies that consider genital mycoplasmas in the context of the vaginal microbiome are needed. PROSPERO REGISTRATION NUMBER CRD42016050962.
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Effects of Hemp Sanitary Pads on the Vaginal Microecology.
Sun, Y, Li, C, Yan, Y, Lai, A, Peng, X, Yue, X, Li, Y, Liu, J, Liu, Y
Computational and mathematical methods in medicine. 2022;2022:4435722
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Under ideal situations, women have a variety of microbes that reside in the vagina which form the normal vaginal microbiome. When combined, the vaginal microbial flora, endocrine regulation system, anatomic structure of the vagina, and local endocrine system constitute the vaginal microecosystem, which is in turn part of the entire human microecosystem. In fact, the choice of appropriate sanitary pads is of high importance during the menstrual period. The aim of this study was to evaluate the effect of hemp cotton sanitary pads on the vaginal microecology. The study is a randomised controlled field trial study which recruited women of childbearing age. The patients were randomly divided into two groups (experimental and control groups). The control group was further divided into 2 subgroups. The subjects in the experimental group used hemp sanitary pads. Results show that: - among women with a normal vaginal microecosystem or a vaginal microecologic imbalance at baseline, the vaginal cleanliness grade and overall vaginal microecologic status were better if hemp sanitary pads were used rather than the ordinary cotton sanitary pads. - there was no significant difference in the vaginal pH values between the two groups. - hemp sanitary pads had no therapeutic effect against vaginal infections. Authors conclude that the use of hemp cotton sanitary pads during menstruation, by women without vaginal inflammation, can help maintain balanced vaginal microecology which will help to prevent reproductive tract infections.
Abstract
OBJECTIVE To evaluate the effect of hemp cotton sanitary pads on the vaginal microecology. METHODS A randomized controlled field trial was used to recruit 1002 community-based women of childbearing age. The women were randomly divided into experimental and control groups. The experimental group used hemp cotton sanitary pads, while the control group used two types of cotton sanitary randomly chosen from the top five sanitary pads in terms of market share in China. The vaginal microecology was compared between the two groups after three months. RESULTS According to the vaginal microecologic examination results at baseline, 1002 women were included in 3 groups: normal vaginal microecologic, vaginal microecological disorders, and suspected vaginal infections. The number of patients in three groups were 39 (3.9%), 652 (65.1%), and 311 (31%), respectively. Three months later, the vaginal microecologic status and vaginal pH value of the suspected vaginal infection group were not significantly different between the experimental group and control group. The experimental group outperformed the control group with respect to vaginal cleanliness and vaginal microecology status in the women without a vaginal infection (normal vaginal microecology or microecological disorders group). The rate of abnormal cleanliness in the experimental group was lower than the control group (31.95% [108/338] vs. 43.62% [154/353]). The incidence of suspected vaginitis in the experimental group was lower than the control group (15.29% [51/338] vs. 23.51% [83/353]). CONCLUSION For women without vaginal inflammation, the use of hemp cotton sanitary pads during menstruation can help maintain the balance of the vaginal microecology to prevent reproductive tract infections.
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9.
Interaction of cervical microbiome with epigenome of epithelial cells: Significance of inflammation to primary healthcare.
Holubekova, V, Kolkova, Z, Kasubova, I, Samec, M, Mazurakova, A, Koklesova, L, Kubatka, P, Rokos, T, Kozubik, E, Biringer, K, et al
Biomolecular concepts. 2022;13(1):61-80
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A female health is one medical area of the framework strategies in predictive, preventive, and personalized (3P) medicine. Cervical cancer is preventable and successfully treatable at early stages that makes the disease as an ideal candidate applicable in the context of 3P medicine. The aim of this study was to examine the interaction of the cervical microbiome with epithelial cells in relation to inflammation, and to assess direct evidence of epigenetic changes related to the cervical microbiome. This study is a systematic review of publications in the field of cervical cancer research. This review shows that: - cervical cancer screening in future integration of precision cancer prevention regimes should match an individual’s risk of cancer in context with genomic and environmental factors. - identification of microbiome population might be one of the key aspects of precision medicine in the future. Microbial composition may early identify the potential risk of precancerous lesion formation or permanent bacterial vaginosis. - the composition of the microbiome can be influenced by dietary composition, which will also affect the epigenetic background of the microbiome. However, food forms the microbiome through epigenetic mechanisms, and it is thus necessary to clarify how cancer risk is increased due to food-related microbially produced metabolites. - an examination of the metabolites during inflammation of the cervical epithelium and bacterial vaginosis may improve the precise identification of inflammatory-induced biomarkers that could aid in the precision medicine in prediction of the risk of cervical dysplasia development. - cancer-associated inflammation pathways can be influenced by phytochemicals with anti-inflammatory effects on immune cells, suppression of proinflammatory transcription factors, cytokines, and chemokines. The biological balance between uncontrolled chronic inflammation and controlled inflammation is essential for cancer prevention, prediction, and prognostication. Authors conclude that their review highlighted the pivotal contribution of cervical microbiome, epigenetic changes, and inflammation to the formation of cervical intraepithelial lesion and progression to cervical cancer.
Abstract
One pillar of the predictive, preventive, and personalized medicine framework strategies is the female health. The evaluation of women's lifestyle and dietary habits in context with genetic and modifiable risk factors may reflect the prevention of cervical cancer before the occurrence of clinical symptoms and prediction of cervical lesion behavior. The main aim of this review is to analyze publications in the field of precision medicine that allow the use of research knowledge of cervical microbiome, epigenetic modifications, and inflammation in potential application in clinical practice. Personalized approach in evaluating patient's risk of future development of cervical abnormality should consider the biomarkers of the local microenvironment characterized by the microbial composition, epigenetic pattern of cervical epithelium, and presence of chronic inflammation. Novel sequencing techniques enable a more detailed characterization of actual state in cervical epithelium. Better understanding of all changes in multiomics level enables a better assessment of disease prognosis and selects the eligible targeted therapy in personalized medicine. Restoring of healthy vaginal microflora and reversing the outbreak of cervical abnormality can be also achieved by dietary habits as well as uptake of prebiotics, probiotics, synbiotics, microbial transplantation, and others.
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A Deep Look at the Vaginal Environment During Pregnancy and Puerperium.
Severgnini, M, Morselli, S, Camboni, T, Ceccarani, C, Laghi, L, Zagonari, S, Patuelli, G, Pedna, MF, Sambri, V, Foschi, C, et al
Frontiers in cellular and infection microbiology. 2022;12:838405
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In healthy reproductive-aged women, the vaginal microbiome is generally dominated by members of the Lactobacillus genus. Lactobacilli promote the maintenance of the vaginal health, preventing the colonization and growth of adverse microorganisms through various mechanisms. The composition of the vaginal bacterial communities and related metabolites play a crucial role in maternal-foetal health. The aim of this study was to deepen the characteristics of the vaginal environment in a cohort of Caucasian women with a normal pregnancy throughout their different gestational ages (i.e., first, second, third trimester) and puerperium. This study is a prospective study of sixty-three Caucasian pregnant women. Participants were enrolled and sampled during all gestational ages; for 30 of them, clinical and microbiological data were also available for the puerperium. Additionally, 9 women who had a spontaneous miscarriage at the first trimester of pregnancy (gestational age: 11-13 weeks) during the study were included. Results show that: - irrespective of the period and type of pregnancy, bacterial vaginosis cases were characterised by a dramatic reduction of Lactobacillus and an increase of anaerobic bacteria. - the vaginal microbiome becomes more stable throughout the entire pregnancy, being less diverse and mainly dominated by lactobacilli. - women receiving an intrapartum antibiotic prophylaxis for Group B Streptococcus were characterized by a vaginal abundance of Prevotella compared to untreated women. - at the puerperium, a significantly lower content of Lactobacillus and higher levels of Gardnerella, Prevotella, Atopobium, and Streptococcus were observed. Authors conclude that their findings may help implement ‘prognostic’ criteria (e.g., evaluation of the risk of spontaneous miscarriage based on the microbiome/metabolome profiles), as well as strategies for the prevention of early pregnancy loss, based on the ‘manipulation’ of the vaginal bacterial inhabitants.
Abstract
A deep comprehension of the vaginal ecosystem may hold promise for unraveling the pathophysiology of pregnancy and may provide novel biomarkers to identify subjects at risk of maternal-fetal complications. In this prospective study, we assessed the characteristics of the vaginal environment in a cohort of pregnant women throughout their different gestational ages and puerperium. Both the vaginal bacterial composition and the vaginal metabolic profiles were analyzed. A total of 63 Caucasian women with a successful pregnancy and 9 subjects who had a first trimester miscarriage were enrolled. For the study, obstetric examinations were scheduled along the three trimester phases (9-13, 20-24, 32-34 gestation weeks) and puerperium (40-55 days after delivery). Two vaginal swabs were collected at each time point, to assess the vaginal microbiome profiling (by Nugent score and 16S rRNA gene sequencing) and the vaginal metabolic composition (1H-NMR spectroscopy). During pregnancy, the vaginal microbiome underwent marked changes, with a significant decrease in overall diversity, and increased stability. Over time, we found a significant increase of Lactobacillus and a decrease of several genera related to bacterial vaginosis (BV), such as Prevotella, Atopobium and Sneathia. It is worth noting that the levels of Bifidobacterium spp. tended to decrease at the end of pregnancy. At the puerperium, a significantly lower content of Lactobacillus and higher levels of Gardnerella, Prevotella, Atopobium, and Streptococcus were observed. Women receiving an intrapartum antibiotic prophylaxis for Group B Streptococcus (GBS) were characterized by a vaginal abundance of Prevotella compared to untreated women. Analysis of bacterial relative abundances highlighted an increased abundance of Fusobacterium in women suffering a first trimester abortion, at all taxonomic levels. Lactobacillus abundance was strongly correlated with higher levels of lactate, sarcosine, and many amino acids (i.e., isoleucine, leucine, phenylalanine, valine, threonine, tryptophan). Conversely, BV-associated genera, such as Gardnerella, Atopobium, and Sneathia, were related to amines (e.g., putrescine, methylamine), formate, acetate, alcohols, and short-chain fatty-acids (i.e., butyrate, propionate).