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Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial.
Costenbader, KH, Cook, NR, Lee, IM, Hahn, J, Walter, J, Bubes, V, Kotler, G, Yang, N, Friedman, S, Alexander, EK, et al
Arthritis & rheumatology (Hoboken, N.J.). 2024
Abstract
OBJECTIVE In the 5.3-year randomized, 2 × 2 factorial, double-blind, placebo-controlled Vitamin D and Omega-3 Trial (VITAL), vitamin D supplementation reduced autoimmune disease (AD) incidence (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.61-0.99). Omega-3 (n-3) fatty acid supplementation showed a statistically nonsignificant reduction (HR 0.85, 95% CI 0.67-1.08). We aimed to confirm further AD cases arising during and after randomization and assess sustained effects with two years of postintervention observation. METHODS Of the 12,786 men aged ≥50 and 13,085 women aged ≥55 initially randomized, we observed surviving and willing participants for two more years. We continued to confirm annual participant-reported new AD by medical record review. Cox models calculated HRs for all confirmed incident AD, (and secondary endpoints, including probable cases, and individual ADs), during the observational and randomized periods. RESULTS A total of 21,592 participants (83.5%) were observed for two more years; 514 participants developed incident confirmed AD (236 since prior report), of whom 255 had been randomized to vitamin D versus 259 to vitamin D placebo (HR 0.98 [95% CI 0.83-1.17] at 7 years). AD was confirmed in 234 participants initially randomized to n-3 fatty acids versus 280 randomized to its placebo (HR 0.83 [95% CI 0.70-0.99] at 7 years). Of newly confirmed cases, 65 had onset during randomization; their inclusion changed randomized results as follows: HR 0.85 (95% CI 0.70-1.04) for vitamin D and HR 0.87 (95% CI 0.71-1.06) for n-3 fatty acids. CONCLUSION Two years after trial termination, the protective effects of 2000 IU/day of vitamin D dissipated, but 1,000 mg/day of n-3 fatty acids had a sustained effect in reducing AD incidence.
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Gut microbiome alterations at acute myeloid leukemia diagnosis are associated with muscle weakness and anorexia.
Pötgens, SA, Havelange, V, Lecop, S, Li, F, Neyrinck, AM, Bindels, F, Neveux, N, Demoulin, JB, Moors, I, Kerre, T, et al
Haematologica. 2024
Abstract
The gut microbiota makes critical contributions to host homeostasis, and its role in the treatment of acute myeloid leukaemia (AML) has attracted attention. We investigated whether the gut microbiome is affected by AML, and whether such changes are associated with cachectic hallmarks. Biological samples and clinical data were collected from 30 antibiotic-free AML patients at diagnosis and matched volunteers (1:1) in a multicenter cross-sectional prospective study. The composition and functional potential of the faecal microbiota were analyzed using shotgun metagenomics. Faecal, blood, and urine metabolomics analyses were performed. AML patients displayed muscle weakness, anorexia, signs of altered gut function, and glycaemic disorders. The composition of the faecal microbiota differed between patients with AML and control subjects, with an increase in oral bacteria. Alterations in bacterial functions and faecal metabolome support an altered redox status in the gut microbiota, which may contribute to the altered redox status observed in patients with AML. Eubacterium eligens, reduced 3-fold in AML patients, was strongly correlated with muscle strength and citrulline, a marker of enterocyte mass and function. Blautia and Parabacteroides, increased in patients with AML, were correlated with anorexia. Several bacterial taxa and metabolites (e.g. Blautia, Prevotella, phenylacetate, and hippurate) previously associated with glycaemic disorders were altered. Our work revealed important perturbations in the gut microbiome of AML patients at diagnosis, which are associated with muscle strength, altered redox status, and anorexia. These findings pave the way for future mechanistic work to explore the function and therapeutic potential of the bacteria identified in this study.
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Unfermented β-fructan Fibers Fuel Inflammation in Select Inflammatory Bowel Disease Patients.
Armstrong, HK, Bording-Jorgensen, M, Santer, DM, Zhang, Z, Valcheva, R, Rieger, AM, Sung-Ho Kim, J, Dijk, SI, Mahmood, R, Ogungbola, O, et al
Gastroenterology. 2023;(2):228-240
Abstract
BACKGROUND & AIMS Inflammatory bowel diseases (IBD) are affected by dietary factors, including nondigestible carbohydrates (fibers), which are fermented by colonic microbes. Fibers are overall beneficial, but not all fibers are alike, and some patients with IBD report intolerance to fiber consumption. Given reproducible evidence of reduced fiber-fermenting microbes in patients with IBD, we hypothesized that fibers remain intact in select patients with reduced fiber-fermenting microbes and can then bind host cell receptors, subsequently promoting gut inflammation. METHODS Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with oligofructose (5 g/L), or fermentation supernatants (24-hour anaerobic fermentation) and immune responses (cytokine secretion [enzyme-linked immunosorbent assay/meso scale discovery] and expression [quantitative polymerase chain reaction]) were assessed. Influence of microbiota in mediating host response was examined and taxonomic classification of microbiota was conducted with Kraken2 and metabolic profiling by HUMAnN2, using R software. RESULTS Unfermented dietary β-fructan fibers induced proinflammatory cytokines in a subset of IBD intestinal biopsies cultured ex vivo, and immune cells (including peripheral blood mononuclear cells). Results were validated in an adult IBD randomized controlled trial examining β-fructan supplementation. The proinflammatory response to intact β-fructan required activation of the NLRP3 and TLR2 pathways. Fermentation of β-fructans by human gut whole microbiota cultures reduced the proinflammatory response, but only when microbes were collected from patients without IBD or patients with inactive IBD. Fiber-induced immune responses correlated with microbe functions, luminal metabolites, and dietary fiber avoidance. CONCLUSION Although fibers are typically beneficial in individuals with normal microbial fermentative potential, some dietary fibers have detrimental effects in select patients with active IBD who lack fermentative microbe activities. The study is publicly accessible at the U.S. National Institutes of Health database (clinicaltrials.gov identification number NCT02865707).
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Metabolic signature of 13C-labeled wheat bran consumption related to gut fermentation in humans: a pilot study.
Meiller, L, Sauvinet, V, Breyton, AE, Ranaivo, H, Machon, C, Mialon, A, Meynier, A, Bischoff, SC, Walter, J, Neyrinck, AM, et al
European journal of nutrition. 2023;(6):2633-2648
Abstract
PURPOSE The aim of this pilot study was to analyze concomitantly the kinetics of production of 13C-labeled gut-derived metabolites from 13C-labeled wheat bran in three biological matrices (breath, plasma, stools), in order to assess differential fermentation profiles among subjects. METHODS Six healthy women consumed a controlled breakfast containing 13C-labeled wheat bran biscuits. H2, CH4 and 13CO2, 13CH4 24 h-concentrations in breath were measured, respectively, by gas chromatography (GC) and GC-isotope ratio mass spectrometry (GC-IRMS). Plasma and fecal concentrations of 13C-short-chain fatty acids (linear SCFAs: acetate, propionate, butyrate, valerate; branched SCFAs: isobutyrate, isovalerate) were quantified using GC-combustion-IRMS. Gut microbiota composition was assessed by16S rRNA gene sequencing analysis. RESULTS H2 and CH4 24 h-kinetics distinguished two groups in terms of fermentation-related gas excretion: high-CH4 producers vs low-CH4 producers (fasting concentrations: 45.3 ± 13.6 ppm vs 6.5 ± 3.6 ppm). Expired 13CH4 was enhanced and prolonged in high-CH4 producers compared to low-CH4 producers. The proportion of plasma and stool 13C-butyrate tended to be higher in low-CH4 producers, and inversely for 13C-acetate. Plasma branched SCFAs revealed different kinetics of apparition compared to linear SCFAs. CONCLUSION This pilot study allowed to consider novel procedures for the development of biomarkers revealing dietary fiber-gut microbiota interactions. The non-invasive assessment of exhaled gas following 13C-labeled fibers ingestion enabled to decipher distinct fermentation profiles: high-CH4 producers vs low-CH4 producers. The isotope labeling permits a specific in vivo characterisation of the dietary fiber impact consumption on microbiota metabolite production. CLINICAL TRIAL REGISTRATION The study has been registered under the number NCT03717311 at ClinicalTrials.gov on October 24, 2018.
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Impact of a Powdered Meal Replacement on Metabolism and Gut Microbiota (PREMIUM) in individuals with excessive body weight: a study protocol for a randomised controlled trial.
Montenegro, J, L P Oliveira, C, Armet, AM, Berg, A, Sharma, AM, Mereu, L, Cominetti, C, Ghosh, S, Richard, C, Nguyen, NK, et al
BMJ open. 2023;(9):e070027
Abstract
INTRODUCTION Excess body weight is associated with a state of low-grade chronic inflammation and alterations of the gut microbiome. Powdered meal replacements (PMR) have been shown to be an effective strategy for weight management; however, their effect on inflammation and the gut microbiome remains unclear. The aim of this 12-week randomised control clinical trial is to investigate the effects of PMR consumption, here given as a soy-yoghurt-honey formula, on inflammation, gut microbiome and overall metabolism in individuals with excessive body weight. METHODS AND ANALYSIS Healthy adults with excess body weight (n=88) are being recruited and randomly assigned to one of the following groups: (1) Control group (CON): maintaining usual diet for 12 weeks, or (2) PMR group: replacing morning and afternoon snacks daily with a PMR for 12 weeks. Participants are asked to maintain body weight throughout the study and fill out a journal with information about PMR consumption, body weight, food intake, appetite sensations and medications. Three study visits are required: baseline, week 6 and week 12. Outcome measures include systemic inflammatory biomarkers, gut microbiome composition, metabolic blood markers, host energy metabolism, body composition, appetite sensations and host gene expression profile. ETHICS AND DISSEMINATION This research protocol was approved by the University of Alberta Ethics Board (Pro00070712) and adheres to the Canadian Tri-Council Policy statement on the use of human participants in research. Procedures and potential risks are fully discussed with participants. Study findings will be disseminated in peer-reviewed journals, conference presentations and social media. TRIAL REGISTRATION NUMBER NCT03235804.
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Starter Culture Development and Innovation for Novel Fermented Foods.
Gänzle, MG, Monnin, L, Zheng, J, Zhang, L, Coton, M, Sicard, D, Walter, J
Annual review of food science and technology. 2023
Abstract
Interest in fermented foods is increasing because fermented foods are promising solutions for more secure food systems with an increased proportion of minimally processed plant foods and a smaller environmental footprint. These developments also pertain to novel fermented food for which no traditional template exists, raising the question of how to develop starter cultures for such fermentations. This review establishes a framework that integrates traditional and scientific knowledge systems for the selection of suitable cultures. Safety considerations, the use of organisms in traditional food fermentations, and the link of phylogeny to metabolic properties provide criteria for culture selection. Such approaches can also select for microbial strains that have health benefits. A science-based approach to the development of novel fermented foods can substantially advance their value through more secure food systems, food products that provide health-promoting microbes, and the provision of foods that improve human health. Expected final online publication date for the Annual Review of Food Science and Technology, Volume 15 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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The separate effects of whole oats and isolated beta-glucan on lipid profile: A systematic review and meta-analysis of randomized controlled trials.
de Morais Junior, AC, Schincaglia, RM, Viana, RB, Armet, AM, Prado, CM, Walter, J, Mota, JF
Clinical nutrition ESPEN. 2023;:224-237
Abstract
BACKGROUND & AIMS It is well known that dietary fiber positively impacts the microbiome and health as a whole. However, the health effects of β-glucan, a dietary fiber extracted from oats, have been questioned when administered alone or incorporated into other foods. The purpose of this systematic review and meta-analysis was to evaluate the impact of oats or β-glucan supplements on the lipid profile. METHODS Randomized controlled trials with parallel-arm or crossover blinded interventions at least two weeks in duration, for hyperlipidemic or non-hyperlipidemic men and women ≥18 years of age were selected. Only single (participants blinded) or double-blinded studies that compared oat or isolated β-glucan with a placebo/control group were considered for this review. The databases EMBASE, PubMed, Web of science and CINHAL were searched, from the earliest indexed year available online to the end of January 2022. Random-effects models were used to combine the estimated effects extracted from individual studies, and data were summarized as standardized mean difference (SMD) and 95% confidence interval (95%CI). RESULTS A total of 811 articles were screened for eligibility, and relevant data were extracted from 28 studies, totaling 1494 subjects. Oat interventions TC (-0.61, 95%CI: -0.84;-0.39, p < 0.00001, and -0.70, 95%CI: -1.07;-0.34, p = 0.0002, respectively) and LDL (-0.51, 95%CI: -0.71;-0.31, p < 0.00001, and -0.38, 95%CI: -0.60;-0.15, p = 0.001, respectively). Moreover, isolated β-glucan interventions from parallel-arm studies decreased TC (-0.73, 95%CI: -1.01;-0.45, p < 0.00001), LDL (-0.58, 95%CI: -0.85;-0.32, p < 0.0001) and triglycerides (-0.30, 95%CI: -0.49;-0.12, p = 0.001). HDL was not altered by either oat or isolated β-glucan (p > 0.05). CONCLUSION Overall, this review showed that both oat and isolated β-glucan interventions improved lipid profiles. Furthermore, the ingestion of oats or isolated β-glucan supplements are effective tools to combat dyslipidemia and should be considered in cardiovascular disease prevention.
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Gut microbiota alterations induced by intensive chemotherapy in acute myeloid leukaemia patients are associated with gut barrier dysfunction and body weight loss.
Pötgens, SA, Lecop, S, Havelange, V, Li, F, Neyrinck, AM, Neveux, N, Maertens, J, Walter, J, Schoemans, H, Delzenne, NM, et al
Clinical nutrition (Edinburgh, Scotland). 2023;(11):2214-2228
Abstract
BACKGROUND & AIMS Acute myeloid leukaemia (AML) chemotherapy has been reported to impact gut microbiota composition. In this study, we investigated using a multi -omics strategy the changes in the gut microbiome induced by AML intense therapy and their association with gut barrier function and cachectic hallmarks. METHODS 10 AML patients, allocated to standard induction chemotherapy (SIC), were recruited. Samples and data were collected before any therapeutic intervention (T0), at the end of the SIC (T1) and at discharge (T4). Gut microbiota composition and function, markers of inflammation, metabolism, gut barrier function and cachexia, as well as faecal, blood and urine metabolomes were assessed. RESULTS AML patients demonstrated decreased appetite, weight loss and muscle wasting during hospitalization, with an incidence of cachexia of 50%. AML intensive treatment transiently impaired the gut barrier function and led to a long-lasting change of gut microbiota composition characterized by an important loss of diversity. Lactobacillaceae and Campylobacter concisus were increased at T1 while Enterococcus faecium and Staphylococcus were increased at T4. Metabolomics analyses revealed a reduction in urinary hippurate and faecal bacterial amino acid metabolites (bAAm) (2-methylbutyrate, isovalerate, phenylacetate). Integration using DIABLO revealed a deep interconnection between all the datasets. Importantly, we identified bacteria which disappearance was associated with impaired gut barrier function (Odoribacter splanchnicus) and body weight loss (Gemmiger formicilis), suggesting these bacteria as actionable targets. CONCLUSION AML intensive therapy transiently impairs the gut barrier function while inducing enduring alterations in the composition and metabolic activity of the gut microbiota that associate with body weight loss. TRIAL REGISTRATION NCT03881826, https://clinicaltrials.gov/ct2/show/NCT03881826.
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Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial.
Hahn, J, Cook, NR, Alexander, EK, Friedman, S, Walter, J, Bubes, V, Kotler, G, Lee, IM, Manson, JE, Costenbader, KH
BMJ (Clinical research ed.). 2022;376:e066452
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Free full text
Expert Review
Conflicts of interest:
None
Take Home Message:
Important from a public health perspective:
- Vitamin D supplementation for five years with or without omega 3 diminished autoimmune conditions by 22%. To promote awareness of essential fatty acids and micronutrients in decreasing the risk of autoimmune disease.
- To offer potential prophylaxis to attenuate the risk of certain autoimmune diseases.
- To provide evidence that Vitamin D supplementation, potentially in conjunction with Omega 3, could reduce the risk of particular autoimmune conditions.
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:
Background
The authors highlighted that autoimmune conditions are the third highest cause of morbidity in high-income nations and a primary cause of death in females. These diseases bear significant health, economic and social burdens considering the sparsity of remediation. Vitamin D and marine derived, long chain Omega 3 fatty acids are being investigated in this study as potential treatments to attenuate the risk of autoimmune conditions.
Objectives
To assess whether Vitamin D and marine derived long chain Omega 3 fatty acids can decrease autoimmune disease risk.
Study Design
Randomized, double blinded, placebo controlled trial in the United States.
Participants
At baseline:
12 786 men ≥50 years
13 085 women ≥55 years
Interventions
- Vitamin D (2000 IU/day) or equivalent placebo, and Omega 3 fatty acids (1000 mg/day) or equivalent placebo were administered to participants.
- Incident autoimmune conditions were self-reported from baseline to a follow up median of 5.3 years. These were validated through a robust assessment of medical records. The principal outcome was confirmation of all incident autoimmune conditions via analysis of these medical records, e.g. autoimmune thyroiditis, inflammatory bowel disorder, polymyalgia rheumatica, rheumatoid arthritis and psoriasis, amongst others.
- Cox proportional hazards models were employed to ascertain the impact of Vitamin D and Omega 3 on the incidence of autoimmune diseases.
Results
- Vitamin D: 123 subjects in the treatment cohort and 155 in the placebo group had a confirmed autoimmune condition (hazard ratio 0.78; 95% confidence interval 0.61 to 0.99; P=0.05).
- Omega 3: 130 subjects in the treatment group and 148 in the placebo cohort had a confirmed autoimmune condition (hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.67 to 1.08; P=0.19).
- In comparison with the Vitamin D and Omega 3 control arms (88 with confirmed autoimmune conditions), 63 participants who were administered vitamin D and Omega 3 (HR 0.69; CI 95% 0.49 to 0.96; P=0.03), 60 subjects who were administered only vitamin D (HR 0.68; CI 95% 0.48 to 0.94; P=0.02) and 67 only Omega 3 (HR 0.74 0.54 to 1.03; P=0.07) had confirmed autoimmune diseases.
Conclusions
Vitamin D supplementation for five years, with or without omega 3 diminished autoimmune conditions by 22%; whereas omega 3 supplementation with or without vitamin D reduced autoimmune diseases by 15% (not statistically significant). Both interventions demonstrated more significant effects than the placebos.
Clinical practice applications:
These findings might be useful for Nutritional Therapists and Clinical Practitioners:
- To inform practitioners of the benefits of supplementation of Vitamin D (2000 IU/day) for reducing the risk of certain autoimmune diseases potentially in tandem with Omega 3 supplementation (1000 mg/day). Omega 3 supplementation would require further investigation based on the lack of statistical significance of some of the results.
- To educate clients regarding the benefits of Vitamin D potentially combined with Omega 3 to reduce the risk of certain autoimmune diseases.
Considerations for future research:
- More extensive Omega 3 interventions could investigate the possible benefits of supplementation to reduce the risk of autoimmune disease.
- Other supplements could be assessed as possible therapeutics to decrease the risk of certain autoimmune conditions.
Abstract
OBJECTIVE To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk. DESIGN Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design. SETTING Nationwide in the United States. PARTICIPANTS 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment. INTERVENTIONS Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence. MAIN OUTCOME MEASURES The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others. RESULTS 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease. CONCLUSIONS Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo). STUDY REGISTRATION ClinicalTrials.gov NCT01351805 and NCT01169259.
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Supplementation with a probiotic mixture accelerates gut microbiome maturation and reduces intestinal inflammation in extremely preterm infants.
Samara, J, Moossavi, S, Alshaikh, B, Ortega, VA, Pettersen, VK, Ferdous, T, Hoops, SL, Soraisham, A, Vayalumkal, J, Dersch-Mills, D, et al
Cell host & microbe. 2022;30(5):696-711.e5
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Plain language summary
Preterm infants display a disrupted and potentially pathogenic gut microbiome compared to infants born at full term. They are also more likely to be born by caesarean section, receive antibiotics and remain in hospital for an extended period, all which can contribute to gut microbiota disruptions. Probiotics are increasingly being given to preterm infants to counteract the disruptions; however, their effects are under researched in this cohort of individuals. This randomised control trial of 57 extremely premature infants aimed to determine the effects of a probiotic supplement on gut microbiota composition and their effects on gut immunity. The results showed that Bifidobacterium strains could colonise the premature infant gut but not Lactabacillus rhamnosus. Probiotics also accelerated the maturation of the gut microbiome in premature infants and Bifidobacterium were responsible for this resulting in an anti-inflammatory effect in the gut. It was concluded that probiotic supplementation with the right microbes can act to mature the gut microbiome of preterm infants resulting in its restoration and associated health benefits. This study could be used by healthcare professionals to understand that preterm infants may have a disordered gut microbiota, but a healthy community can be restored through using a probiotic containing Bifidobacterium.
Abstract
Probiotics are increasingly administered to premature infants to prevent necrotizing enterocolitis and neonatal sepsis. However, their effects on gut microbiome assembly and immunity are poorly understood. Using a randomized intervention trial in extremely premature infants, we tested the effects of a probiotic product containing four strains of Bifidobacterium species autochthonous to the infant gut and one Lacticaseibacillus strain on the compositional and functional trajectory of microbiome. Daily administration of the mixture accelerated the transition into a mature, term-like microbiome with higher stability and species interconnectivity. Besides infant age, Bifidobacterium strains and stool metabolites were the best predictors of microbiome maturation, and structural equation modeling confirmed probiotics as a major determinant for the trajectory of microbiome assembly. Bifidobacterium-driven microbiome maturation was also linked to an anti-inflammatory intestinal immune milieu. This demonstrates that Bifidobacterium strains are ecosystem engineers that lead to an acceleration of microbiome maturation and immunological consequences in extremely premature infants.