Publications by authors named "Hermie J M Harmsen"

82 Publications

Nutritional and ecological perspectives of the interrelationships between diet and the gut microbiome in multiple sclerosis: Insights from marmosets.

iScience 2021 Jul 10;24(7):102709. Epub 2021 Jun 10.

Department of Agricultural, Nutritional and Food Science, University of Alberta, Edmonton, AB T6G 2P5, Canada.

Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, have shown potential links between diet components, microbiome composition, and modulation of immune responses. In this review, we reanalyze and discuss findings in an outbred marmoset EAE model in which a yogurt-based dietary supplement decreased disease frequency and severity. We show that although diet has detectable effects on the fecal microbiome, microbiome changes are more strongly associated with the EAE development. Using an ecological framework, we further show that the dominant factors influencing the gut microbiota were marmoset sibling pair and experimental time point. These findings emphasize challenges in assigning cause-and-effect relationships in studies of diet-microbiome-host interactions and differentiating the diet effects from other environmental, stochastic, and host-related factors. We advocate for animal experiments to be designed to allow causal inferences of the microbiota's role in pathology while considering the complex ecological processes that shape microbial communities.
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http://dx.doi.org/10.1016/j.isci.2021.102709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282968PMC
July 2021

Weight shapes the intestinal microbiome in preterm infants: results of a prospective observational study.

BMC Microbiol 2021 Jul 21;21(1):219. Epub 2021 Jul 21.

Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Background: The intestinal microbiome in preterm infants differs markedly from term infants. It is unclear whether the microbiome develops over time according to infant specific factors.

Methods: We analysed (clinical) metadata - to identify the main factors influencing the microbiome composition development - and the first meconium and faecal samples til the 4th week via 16 S rRNA amplican sequencing.

Results: We included 41 infants (gestational age 25-30 weeks; birth weight 430-990 g. Birth via Caesarean section (CS) was associated with placental insufficiency during pregnancy and lower BW. In meconium samples and in samples from weeks 2 and 3 the abundance of Escherichia and Bacteroides (maternal faecal representatives) were associated with vaginal delivery while Staphylococcus (skin microbiome representative) was associated with CS. Secondly, irrespective of the week of sampling or the mode of birth, a transition was observed as children children gradually increased in weight from a microbiome dominated by Staphylococcus (Bacilli) towards a microbiome dominated by Enterobacteriaceae (Gammaproteobacteria).

Conclusions: Our data show that the mode of delivery affects the meconium microbiome composition. They also suggest that the weight of the infant at the time of sampling is a better predictor for the stage of progression of the intestinal microbiome development/maturation than postconceptional age as it less confounded by various infant-specific factors.
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http://dx.doi.org/10.1186/s12866-021-02279-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293572PMC
July 2021

The effect of calcium palmitate on bacteria associated with infant gut microbiota.

Microbiologyopen 2021 Jun;10(3):e1187

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Gut microbiota development in formula-fed and breast-fed infants is known to differ. This could relate to the usage of unmodified vegetable oil instead of mammalian fat in infant formula (IF), causing the enhanced formation of the poorly soluble soap calcium palmitate (CP) in the infant's gut. Here we investigate in vitro the possible influence of CP on the infant gut bacteria. The growth of several bacterial species dominant in the infant's gut was analyzed by culturing in media with CP. Faecalibacterium prausnitzii as a sensitive representative was analyzed in detail by scanning transmission electron microscopy, membrane staining, gas chromatography, and microbial fuel cell experiments. Of all bacteria tested, the growth of several bifidobacteria and F. prausnitzii was reduced at 0.01 mg/ml CP, Bifidobacterium infantis stopped growing completely. CP reduced the cell envelope thickness of F. prausnitzii, disturbed the cell membrane fatty acids and function of membrane proteins involved in electron transport. CP inhibited the growth of bifidobacteria and faecalibacteria. This suggests that modification of fat in IF may benefit the development of the gut microbiota in formula-fed infants by supporting the colonization of important beneficial bacteria in early life. Future clinical studies are needed to confirm this.
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http://dx.doi.org/10.1002/mbo3.1187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123918PMC
June 2021

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation.

Eur J Cancer 2021 Aug 12;153:27-39. Epub 2021 Jun 12.

Department of Medical Microbiology, University Medical Centre Groningen, The University of Groningen, Groningen, the Netherlands.

Background: Chemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them.

Methods/results: Here, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery (P < 0.0001) whilst increasing diarrhoea severity (P = 0.0007) and treatment-related mortality (P = 0.0045). Importantly, these detrimental effects were reversed when the microbiome was restored using autologous FMT (P = 0.03), a phenomenon dictated by the uptake and subsequent expansion of Muribaculaceae.

Conclusions: These are the first data to show that clinically impactful symptoms of gastrointestinal toxicity are dictated by the microbiome and provide a clear rationale for how and when to target the microbiome to mitigate the acute and chronic complications caused by disruption of the gastrointestinal microenvironment. Translation of this new knowledge should focus on stabilising and strengthening the gut microbiome before chemotherapy and developing new microbial approaches to accelerate recovery of the mucosa. By controlling the depth and duration of mucosal injury, secondary consequences of gastrointestinal toxicity may be avoided.
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http://dx.doi.org/10.1016/j.ejca.2021.05.015DOI Listing
August 2021

Discrepancy between self-perceived mycophenolic acid-associated diarrhea and stool water content after kidney transplantation.

Clin Transplant 2021 07 2;35(7):e14321. Epub 2021 May 2.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Diarrhea is a well-known side effect of mycophenolic acid (MPA) use in kidney transplant recipients (KTRs). It is unknown whether self-reported diarrhea using the Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) corresponds to stool water content and how both relate to MPA usage.

Methods: MTSOSD-59R questionnaires filled out by 700 KTRs from the TransplantLines Biobank and Cohort Study (NCT03272841) were analyzed and compared with stool water content. Stool samples (N = 345) were freeze-dried, and a water content ≥80% was considered diarrhea.

Results: Self-perceived diarrhea was reported by 46%, while stool water content ≥80% was present in 23% of KTRs. MPA use was not associated with self-perceived diarrhea (odds ratio(OR) 1.32; 95% confidence interval(CI), 0.87-1.99, p = .2), while it was associated with stool water content ≥80% (OR 2.88; 95%CI, 1.41-5.89, p = .004), independent of potential confounders. Adjustment for prior MPA discontinuation because of severe diarrhea, uncovered an association between MPA use and self-perceived diarrhea (OR 1.80; 95%CI, 1.13-2.89, p = .01).

Conclusions: These results suggest that reporting bias could add to the discrepancy between both methods for diarrhea assessment. We recommend use of objective biomarkers or more extensive questionnaires which assess information on stool frequency and stool consistency, to investigate post-transplantation diarrhea.
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http://dx.doi.org/10.1111/ctr.14321DOI Listing
July 2021

Prophylactic Treatment with Vitamins C and B2 for Methotrexate-Induced Gastrointestinal Mucositis.

Biomolecules 2020 Dec 29;11(1). Epub 2020 Dec 29.

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EB80, 9713 GZ Groningen, The Netherlands.

Mucositis is a common side-effect of chemotherapy treatment, inducing alterations in the composition of the gut microbiota. Redox active compounds, such as vitamins B2 and C, have been shown to reduce inflammation and enhance the growth of anaerobic bacteria in the gut. We therefore aimed to (1) validate the ability of these compounds to promote bacterial cell growth in vitro, and (2) determine their prophylactic efficacy in a rat model of methotrexate (MTX)-induced mucositis. Bacterial growth curves were performed to assess the growth kinetics of bacteria exposed to Vitamins C and B2 (0.5 mM). Male wistar rats (150-200 g) received vitamins B2 (12 mg/day) and C (50 mg/day) via daily oral gavage (from day -1 to day 10). MTX (45 mg/Kg) was administrated via I.V. injection (N = 4-8/group) on day 0. Body weight, water/food consumption and diarrhea were assessed daily. Blood and faecal samples were collected longitudinally to assess citrulline levels (mucositis biomarker) and gut microbiota composition. Vitamins C/B2 enhanced the in vitro growth of anaerobic bacteria and . Contrarily to vitamin B2, in vivo administration of Vitamin C significantly attenuated clinical symptoms of mucositis. Despite their influence on the composition of the gut microbiota, both vitamins did not modulate the course of MTX-induced mucositis, as accessed by plasma citrulline. Vitamins B2 and C enhanced anaerobic bacterial growth in vitro, however their ability to mitigate MTX-induced mucositis was limited.
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http://dx.doi.org/10.3390/biom11010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823339PMC
December 2020

Effects of Different Human Milk Oligosaccharides on Growth of in Monoculture and Co-culture With .

Front Microbiol 2020 30;11:569700. Epub 2020 Oct 30.

Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Human milk oligosaccharides (hMOs) are important bioactive components in mother's milk contributing to infant health by supporting colonization and growth of gut microbes. In particular, genus is considered to be supported by hMOs. Approximately 200 different hMOs have been discovered and characterized, but only a few abundant hMOs can be produced in sufficient amounts to be applied in infant formula. These hMOs are usually supplied in infant formula as single molecule, and it is unknown which and how individual hMOs support growth of individual gut bacteria. To investigate how individual hMOs influence growth of several relevant intestinal bacteria species, we studied the effects of three hMOs (2'-fucosyllactose, 3-fucosyllactose, and 6'-sialyllactose) and an hMO acid hydrolysate (lacto-N-triose) on three and one and introduced a co-culture system of two bacterial strains to study possible cross-feeding in presence and absence of hMOs. We observed that in monoculture, subsp. could grow well on all hMOs but in a structure-dependent way. reached a lower cell density on the hMOs in stationary phase compared to glucose, while subsp. and were not able to grow on the tested hMOs. In a co-culture of subsp. with , different effects were observed with the different hMOs; 6'-sialyllactose, rather than 2'-fucosyllactose, 3-fucosyllactose, and lacto-N-triose, was able to promote the growth of subsp. . Our observations demonstrate that effects of hMOs on the tested gut microbiota are hMO-specific and provide new means to support growth of these specific beneficial microorganisms in the intestine.
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http://dx.doi.org/10.3389/fmicb.2020.569700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662573PMC
October 2020

Effect of High versus Low Dairy Consumption on the Gut Microbiome: Results of a Randomized, Cross-Over Study.

Nutrients 2020 Jul 17;12(7). Epub 2020 Jul 17.

Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

The influence of dairy on the gut microbiome has not been studied extensively. We performed a randomized cross-over study to analyze the effect of high dairy intake on the gut microbiome. Subjects were randomly assigned to a high-dairy diet (HDD) (5-6 dairy portions per day) and a low-dairy diet (LDD) (≤1 dairy portion per day) for 6 weeks with a washout period of 4 weeks in between both diets. The gut microbiome was assessed using 16S rRNA gene sequencing. Compositionality and functionality of the gut microbiome was assessed using Quantitative Insights Into Microbial Ecology (QIIME) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Stool consistency was evaluated using the Bristol stool chart. In total, 46 healthy overweight subjects (BMI range 25-30 kg/m) completed both intervention periods. During the HDD, there was a significantly higher abundance of the genera , , and , and the species , and ( < 0.10). Furthermore, during the HDD, there was a significantly lower abundance of the genera and , and the species , , , and ( < 0.10). There were eight subjects who became constipated during the HDD and these subjects all had a lower abundance of . This is the first cross-over study in which the effect of an HDD compared to an LDD on the gut microbiome has been studied. An HDD led to a significantly different composition of the gut microbiome, with a particularly lower abundance of and a higher abundance of . Constipation was observed in several subjects during the HDD. Predicted metabolic pathways were not significantly altered due to an HDD.
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http://dx.doi.org/10.3390/nu12072129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400927PMC
July 2020

Pitfalls and novel experimental approaches to optimize microbial interventions for chemotherapy-induced gastrointestinal mucositis.

Curr Opin Support Palliat Care 2020 06;14(2):127-134

Department of Medical Microbiology.

Purpose Of Review: There is a growing number of studies implicating gut dysbiosis in mucositis development. However, few studies have shed light on the causal relationship limiting translational potential. Here, we detail the key supportive evidence for microbial involvement, candidate mechanisms by which the microbiome may contribute to mucositis and emerging approaches to model host-microbe interactions with clinical relevance and translational potential.

Recent Findings: Synthesis of existing clinical data demonstrate that modulating the microbiome drastically alters the development and severity of mucositis, providing a strong rationale for its involvement. Review of the literature revealed potential microbiome-dependent mechanisms of mucosal injury including altered drug metabolism, bile acid synthesis and regulation of the intestinal barrier. Current studies are limited in their mechanistic insight due to cross-sectional and would benefit from longitudinal analyses and baseline phenotyping.

Summary: The causative role of the microbiome in mucositis development remains unclear. Future studies must adopt comprehensive microbial analyses with functional assessment, and utilize emerging ex-vivo models to interrogate host-microbe interactions in mucositis.
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http://dx.doi.org/10.1097/SPC.0000000000000497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259380PMC
June 2020

Altered Gut Microbial Fermentation and Colonization with in Renal Transplant Recipients.

J Clin Med 2020 Feb 14;9(2). Epub 2020 Feb 14.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Renal transplant recipients (RTRs) often suffer from posttransplant diarrhea. The observed dysbiosis in RTR may influence the fermentation processes in the gut. In this study, we aimed to investigate whether fermentation differs between RTRs and healthy controls (HCs), by measuring breath H and CH concentrations. Additionally, we determined the fecal presence of the methanogen (), which plays a main role in the process of methanogenesis. Data from the TransplantLines Biobank and Cohort Study (NCT03272841) was used. A total of 142 RTRs and 77 HCs were included. Breath H concentrations in RTRs were not significantly different from HCs. Breath CH concentrations in RTRs were significantly lower compared with HCs (median [interquartile range (IQR)] 7.5 [3.9-10.6] ppm vs. 16.0 [8.0-45.5] ppm, < 0.001). was less frequently present in the feces of RTRs compared to HCs (28.6% vs. 86.4% resp., < 0.001). Our findings regarding the altered methanogenesis in the gut of RTRs show similarities with previous results in inflammatory bowel disease patients. These findings provide novel insight into the alterations of fermentation after renal transplantation, which may contribute to understanding the occurrence of posttransplant diarrhea.
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http://dx.doi.org/10.3390/jcm9020518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073595PMC
February 2020

Characteristics and Dysbiosis of the Gut Microbiome in Renal Transplant Recipients.

J Clin Med 2020 Feb 1;9(2). Epub 2020 Feb 1.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.

Renal transplantation is life-changing in many aspects. This includes changes to the gut microbiome likely due to exposure to immunosuppressive drugs and antibiotics. As a consequence, renal transplant recipients (RTRs) might suffer from intestinal dysbiosis. We aimed to investigate the gut microbiome of RTRs and compare it with healthy controls and to identify determinants of the gut microbiome of RTRs. Therefore, RTRs and healthy controls participating in the TransplantLines Biobank and Cohort Study (NCT03272841) were included. We analyzed the gut microbiome using 16S rRNA sequencing and compared the composition of the gut microbiome of RTRs to healthy controls using multivariate association with linear models (MaAsLin). Fecal samples of 139 RTRs (50% male, mean age: 58.3 ± 12.8 years) and 105 healthy controls (57% male, mean age: 59.2 ± 10.6 years) were collected. Median time after transplantation of RTRs was 6.0 (1.5-12.5)years. The microbiome composition of RTRs was significantly different from that of healthy controls, and RTRs had a lower diversity of the gut microbiome ( < 0.01). Proton-pump inhibitors, mycophenolate mofetil, and estimated glomerular filtration rate (eGFR) are significant determinants of the gut microbiome of RTRs ( < 0.05). Use of mycophenolate mofetil correlated to a lower diversity ( < 0.01). Moreover, significant alterations were found in multiple bacterial taxa between RTRs and healthy controls. The gut microbiome of RTRs contained more Proteobacteria and less Actinobacteria, and there was a loss of butyrate-producing bacteria in the gut microbiome of RTRs. By comparing the gut microbiome of RTRs to healthy controls we have shown that RTRs suffer from dysbiosis, a disruption in the balance of the gut microbiome.
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http://dx.doi.org/10.3390/jcm9020386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074359PMC
February 2020

Marked Changes in Gut Microbiota in Cardio-Surgical Intensive Care Patients: A Longitudinal Cohort Study.

Front Cell Infect Microbiol 2019 15;9:467. Epub 2020 Jan 15.

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Virtually no studies on the dynamics of the intestinal microbiota in patients admitted to the intensive care unit (ICU) are published, despite the increasingly recognized important role of microbiota on human physiology. Critical care patients undergo treatments that are known to influence the microbiota. However, dynamics and extent of such changes are not yet fully understood. To address this topic, we analyzed the microbiota before, during and after planned major cardio surgery that, for the first time, allowed us to follow the microbial dynamics of critical care patients. In this prospective, observational, longitudinal, single center study, we analyzed the fecal microbiota using 16S rRNA gene sequencing. Samples of 97 patients admitted between April 2015 and November 2016 were included. In 32 patients, data of all three time points (before, during and after admission) were available for analysis. We found a large intra-individual variation in composition of gut microbiota. During admission, a significant change in microbial composition occurred in most patients, with a significant increase in pathobionts combined with a decrease in strictly anaerobic gut bacteria, typically beneficial for health. A lower bacterial diversity during admission was associated with longer hospitalization. In most patients analyzed at all three time points, the change in microbiota during hospital stay reverted to the original composition post-discharge. Our study shows that, even with a short ICU stay, patients present a significant change in microbial composition shortly after admission. The unique longitudinal setup of this study displayed a restoration of the microbiota in most patients to baseline composition post-discharge, which demonstrated its great restorative capacity. A relative decrease in benign or even beneficial bacteria and increase of pathobionts shifts the microbial balance in the gut, which could have clinical relevance. In future studies, the microbiota of ICU patients should be considered a good target for optimisation.
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http://dx.doi.org/10.3389/fcimb.2019.00467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974539PMC
September 2020

Riboflavin Supplementation in Patients with Crohn's Disease [the RISE-UP study].

J Crohns Colitis 2020 Jun;14(5):595-607

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background And Aims: Crohn's disease [CD] is characterised by chronic intestinal inflammation and dysbiosis in the gut. Riboflavin [vitamin B2] has anti-inflammatory, antioxidant and microbiome-modulatory properties. Here, we analysed the effect of riboflavin on oxidative stress, markers of inflammation, clinical symptoms, and faecal microbiome in patients with CD.

Methods: In this prospective clinical intervention study, patients received 100 mg riboflavin [DSM, Nutritional Products Ltd] daily for 3 weeks. Clinical disease activity [Harvey-Bradshaw Index: HBI], serum biomarkers of inflammation and redox status [plasma free thiols], and faecal microbiome taxonomical composition and functionality [fluorescent in situ hybridisation: FISH; and metagenomic shotgun sequencing: MGS], were analysed before and after riboflavin intervention.

Results: In total, 70 patients with CD with varying disease activity were included. Riboflavin supplementation significantly decreased serum levels of inflammatory markers. In patients with low faecal calprotectin [FC] levels, IL-2 decreased, and in patients with high FC levels, C-reactive protein [CRP] was reduced and free thiols significantly increased after supplementation. Moreover, HBI was significantly decreased by riboflavin supplementation. Riboflavin supplementation led to decreased Enterobacteriaceae in patients with low FC levels as determined by FISH; however, MGS analysis showed no effects on diversity, taxonomy, or metabolic pathways of the faecal microbiome.

Conclusions: Three weeks of riboflavin supplementation resulted in a reduction in systemic oxidative stress, mixed anti-inflammatory effects, and a reduction in clinical symptoms [HBI]. FISH analysis showed decreased Enterobacteriaceae in patients with CD with low FC levels, though this was not observed in MGS analysis. Our data demonstrate that riboflavin supplementation has a number of anti-inflammatory and anti-oxidant effects in CD.
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http://dx.doi.org/10.1093/ecco-jcc/jjz208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303596PMC
June 2020

Heterogeneous antimicrobial activity in broncho-alveolar aspirates from mechanically ventilated intensive care unit patients.

Virulence 2019 12;10(1):879-891

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Pneumonia is an infection of the lungs, where the alveoli in the affected area are filled with pus and fluid. Although ventilated patients are at risk, not all ventilated patients develop pneumonia. This suggests that the sputum environment may possess antimicrobial activities. Despite the generally acknowledged importance of antimicrobial activity in protecting the human lung against infections, this has not been systematically assessed to date. Therefore, the objective of the present study was to measure antimicrobial activity in broncho-alveolar aspirate ('sputum") samples from patients in an intensive care unit (ICU) and to correlate the detected antimicrobial activity with antibiotic levels, the sputum microbiome, and the respective patients' characteristics. To this end, clinical metadata and sputum were collected from 53 mechanically ventilated ICU patients. The antimicrobial activity of sputum samples was tested against and . Here we show that sputa collected from different patients presented a high degree of variation in antimicrobial activity, which can be partially attributed to antibiotic therapy. The sputum microbiome, although potentially capable of producing antimicrobial agents, seemed to contribute in a minor way, if any, to the antimicrobial activity of sputum. Remarkably, despite its potentially protective effect, the level of antimicrobial activity in the investigated sputa correlated inversely with patient outcome, most likely because disease severity outweighed the beneficial antimicrobial activities.
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http://dx.doi.org/10.1080/21505594.2019.1682797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844299PMC
December 2019

Corrigendum: Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases.

Front Immunol 2019;10:1486. Epub 2019 Jun 28.

Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.

[This corrects the article DOI: 10.3389/fimmu.2019.00277.].
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http://dx.doi.org/10.3389/fimmu.2019.01486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611342PMC
June 2019

Response to Comment on "Mucus Microbiome of Anastomotic Tissue During Surgery Has Predictive Value for Colorectal Anastomotic Leakage".

Ann Surg 2019 05;269(5):e69-e70

Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1097/SLA.0000000000002857DOI Listing
May 2019

Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases.

Front Immunol 2019 11;10:277. Epub 2019 Mar 11.

Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.

Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.
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http://dx.doi.org/10.3389/fimmu.2019.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421268PMC
September 2020

Assessing intestinal permeability in Crohn's disease patients using orally administered 52Cr-EDTA.

PLoS One 2019 7;14(2):e0211973. Epub 2019 Feb 7.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Intestinal permeability can be assessed by monitoring renal excretion of orally administered radioactively 51Cr-labeled ethylenediaminetetraacetic acid (51Cr-EDTA). Although considered safe, patient participation in using radio-labeled tracers is low. Here, we used orally administered 52Cr-EDTA as non-radioactive alternative to assess intestinal permeability in CD and analyzed the association with disease activity, disease location and gut microbial dysbiosis.

Materials And Methods: 60 CD patients with low (n = 25) and increased (n = 35) fecal calprotectin levels (cut-off: 100 μg/g feces) ingested 20 mL 52Cr-EDTA (20 mmol/L) solution whereafter 24-h urine was collected. Urinary 52Cr-EDTA concentrations were quantified using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Fecal Enterobacteriaceae and Faecalibacterium prausnitzii were quantified using FISH. Correlations between urinary 52Cr-EDTA excretion and other parameters were established using nonparametric Spearman's correlation coefficients (ρ).

Results: CD patients with increased fecal calprotectin levels (> 100 μg/g) demonstrated an elevated urinary 52Cr-EDTA/creatinine ratio (772 vs. 636 μmol/mol, P = 0.132). Patients with primarily colonic disease showed the highest 52Cr-EDTA excretion. Importantly, a positive correlation was observed for the urinary 52Cr-EDTA/creatinine ratio and fecal calprotectin levels (ρ = 0.325, P < 0.05). Finally, urinary 52Cr-EDTA/creatinine ratio negatively correlated with the relative abundance of Faecalibacterium prausnitzii (ρ = -0.221, P = 0.092), while positively correlating with Enterobacteriaceae (ρ = 0.202, P = 0.126).

Conclusions: Orally administered and renal excreted 52Cr-EDTA may be used to assess intestinal permeability in CD and correlates with fecal calprotectin levels and bacterial species relevant to CD. This test may improve non-invasive detection of disease exacerbations and help monitor disease activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211973PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366711PMC
November 2019

Normal vaginal microbiome in women with primary Sjögren's syndrome-associated vaginal dryness.

Ann Rheum Dis 2019 05 28;78(5):707-709. Epub 2018 Nov 28.

Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2018-214404DOI Listing
May 2019

Absence of Intestinal Microbiota during Gestation and Lactation Does Not Alter the Metabolic Response to a Western-type Diet in Adulthood.

Mol Nutr Food Res 2019 02 5;63(3):e1800809. Epub 2018 Dec 5.

Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands.

Scope: Microbiota composition in early life is implied to affect the risk to develop obesity in adulthood. It is unclear whether this risk is due to long-lasting microbiome-induced changes in host metabolism. This study aims to identify whether the presence or total absence of early-life microbiota affects host metabolism in adulthood.

Methods And Results: The effects of a germ-free (Former GF) versus conventional status during gestation and lactation on the metabolic status in adult offspring are compared. Upon conventionalization at weaning, all mice were metabolically challenged with a Western-type diet (WTD) at 10 weeks age. Between age 10 and 30 weeks, a former GF status does not notably affect overall body weight gain, cholesterol metabolism, glucose tolerance or insulin sensitivity at adult age. However, Former GF mice have lower bile flow and bile acid secretion in adulthood, but similar bile acid composition.

Conclusions: A germ-free status during gestation and lactation does not substantially affect key parameters of the metabolic status before 10 weeks of age on chow diet or in adulthood following a WTD challenge. These data imply that microbiota in early life does not critically affect adult metabolic plasticity.
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http://dx.doi.org/10.1002/mnfr.201800809DOI Listing
February 2019

Shared gut, but distinct oral microbiota composition in primary Sjögren's syndrome and systemic lupus erythematosus.

J Autoimmun 2019 02 9;97:77-87. Epub 2018 Nov 9.

Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

Objective: Alterations in the microbiota composition of the gastro-intestinal tract are suspected to be involved in the etiopathogenesis of two closely related systemic inflammatory autoimmune diseases: primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Our objective was to assess whether alterations in gut and oral microbiota compositions are specific for pSS and SLE.

Methods: 16S ribosomal RNA gene sequencing was performed on fecal samples from 39 pSS patients, 30 SLE patients and 965 individuals from the general population, as well as on buccal swab and oral washing samples from the same pSS and SLE patients. Alpha-diversity, beta-diversity and relative abundance of individual bacteria were used as outcome measures. Multivariate analyses were performed to test associations between individual bacteria and disease phenotype, taking age, sex, body-mass index, proton-pump inhibitor use and sequencing-depth into account as possible confounding factors.

Results: Fecal microbiota composition from pSS and SLE patients differed significantly from population controls, but not between pSS and SLE. pSS and SLE patients were characterized by lower bacterial richness, lower Firmicutes/Bacteroidetes ratio and higher relative abundance of Bacteroides species in fecal samples compared with population controls. Oral microbiota composition differed significantly between pSS patients and SLE patients, which could partially be explained by oral dryness in pSS patients.

Conclusions: pSS and SLE patients share similar alterations in gut microbiota composition, distinguishing patients from individuals in the general population, while oral microbiota composition shows disease-specific differences between pSS and SLE patients.
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http://dx.doi.org/10.1016/j.jaut.2018.10.009DOI Listing
February 2019

Targeted Diet Modification Reduces Multiple Sclerosis-like Disease in Adult Marmoset Monkeys from an Outbred Colony.

J Immunol 2018 12 19;201(11):3229-3243. Epub 2018 Oct 19.

Department of Immunobiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, the Netherlands.

Experimental autoimmune encephalomyelitis (EAE) in common marmosets is a translationally relevant model of the chronic neurologic disease multiple sclerosis. Following the introduction of a new dietary supplement in our purpose-bred marmoset colony, the percentage of marmosets in which clinically evident EAE could be induced by sensitization against recombinant human myelin oligodendrocyte glycoprotein in IFA decreased from 100 to 65%. The reduced EAE susceptibility after the dietary change coincided with reduced expression in the colony, an EBV-related γ1-herpesvirus associated with EAE. We then investigated, in a controlled study in marmoset twins, which disease-relevant parameters were affected by the dietary change. The selected twins had been raised on the new diet for at least 12 mo prior to the study. In twin siblings reverted to the original diet 8 wk prior to EAE induction, 100% disease prevalence (eight out of eight) was restored, whereas in siblings remaining on the new diet the EAE prevalence was 75% (six out of eight). Spinal cord demyelination, a classical hallmark of the disease, was significantly lower in new-diet monkeys than in monkeys reverted to the original diet. In new-diet monkeys, the proinflammatory T cell response to recombinant human myelin oligodendrocyte glycoprotein was significantly reduced, and RNA-sequencing revealed reduced apoptosis and enhanced myelination in the brain. Systematic typing of the marmoset gut microbiota using 16S rRNA sequencing demonstrated a unique, Bifidobacteria-dominated composition, which changed after disease induction. In conclusion, targeted dietary intervention exerts positive effects on EAE-related parameters in multiple compartments of the marmoset's gut-immune-CNS axis.
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http://dx.doi.org/10.4049/jimmunol.1800822DOI Listing
December 2018

Talk to your gut: the oral-gut microbiome axis and its immunomodulatory role in the etiology of rheumatoid arthritis.

FEMS Microbiol Rev 2019 01;43(1):1-18

University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, Hanzeplein 1, 9700 RB Groningen, the Netherlands.

Microbial communities inhabiting the human body, collectively called the microbiome, are critical modulators of immunity. This notion is underpinned by associations between changes in the microbiome and particular autoimmune disorders. Specifically, in rheumatoid arthritis, one of the most frequently occurring autoimmune disorders worldwide, changes in the oral and gut microbiomes have been implicated in the loss of tolerance against self-antigens and in increased inflammatory events promoting the damage of joints. In the present review, we highlight recently gained insights in the roles of microbes in the etiology of rheumatoid arthritis. In addition, we address important immunomodulatory processes, including biofilm formation and neutrophil function, which have been implicated in host-microbe interactions relevant for rheumatoid arthritis. Lastly, we present recent advances in the development and evaluation of emerging microbiome-based therapeutic approaches. Altogether, we conclude that the key to uncovering the etiopathogenesis of rheumatoid arthritis will lie in the immunomodulatory functions of the oral and gut microbiomes.
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http://dx.doi.org/10.1093/femsre/fuy035DOI Listing
January 2019

Dysbiosis of the buccal mucosa microbiome in primary Sjögren's syndrome patients.

Rheumatology (Oxford) 2018 12;57(12):2225-2234

Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: Environmental factors in the aetiology of primary Sjögren's syndrome (pSS) are largely unknown. Host-microbiome interaction at mucosal surfaces is presumed to be involved in the aetiopathogenesis of pSS. Here, we assessed whether the microbiome of the buccal mucosa is specific for pSS compared with symptom-controls.

Methods: The bacterial composition of buccal swab samples from 37 pSS patients, 86 non-SS sicca patients (with similar dryness symptoms to pSS patients, but not fulfilling the classification criteria) and 24 healthy controls (HCs) was determined with 16S rRNA sequencing. Multivariate Association with Linear Models was used to find associations between individual taxa and pSS, taking into account smoking and dental status. Associations were replicated in a general population cohort (n = 103).

Results: The buccal mucosa microbiome of pSS and non-SS sicca patients both differed from HCs. A higher Firmicutes/Proteobacteria ratio was characteristic for both pSS and non-SS sicca patients. Disease status (pSS, non-SS sicca, HCs) and salivary secretion rate contributed almost equally to the variation in bacterial composition between individuals (3.8 and 4.3%, respectively). Two taxa were associated with pSS compared with non-SS sicca patients and 19 compared with HCs. When salivary secretion rate was taken into account, no taxon was associated with pSS compared with non-SS sicca. Twelve of the 19 pSS-associated taxa were correlated with salivary secretion.

Conclusion: Dysbiosis of the buccal mucosa microbiome in pSS patients resembles that of symptom-controls. The buccal mucosa microbiome in pSS patients is determined by a combination of reduced salivary secretion and disease-specific factors.
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http://dx.doi.org/10.1093/rheumatology/key215DOI Listing
December 2018

The role of the microbiome for human health: from basic science to clinical applications.

Eur J Nutr 2018 May;57(Suppl 1):1-14

DSM Nutritional Products Ltd, Kaiseraugst, Switzerland.

The 2017 annual symposium organized by the University Medical Center Groningen in The Netherlands focused on the role of the gut microbiome in human health and disease. Experts from academia and industry examined interactions of prebiotics, probiotics, or vitamins with the gut microbiome in health and disease, the development of the microbiome in early-life and the role of the microbiome on the gut-brain axis. The gut microbiota changes dramatically during pregnancy and intrinsic factors (such as stress), in addition to extrinsic factors (such as diet, and drugs) influence the composition and activity of the gut microbiome throughout life. Microbial metabolites, e.g. short-chain fatty acids affect gut-brain signaling and the immune response. The gut microbiota has a regulatory role on anxiety, mood, cognition and pain which is exerted via the gut-brain axis. Ingestion of prebiotics or probiotics has been used to treat a range of conditions including constipation, allergic reactions and infections in infancy, and IBS. Fecal microbiota transplantation (FMT) highly effective for treating recurrent Clostridium difficile infections. The gut microbiome affects virtually all aspects of human health, but the degree of scientific evidence, the models and technologies and the understanding of mechanisms of action vary considerably from one benefit area to the other. For a clinical practice to be broadly accepted, the mode of action, the therapeutic window, and potential side effects need to thoroughly be investigated. This calls for further coordinated state-of-the art research to better understand and document the human gut microbiome's effects on human health.
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http://dx.doi.org/10.1007/s00394-018-1703-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962619PMC
May 2018

Reduced salivary secretion contributes more to changes in the oral microbiome of patients with primary Sjögren's syndrome than underlying disease.

Ann Rheum Dis 2018 10 23;77(10):1542-1544. Epub 2018 Mar 23.

Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2018-213026DOI Listing
October 2018

Mucus Microbiome of Anastomotic Tissue During Surgery Has Predictive Value for Colorectal Anastomotic Leakage.

Ann Surg 2019 05;269(5):911-916

Department of Surgery, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.

Objective: The aim of the present study is to investigate the association of gut microbiota, depending on treatment method, with the development of colorectal anastomotic leakage (AL).

Background: AL is a major cause for morbidity and mortality after colorectal surgery, but the mechanism behind this complication still is not fully understood.

Methods: Bacterial DNA was isolated from 123 "donuts" of patients where a stapled colorectal anastomosis was made and was analyzed using 16S MiSeq sequencing. In 63 patients, this anastomosis was covered with a C-seal, a bioresorbable sheath stapled to the anastomosis.

Results: In non-C-seal patients, AL development was associated with low microbial diversity (P = 0.002) and correspondingly with a high abundance of the dominant Bacteroidaceae and Lachnospiraceae families (P = 0.008 and 0.010, respectively). In C-seal samples, where AL rates were slightly higher (25% vs 17%), an association with the gut microbiota composition was almost undetectable. Only a few opportunistic pathogenic groups of low abundance were associated with AL in C-seal patients, in particular Prevotella oralis (P = 0.007).

Conclusions: AL in patients without a C-seal can be linked to the intestinal microbiota, in particular with a low microbial diversity and a higher abundance of especially mucin-degrading members of the Bacteroidaceae and Lachnospiraceae families. In C-seal patients, however, it seems that any potential protective benefits or harmful consequences of the gut microbiota composition in regard to wound healing are negated, as progression to AL is independent of the initially dominant bacterial composition.
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http://dx.doi.org/10.1097/SLA.0000000000002651DOI Listing
May 2019

Recent Development of Prebiotic Research-Statement from an Expert Workshop.

Nutrients 2017 Dec 20;9(12). Epub 2017 Dec 20.

DSM Nutritional Products Ltd., R & D Human Nutrition and Health, P.O. Box 2676, CH-4002 Basel, Switzerland.

A dietary prebiotic is defined as 'a substrate that is selectively utilized by host microorganisms conferring a health benefit'. Although this definition evolved concomitantly with the knowledge and technological developments that accrued in the last twenty years, what qualifies as prebiotic continues to be a matter of debate. In this statement, we report the outcome of a workshop where academic experts working in the field of prebiotic research met with scientists from industry. The workshop covered three main topics: (i) evolution of the prebiotic concept/definition; (ii) the gut modeling in vitro technology PolyFermS to study prebiotic effects; and (iii) the potential novel microbiome-modulating effects associated with vitamins. The future of prebiotic research is very promising. Indeed, the technological developments observed in recent years provide scientists with powerful tools to investigate the complex ecosystem of gut microbiota. Combining multiple in vitro approaches with in vivo studies is key to understanding the mechanisms of action of prebiotics consumption and their potential beneficial effects on the host.
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http://dx.doi.org/10.3390/nu9121376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748826PMC
December 2017

The tongue microbiome in healthy subjects and patients with intra-oral halitosis.

J Breath Res 2017 Sep 6;11(3):036010. Epub 2017 Sep 6.

Center for Dentistry and Oral Hygiene, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Intra-oral halitosis (IOH) is an unpleasant odor emanating from the oral cavity. It is thought that the microbiota of the dorsal tongue coating plays a crucial role in this condition. The aim of the study was to investigate the composition of the tongue microbiome in subjects with and without IOH. A total of 26 subjects, 16 IOH patients and 10 healthy subjects were recruited based on their organoleptic score and volatile sulfur compound (VSC) measurements. The composition of the tongue microbiome was studied using the 16s amplicon sequencing of the V3-V4 hyper variable region with an Illumina MiSeq. The sequenced data were analyzed using QIIME, and the sequences obtained were distributed across 7 phyla, 27 genera and 825 operational taxonomic units (OTUs). At a higher taxon level, TM7 was associated with IOH patients whereas Gemellaceae was significantly abundant in the healthy subjects. At OTU level, we found several significant OTUs that differentiated the IOH patients from the controls. These included Aggregatibacter (OTU id 4335776), Aggregatibacter segnis (A. segnis), Campylobacter, Capnocytophaga, Clostridiales, Dialister, Leptotrichia, Parvimonas, Peptostreptococcus, Peptococcus, Prevotella, Selenomonas, SR1, Tannerella, TM7-3 and Treponema in the IOH group. In the control group, Aggregatibacter (OTU id 4363066), Haemophilus, Haemophilus parainfluenza (H. parainfluenza), Moryella, Oribacterium, Prevotella, several Streptococcus, Rothia dentocariosa (R. dentocariosa) and OTU from Gemellaceae were significantly abundant. Based on our observation, it was concluded that the bacterial qualitative composition of the IOH and the control group was almost the same, except for the few above-mentioned bacterial species and genera.
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http://dx.doi.org/10.1088/1752-7163/aa7c24DOI Listing
September 2017

Intestinal colonisation patterns in breastfed and formula-fed infants during the first 12 weeks of life reveal sequential microbiota signatures.

Sci Rep 2017 08 21;7(1):8327. Epub 2017 Aug 21.

Departments of Pediatrics and Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands.

The establishment of the infant gut microbiota is a highly dynamic process dependent on extrinsic and intrinsic factors. We characterized the faecal microbiota of 4 breastfed infants and 4 formula-fed infants at 17 consecutive time points during the first 12 weeks of life. Microbiota composition was analysed by a combination of 16S rRNA gene sequencing and quantitative PCR (qPCR). In this dataset, individuality was a major driver of microbiota composition (P = 0.002) and was more pronounced in breastfed infants. A developmental signature could be distinguished, characterized by sequential colonisation of i) intrauterine/vaginal birth associated taxa, ii) skin derived taxa and other typical early colonisers such as Streptococcus and Enterobacteriaceae, iii) domination of Bifidobacteriaceae, and iv) the appearance of adultlike taxa, particularly species associated with Blautia, Eggerthella, and the potential pathobiont Clostridium difficile. Low abundance of potential pathogens was detected by 16S profiling and confirmed by qPCR. Incidence and dominance of skin and breast milk associated microbes were increased in the gut microbiome of breastfed infants compared to formula-fed infants. The approaches in this study indicate that microbiota development of breastfed and formula-fed infants proceeds according to similar developmental stages with microbiota signatures that include stage-specific species.
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http://dx.doi.org/10.1038/s41598-017-08268-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567133PMC
August 2017
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