Showing papers by "Jeroen Raes published in 2019"

Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.

Abstract: Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus1. The gut microbiota is a new key contributor involved in the onset of obesity-related disorders2. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension3–8. Since the administration of A. muciniphila has never been investigated in humans, we conducted a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers; 40 were enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (−34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (−8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (−2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115) shows that the intervention was safe and well tolerated and that supplementation with A. muciniphila improves several metabolic parameters. Supplementation with Akkermansia muciniphila, a gut microbe previously associated with metabolic health in preclinical models, is safe and well tolerated in humans and may improve metabolic parameters in overweight and obese patients.

The neuroactive potential of the human gut microbiota in quality of life and depression

Abstract: The relationship between gut microbial metabolism and mental health is one of the most intriguing and controversial topics in microbiome research. Bidirectional microbiota-gut-brain communication has mostly been explored in animal models, with human research lagging behind. Large-scale metagenomics studies could facilitate the translational process, but their interpretation is hampered by a lack of dedicated reference databases and tools to study the microbial neuroactive potential. Surveying a large microbiome population cohort (Flemish Gut Flora Project, n =1,054) with validation in independent data sets (n(total) =1,070), we studied how microbiome features correlate with host quality of life and depression. Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators. Together with Dialister, Coprococcus spp. were also depleted in depression, even after correcting for the confounding effects of antidepressants. Using a module-based analytical framework, we assembled a catalogue of neuroactive potential of sequenced gut prokaryotes. Gut-brain module analysis of faecal metagenomes identified the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid as correlating positively with mental quality of life and indicated a potential role of microbial gamma-aminobutyric acid production in depression. Our results provide population-scale evidence for microbiome links to mental health, while emphasizing confounder importance.

Population-level analysis of Blastocystis subtype prevalence and variation in the human gut microbiota.

Abstract: Objective Human gut microbiome studies are mainly bacteria- and archaea-oriented, overlooking the presence of single-cell eukaryotes such as Blastocystis, an enteric stramenopiles with worldwide distribution Here, we surveyed the prevalence and subtype variation of Blastocystis in faecal samples collected as part of the Flemish Gut Flora Project (FGFP), a Western population cohort We assessed potential links between Blastocystis subtypes and identified microbiota–host covariates and quantified microbiota differentiation relative to subtype abundances Design We profiled stool samples from 616 healthy individuals from the FGFP cohort as well as 107 patients with IBD using amplicon sequencing targeting the V4 variable region of the 16S rRNA and 18S rRNA genes We evaluated associations of Blastocystis, and their subtypes, with host parameters, diversity and composition of bacterial and archaeal communities Results Blastocystis prevalence in the non-clinical population cohort was 30% compared with 4% among Flemish patients with IBD Within the FGFP cohort, out of 69 previously identified gut microbiota covariates, only age was associated with Blastocystis subtype carrier status In contrast, a strong association between microbiota community composition and Blastocystis subtypes was observed, with effect sizes larger than that of host covariates Microbial richness and diversity were linked to both Blastocystis prevalence and subtype variation All Blastocystis subtypes detected in this cohort were found to be less prevalent in Bacteroides enterotyped samples Interestingly, Blastocystis subtypes 3 and 4 were inversely correlated with Akkermansia, suggesting differential associations of subtypes with host health Conclusions These results emphasise the role of Blastocystis as a common constituent of the healthy gut microbiota We show its prevalence is reduced in patients with active IBD and demonstrate that subtype characterisation is essential for assessing the relationship between Blastocystis, microbiota profile and host health These findings have direct clinical applications, especially in donor selection for faecal transplantation

Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses.

Abstract: Recent work has highlighted the importance of confounder control in microbiome association studies1,2. For instance, multiple pathologies previously linked to gut ecosystem dysbiosis display concomitant changes in stool consistency3–6, a major covariate of microbiome variation2,7. In those cases, observed microbiota alterations could largely reflect variation in faecal water content. Moreover, stool moisture variation has been linked to fluctuations in faecal microbial load, inducing artefacts in relative abundance profile analyses8,9. Hence, the identification of associations between the gut microbiota and specific disease manifestations in pathologies with complex aetiologies requires a deconfounded, quantitative assessment of microbiome variation. Here, we revisit a disease association microbiome data set comprising 106 patients with primary sclerosing cholangitis (PSC) and/or inflammatory bowel disease10. Assessing quantitative taxon abundances9, we study microbiome alterations beyond symptomatic stool moisture variation. We observe an increased prevalence of a low cell count Bacteroides 2 enterotype across the pathologies studied, with microbial loads correlating inversely with intestinal and systemic inflammation markers. Quantitative analyses allow us to differentiate between taxa associated with either intestinal inflammation severity (Fusobacterium) or cholangitis/biliary obstruction (Enterococcus) among previously suggested PSC marker genera. We identify and validate a near-exclusion pattern between the inflammation-associated Fusobacterium and Veillonella genera, with Fusobacterium detection being restricted to Crohn’s disease and patients with PSC–Crohn’s disease. Overall, through absolute quantification and confounder control, we single out clear-cut microbiome markers associated with pathophysiological manifestations and disease diagnosis. Here, the authors apply quantitative microbiome profiling to a metagenomics data set comprising patients with primary sclerosing cholangitis and/or inflammatory bowel disease and identify microbial taxa associated with inflammation or specific disease indicators, which were validated in an independent inflammatory bowel disease cohort.

Synthetic ecology of the human gut microbiota.

Abstract: Despite recent advances in sequencing and culturing, a deep knowledge of the wiring and functioning of the human gut ecosystem and its microbiota as a community is still missing. A holistic mechanistic understanding will require study of the gut microbiota as an interactive and spatially organized biological system, which is difficult to do in complex natural communities. Synthetic gut microbial ecosystems can function as model systems to further current understanding of the composition, stability and functional activities of the microbiota. In this Review, we provide an overview of the current synthetic ecology strategies that can be used towards a more comprehensive understanding of the human gut ecosystem. Such approaches that integrate in vitro experiments using cultured isolates with mathematical modelling will enable the ultimate goal: translating mechanistic and ecological knowledge into novel and effective therapies. Going from description of the diversity and disease associations of the human gut microbiota towards functional understanding and applications is challenging. In this Review, Raes and colleagues present synthetic ecology approaches that reduce the complexity and advance translation of human gut microbiota research.

Microbial communities of the house fly Musca domestica vary with geographical location and habitat

Abstract: House flies (Musca domestica) are widespread, synanthropic filth flies commonly found on decaying matter, garbage, and feces as well as human food. They have been shown to vector microbes, including clinically relevant pathogens. Previous studies have demonstrated that house flies carry a complex and variable prokaryotic microbiota, but the main drivers underlying this variability and the influence of habitat on the microbiota remain understudied. Moreover, the differences between the external and internal microbiota and the eukaryotic components have not been examined. To obtain a comprehensive view of the fly microbiota and its environmental drivers, we sampled over 400 flies from two geographically distinct countries (Belgium and Rwanda) and three different environments—farms, homes, and hospitals. Both the internal as well as external microbiota of the house flies were studied, using amplicon sequencing targeting both bacteria and fungi. Results show that the house fly’s internal bacterial community is very diverse yet relatively consistent across geographic location and habitat, dominated by genera Staphylococcus and Weissella. The external bacterial community, however, varies with geographic location and habitat. The fly fungal microbiota carries a distinct signature correlating with the country of sampling, with order Capnodiales and genus Wallemia dominating Belgian flies and genus Cladosporium dominating Rwandan fly samples. Together, our results reveal an intricate country-specific pattern for fungal communities, a relatively stable internal bacterial microbiota and a variable external bacterial microbiota that depends on geographical location and habitat. These findings suggest that vectoring of a wide spectrum of environmental microbes occurs principally through the external fly body surface, while the internal microbiome is likely more limited by fly physiology.

Metformin induces weight loss associated with gut microbiota alteration in non-diabetic obese women: a randomized double-blind clinical trial.

Abstract: Objective The increasing prevalence of obesity over the past few decades constitutes a global health challenge. Pharmacological therapy is recommended to accompany life-style modification for obesity management. Here, we perform a clinical trial to investigate the effects of metformin on anthropometric indices and gut microbiota composition in non-diabetic, treatment-naive obese women with a low-calorie diet (LCD). Design Randomized double-blind parallel-group clinical trial. Methods Forty-six obese women were randomly assigned to the metformin (500 mg/tab) or placebo groups using computer-generated random numbers. Subjects in both groups took two tablets per day for 2 months. Anthropometric measurements and collection of blood and fecal samples were done at the baseline and at the end of the trial. Gut microbiota composition was assessed using 16S rRNA amplicon sequencing. Results Twenty-four and twenty-two subjects were included in the metformin + LCD and placebo + LCD groups, respectively; at the end of trial, 20 and 16 subjects were analyzed. The metformin + LCD and placebo + LCD caused a 4.5 and 2.6% decrease in BMI from the baseline values, respectively (P < 0.01). Insulin concentration decreased in the metformin + LCD group (P = 0.046). The overall fecal microbiota composition and diversity were unaffected in the metformin + LCD group. However, a significant specific increase in Escherichia/Shigella abundance was observed after metformin + LCD intervention (P = 0.026). Fecal acetate concentration, but not producers, was significantly higher in the placebo + LCD group, adjusted for baseline values and BMI (P = 0.002). Conclusions Despite the weight reduction after metformin intake, the overall fecal microbiota composition remained largely unchanged in obese women, with exception of changes in specific proteobacterial groups.

Gut microbiota dynamics and uraemic toxins: one size does not fit all

Abstract: In the recent paper by Chu and colleagues,1 the potential role of microbiota-related metabolites in the progression of non-alcoholic fatty liver disease is discussed. This topic has been studied in the context of chronic kidney disease (CKD), characterised by changes in gut microbiota composition,2 accumulation of microbiota-derived metabolites,3 interruption of intestinal barrier function and chronic inflammation.4 In line with this, we focused, in a cohort of 17 patients with end-stage kidney disease (ESKD), on the role of gut microbiota in the generation of precursors of specific uraemic toxins which are associated with negative outcomes in these patients.5 By collecting multiple samples over time, assessment of variability within and between patients in relation to disease progress and clinical variables was possible. Faecal and serum samples were collected at eight time-points over a 4-month period (online supplementary table 1). Uraemic metabolites and microbial profiling were determined by HPLC and 16S rRNA amplicon sequencing, respectively (see Supplementary data). Variation in microbial profiles of patients with ESKD was compared with that of 1106 subjects from a population-based cohort, the Flemish Gut Flora Project (FGFP),6 which have a similar genetic and environmental background as well as to a subset of age-matched controls of comparable health status (n=32). ### Supplementary data [gutjnl-2018-317561supp001.pdf] In this longitudinal study, within-patient analyses showed that variations in peripheral levels of p -cresyl conjugates (the composite of p -cresyl sulfate (pCS)/glucuronide (pCG); p C), indoxyl sulfate (IxS), indole acetic acid and …

Metabolic Architecture of the Deep Ocean Microbiome

Abstract: This work was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) through the Consolider-Ingenio program (Malaspina 2010 Expedition, ref. CSD2008-00077). The sequencing of 58 bathypelagic metagenomes was done by the U.S. Department of Energy Joint Genome Institute, supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02 05CH11231 to SGA. Additional funding was provided by the project MAGGY (CTM2017-87736-R) to SGA from the Spanish Ministry of Economy and Competitiveness, Grup de Recerca 2017SGR/1568 from Generalitat de Catalunya, and King Abdullah University of Science and Technology (KAUST) under contract OSR #3362. HighPerformance computing analyses were run at the Marine Bioinformatics Service (MARBITS) of the Institut de Ciencies del Mar (ICM-CSIC), Barcelona Supercomputing Center (Grant BCV2013-2-0001) and KAUST's Ibex HPC. We thank the R/V Hesperides crew, the chief scientists in Malaspina legs, and all project participants for their help in making this project possible. We thank Shook Studio for assistance with figure design and execution.

The human microbiome in health and disease: hype or hope

Abstract: Objectives: The prognostic, diagnostic, and therapeutic potential of the human gut microbiota is widely recognised. However, translation of microbiome findings to clinical practice is challenging. ...

Worldwide trends in scientific publications on association of gut microbiota with obesity.

Abstract: Objective(s): Recent evidence has shown underlying roles of gut dysbiosis and metabolic endotoxemia in obesity and its complications. Despite the large number of experimental and clinical researches performed on gut microbiota and obesity, no bibliometrics’ study has been conducted so far. We aimed to assess the trend of global scientific publications in the field of gut microbiota and obesity. Materials and Methods: The bibliometrics’ data from January 2000 to April 2017 were retrieved based on Scopus database. The analysis of the publication year, main source, citation, subject area, co-authorship network, and geographical distribution were carried out, accordingly. The data were analyzed using the Scopus analysis tools, SPSS version 15 and Visualizing Scientific Landscapes (VOS) viewer version 1.6.5. Results: Out of 4384 documents that were identified, the United States published the highest number (28.2%), followed by China and United Kingdom. The number of publications showed an increasing trend over the years of which the most productive year was 2016. The leading subject area was medicine. Most of published scientific documents were original articles and the top source was “PLoS One”. The documents were cited totally 153576 times with average citations per article as 35.03, and h-index of 159. Top author in the co-authorship network assessment was “Wang J.” from China. Conclusion: This study could provide practical sources to researchers to find highly cited studies. Moreover, the study could pave the way for researchers to be engaged in studies which potentially lead to more publication in the field.

Tracking humans and microbes.

Abstract: The Human Microbiome Project put the health-associated microbes found in humans on centre stage. The project’s second phase shows how microbial disturbance in disease is linked to host processes. The second phase of studies of the Human Microbiome Project.

Isolation of wheat bran-colonizing and metabolizing species from the human fecal microbiota.

Abstract: Undigestible, insoluble food particles, such as wheat bran, are important dietary constituents that serve as a fermentation substrate for the human gut microbiota. The first step in wheat bran fermentation involves the poorly studied solubilization of fibers from the complex insoluble wheat bran structure. Attachment of bacteria has been suggested to promote the efficient hydrolysis of insoluble substrates, but the mechanisms and drivers of this microbial attachment and colonization, as well as subsequent fermentation remain to be elucidated. We have previously shown that an individually dependent subset of gut bacteria is able to colonize the wheat bran residue. Here, we isolated these bran-attached microorganisms, which can then be used to gain mechanistic insights in future pure culture experiments. Four healthy fecal donors were screened to account for inter-individual differences in gut microbiota composition. A combination of a direct plating and enrichment method resulted in the isolation of a phylogenetically diverse set of species, belonging to the Bacteroidetes, Firmicutes, Proteobacteria and Actinobacteria phyla. A comparison with 16S rRNA gene sequences that were found enriched on wheat bran particles in previous studies, however, showed that the isolates do not yet cover the entire diversity of wheat-bran colonizing species, comprising among others a broad range of Prevotella, Bacteroides and Clostridium cluster XIVa species. We, therefore, suggest several modifications to the experiment set-up to further expand the array of isolated species.

Expanding the scope and scale of microbiome research.

Abstract: Although the draft human genome was completed in 2001 [1, 2], only in 2006 [3] did we come to realize that the vast majority of the genes in our own species, or any species, remained uncharacterized in ‘genome projects’. Indeed, our understanding of the roles played by complex microbial communities, often termed ‘microbiomes’, in the human body and in the environment continues to expand dramatically. This Special Issue, published jointly by Genome Biology and BMC Biology, is a timely exploration and expansion both of our knowledge of microbiomes in different systems and of ways to study microbiomes more effectively. It builds on Genome Biology’s nearly decade-long tradition of publishing cutting-edge microbiome research and techniques, and on the journal’s 20-year tradition of publishing sweeping analyses of genomic features across broad swathes of the tree of life. Many of the articles in this Special Issue focus on new ways to acquire information from DNA sequences obtained using high-throughput sequencing approaches. For example, Fukuyama [4] introduce a new framework for calculating phylogenetic distances that emphasizes deep or shallow branches within the phylogenetic tree, offering different pictures of relationships among microbiomes depending on whether recent or ancient differences are more relevant to the response to a given biological driving factor. Zhu et al. [5] demonstrate that analysis of ‘unmapped reads’, that is, DNA sequences from shotgun metagenomics that don’t match any known genome, can substantially improve our ability to classify samples according to whether they are healthy or diseased, reinforcing the fact that an increased number of complete genome databases for microbes are urgently needed in order to ‘rescue’ these sequences and determine these functions [6]. An alternative approach is to avoid the difficult problem of identifying assembled sequences from short-read data, and to instead associate features of the assembly graph with the host phenotype [7]. Together, these tools will substantially assist efforts to characterize the microbial unknown, and to verify that this characterization is correct. Several articles in the Special Issue go beyond shortread sequencing. The combination of long-read sequencing and proximity ligation allows the identification of antimicrobial genes and the detection of the plasmids and chromosomes that they are associated with [8]. This approach improves our ability to find pathways of antimicrobial resistance transfer and to determine when plasmids escape their original bacterial host [8]. A readout of the RNA from metatranscriptomic data, rather than just the DNA sequences, has been integral to the discovery of a diverse antibiotic resistance gene reservoir in birds [9]. Similarly, the combination of DNA-based and culture-based approaches was important for the identification of new members of the Bifidobacteria in the gut [10], substantially expanding what we know about this key clade of bacteria. Many important questions about the human microbiome remain unaddressed, especially those relating to the dynamics of the microbiome. The field as a whole is moving from observational studies towards intervention studies, in which temporally resolved study designs offer considerably more power to detect and understand changes [11]. Bouslimani et al. [12] demonstrate the highly personalized dynamic nature of the skin microbiome and metabolome, and show that both the microbial and chemical repertoire of the skin can be changed radically by changing skin-care products. Moving beyond a parochial view of our own species, Rhoades et al. [13] provide the highest-resolution view yet of the development of the microbiome of infant Rhesus macaques, an important model animal for biomedical research, whereas Malmuthuge et al. [14] provide a highresolution view of the developing rumen microbiome. Complex microbial communities are by no means limited to those associated with hosts. This Special Issue

Microbiome Determinants and Physiological Effects of the Benzoate-Hippurate Microbial-Host Co-Metabolic Pathway

Abstract: Objective Gut microbial products are involved in type 2 diabetes, obesity and insulin resistance. In particular, hippurate, a hepatic phase 2 conjugation product of microbial benzoate metabolism, has been associated with a healthy phenotype. This study aims to identify metagenomic determinants and test protective effects of hippurate. Design We profiled the urine metabolome by 1H Nuclear Magnetic Resonance (NMR) spectroscopy to derive associations with metagenomic sequences in 271 middle-aged Danish individuals to identify dietary patterns in which urine hippurate levels were associated with health benefits. We follow up with benzoate and hippurate infusion in mice to demonstrate causality on clinical phenotypes. Results In-depth analysis identifies that the urine hippurate concentration is associated with microbial gene richness, microbial functional redundancy as well as functional modules for microbial benzoate biosynthetic pathways across several enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate, independently of gene richness, accounts for links with metabolic health that we previously associated with gene richness. We then demonstrate causality in vivo through chronic subcutaneous infusions of hippurate or benzoate (20 nmol/day) resulting in improved glycemic control in mice fed a high-fat diet. Hippurate improved insulin secretion through increased β-cell mass and reduced liver inflammation and fibrosis, whereas benzoate treatment resulted in liver inflammation. Conclusion Our translational study shows that the benzoate-hippurate pathway brings a range of metabolic improvements in the context of high-fat diets, highlighting the potential of hippurate as a mediator of metabolic health.

Practical guidelines for gut microbiome analysis in microbiota-gut-brain axis research

Abstract: The microbiota-gut-brain (MGB) axis field is at an exciting stage, but the most recent developments in microbiota research still have to find their way into MGB studies. Here we outline the standards for microbiome data generation, the appropriate statistical techniques, and the covariates that should be included in MGB studies to optimize discovery and translation to clinical applications.