Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Sugar Beet Pectin Supplementation Did Not Alter Profiles of Fecal Microbiota and Exhaled Breath in Healthy Young Adults and Healthy Elderly
An, Ran ; Wilms, Ellen ; Smolinska, Agnieszka ; Hermes, Gerben D.A. ; Masclee, Ad A.M. ; Vos, Paul de; Schols, Henk A. ; Schooten, Frederik J. van; Smidt, Hauke ; Jonkers, Daisy M.A.E. ; Zoetendal, Erwin G. ; Troost, Freddy J. - \ 2019
Nutrients 11 (2019)9. - ISSN 2072-6643
aging - dietary fiber - elderly - exhaled air - microbiota - pectin - young adults

Aging is accompanied with increased frailty and comorbidities, which is potentially associated with microbiome perturbations. Dietary fibers could contribute to healthy aging by beneficially impacting gut microbiota and metabolite profiles. We aimed to compare young adults with elderly and investigate the effect of pectin supplementation on fecal microbiota composition, short chain fatty acids (SCFAs), and exhaled volatile organic compounds (VOCs) while using a randomized, double-blind, placebo-controlled parallel design. Fifty-two young adults and 48 elderly consumed 15 g/day sugar beet pectin or maltodextrin for four weeks. Fecal and exhaled breath samples were collected before and after the intervention period. Fecal samples were used for microbiota profiling by 16S rRNA gene amplicon sequencing, and for analysis of SCFAs by gas chromatography (GC). Breath was used for VOC analysis by GC-tof-MS. Young adults and elderly showed similar fecal SCFA and exhaled VOC profiles. Additionally, fecal microbiota profiles were similar, with five genera significantly different in relative abundance. Pectin supplementation did not significantly alter fecal microbiota, SCFA or exhaled VOC profiles in elderly or young adults. In conclusion, aside from some minor differences in microbial composition, healthy elderly and young adults showed comparable fecal microbiota composition and activity, which were not altered by pectin supplementation.

NG-Tax, a highly accurate and validated pipeline for analysis of 16S rRNA amplicons from complex biomes
Ramiro-Garcia, Javier ; Hermes, Gerben D.A. ; Giatsis, Christos ; Sipkema, Detmer ; Zoetendal, Erwin G. ; Schaap, Peter J. ; Smidt, Hauke - \ 2018
F1000 Research 5 (2018). - ISSN 2046-1402

Background Massive high-throughput sequencing of short, hypervariable segments of the 16S ribosomal RNA (rRNA) gene has transformed the methodological landscape describing microbial diversity within and across complex biomes. However, several studies have shown that the methodology rather than the biological variation is responsible for the observed sample composition and distribution. This compromises true meta-analyses, although this fact is often disregarded. Results To facilitate true meta-analysis of microbiome studies, we developed NG-Tax, a pipeline for 16S rRNA gene amplicon sequence analysis that was validated with different mock communities and benchmarked against QIIME as the currently most frequently used pipeline. The microbial composition of 49 independently amplified mock samples was characterized by sequencing two variable 16S rRNA gene regions, V4 and V5-V6, in three separate sequencing runs on Illumina's HiSeq2000 platform. This allowed evaluating important factors of technical bias in taxonomic classification: 1) run-to-run sequencing variation, 2) PCR-error, and 3) region/primer specific amplification bias. Despite the short read length (~140 nt) and all technical biases, the average specificity of the taxonomic assignment for the phylotypes included in the mock communities was 96%. On average 99.94% and 92.02% of the reads could be assigned to at least family or genus level, respectively, while assignment to 'spurious genera' represented on average only 0.02% of the reads per sample. Analysis of α- and β-diversity confirmed conclusions guided by biology rather than the aforementioned methodological aspects, which was not the case when samples were analysed using QIIME. Conclusions Different biological outcomes are commonly observed due to 16S rRNA region-specific performance. NG-Tax demonstrated high robustness against choice of region and other technical biases associated with 16S rRNA gene amplicon sequencing studies, diminishing their impact and providing accurate qualitative and quantitative representation of the true sample composition. This will improve comparability between studies and facilitate efforts towards standardization.

Gut Microbiota and Body Weight in School-Aged Children : The KOALA Birth Cohort Study
Mbakwa, Catherine A. ; Hermes, Gerben D.A. ; Penders, John ; Savelkoul, Paul H.M. ; Thijs, Carel ; Dagnelie, Pieter C. ; Mommers, Monique ; Zoetendal, Erwin G. ; Smidt, Hauke ; Arts, Ilja C.W. - \ 2018
Obesity 26 (2018)11. - ISSN 1930-7381 - p. 1767 - 1776.

Objective: This study aimed to examine the intestinal microbiota composition of school-aged children in association with (over)weight. Methods: The fecal microbiota composition of 295 children was analyzed using the Human Intestinal Tract Chip. Anthropometric outcomes (overweight [BMI ≥ 85th percentile], age- and sex-standardized BMI and weight z scores) were measured at 6 to 7 years of age, and elastic net was used to select genus-like bacterial groups related to all anthropometric outcomes. Subsequently, multiple linear and logistic regression models were used to model associations between selected bacterial groups and anthropometric measures while controlling for confounders. Results: Prevotella melaninogenica, Prevotella oralis, Dialister, and uncultured Clostridiales II (UCII) accounted for 26.1% of the variation in microbiota composition. Several bacterial groups were inversely associated with the anthropometric outcomes: Sutterella wadsworthensis, Marvinbryantia formatexigens, Prevotella melanogenica, P oralis, Burkholderia, uncultured Clostridiales II, and Akkermansia, while Streptococcus bovis was positively associated with overweight. Microbial diversity and richness, and Bacteroidetes to Firmicutes ratio, were not significantly associated with any of the outcomes. Conclusions: In the largest population-based study on childhood gut microbiota and body weight so far, both new and previously identified bacterial groups were found to be associated with overweight. Further research should elucidate their role in energy metabolism.

Short-Term Microbiota Manipulation and Forearm Substrate Metabolism in Obese Men : A Randomized, Double-Blind, Placebo-Controlled Trial
Reijnders, Dorien ; Goossens, Gijs H. ; Hermes, Gerben D.A. ; Smidt, Hauke ; Zoetendal, Erwin G. ; Blaak, Ellen E. - \ 2018
Obesity Facts 11 (2018). - ISSN 1662-4025 - p. 318 - 326.

Objective: To investigate the impact of gut microbiota manipulation on fasting and postprandial skeletal muscle metabolism in humans. Methods: 40 obese, insulin-resistant males were randomized to amoxicillin (broad-spectrum antibiotic), vancomycin (narrow-spectrum antibiotic), or placebo (7 days, 1,500 mg/day). Before and after treatment, forearm blood flow and metabolite fluxes across forearm muscle were measured under fasting and postprandial (high-fat mixed-meal) conditions. Results: Vancomycin decreased bacterial diversity, reduced the abundance of Gram-positive Firmicutes, and increased the abundance of Gram-negative Proteobacteria, whereas amoxicillin did not affect microbial composition. Neither vancomycin nor amoxicillin treatment affected fasting and postprandial plasma glucose, free fatty acid (FFA), triacylglycerol (TAG), glycerol, lactate, and insulin concentrations or forearm blood flow. Fasting and postprandial net forearm muscle glucose uptake and the release of lactate were not significantly altered by antibiotic treatment as compared to placebo. Finally, antibiotic treatment did not change fasting and postprandial glycerol, FFA, and TAG fluxes across forearm muscle. Conclusion: The present study demonstrates that short-term antibiotic treatment has no effects on fasting and postprandial forearm substrate metabolism and blood flow in obese men with impaired glucose metabolism. These data suggest that short-term strategies targeting the gut microbiota to improve metabolic health may not be effective in obese humans.

Host and environmental factors affecting the intestinal microbiota in chickens
Kers, Jannigje G. ; Velkers, Francisca C. ; Fischer, Egil A.J. ; Hermes, Gerben D.A. ; Stegeman, J.A. ; Smidt, Hauke - \ 2018
Frontiers in Microbiology 9 (2018)FEB. - ISSN 1664-302X
16S rRNA - Confounding factors - Gut health - Gut microbiota - Microbiome - Poultry
The initial development of intestinal microbiota in poultry plays an important role in production performance, overall health and resistance against microbial infections. Multiplexed sequencing of 16S ribosomal RNA gene amplicons is often used in studies, such as feed intervention or antimicrobial drug trials, to determine corresponding effects on the composition of intestinal microbiota. However, considerable variation of intestinal microbiota composition has been observed both within and across studies. Such variation may in part be attributed to technical factors, such as sampling procedures, sample storage, DNA extraction, the choice of PCR primers and corresponding region to be sequenced, and the sequencing platforms used. Furthermore, part of this variation in microbiota composition may also be explained by different host characteristics and environmental factors. To facilitate the improvement of design, reproducibility and interpretation of poultry microbiota studies, we have reviewed the literature on confounding factors influencing the observed intestinal microbiota in chickens. First, it has been identified that host-related factors, such as age, sex, and breed, have a large effect on intestinal microbiota. The diversity of chicken intestinal microbiota tends to increase most during the first weeks of life, and corresponding colonization patterns seem to differ between layer- and meat-type chickens. Second, it has been found that environmental factors, such as biosecurity level, housing, litter, feed access and climate also have an effect on the composition of the intestinal microbiota. As microbiota studies have to deal with many of these unknown or hidden host and environmental variables, the choice of study designs can have a great impact on study outcomes and interpretation of the data. Providing details on a broad range of host and environmental factors in articles and sequence data repositories is highly recommended. This creates opportunities to combine data from different studies for meta-analysis, which will facilitate scientific breakthroughs toward nutritional and husbandry associated strategies to improve animal health and performance.
Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition
Kootte, Ruud S. ; Levin, Evgeni ; Salojärvi, Jarkko ; Smits, Loek P. ; Hartstra, Annick V. ; Udayappan, Shanti D. ; Hermes, Gerben ; Bouter, Kristien E. ; Koopen, Annefleur M. ; Holst, Jens J. ; Knop, Filip K. ; Blaak, Ellen E. ; Zhao, Jing Hua ; Smidt, Hauke ; Harms, Amy C. ; Hankemeijer, Thomas ; Bergman, Jacques J.G.H.M. ; Romijn, Hans A. ; Schaap, Frank G. ; Olde Damink, Steven W.M. ; Ackermans, Mariette T. ; Dallinga-Thie, Geesje M. ; Zoetendal, Erwin ; Vos, Willem M. de; Serlie, Mireille J. ; Stroes, Erik S.G. ; Groen, Albert K. ; Nieuwdorp, Max - \ 2017
Cell Metabolism 26 (2017)4. - ISSN 1550-4131 - p. 611 - 619.e6.
fecal microbiota transplantation - insulin sensitivity - intestinal microbiota composition - plasma metabolites

The intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We therefore studied the effect of lean donor (allogenic) versus own (autologous) fecal microbiota transplantation (FMT) to male recipients with the metabolic syndrome. Whereas we did not observe metabolic changes at 18 weeks after FMT, insulin sensitivity at 6 weeks after allogenic FMT was significantly improved, accompanied by altered microbiota composition. We also observed changes in plasma metabolites such as γ-aminobutyric acid and show that metabolic response upon allogenic FMT (defined as improved insulin sensitivity 6 weeks after FMT) is dependent on decreased fecal microbial diversity at baseline. In conclusion, the beneficial effects of lean donor FMT on glucose metabolism are associated with changes in intestinal microbiota and plasma metabolites and can be predicted based on baseline fecal microbiota composition. Kootte et al. show that fecal microbiota transplantation from lean donors to obese patients with metabolic syndrome improves insulin sensitivity, a transient effect associated with changes in microbiota composition and fasting plasma metabolites. Baseline fecal microbiota composition in recipients predicts the response to lean donor fecal microbiota transplantation.

Supplementation of Diet With Galacto-oligosaccharides Increases Bifidobacteria, but Not Insulin Sensitivity, in Obese Prediabetic Individuals
Canfora, Emanuel E. ; Beek, Christina M. van der; Hermes, Gerben D.A. ; Goossens, Gijs H. ; Jocken, Johan W.E. ; Holst, Jens J. ; Eijk, Hans M. van; Venema, Koen ; Smidt, Hauke ; Zoetendal, Erwin G. ; Dejong, Cornelis H.C. ; Lenaerts, Kaatje ; Blaak, Ellen E. - \ 2017
Gastroenterology 153 (2017)1. - ISSN 0016-5085 - p. 87 - 97.
Metabolic Control - Microbial Obesity - Prebiotics - Short-Chain Fatty Acids

Background & Aims: The gut microbiota affects host lipid and glucose metabolism, satiety, and chronic low-grade inflammation to contribute to obesity and type 2 diabetes. Fermentation end products, in particular the short-chain fatty acid (SCFA) acetate, are believed to be involved in these processes. We investigated the long-term effects of supplementation with galacto-oligosaccharides (GOS), an acetogenic fiber, on the composition of the human gut microbiota and human metabolism. Methods: We performed a double-blinded, placebo-controlled, parallel intervention study of 44 overweight or obese (body mass index, 28-40 kg/m2) prediabetic men and women (ages, 45-70 y) from October 2014 through October 2015 in Maastricht, The Netherlands. The participants were assigned randomly to groups who ingested 15 g GOS or isocaloric placebo (maltodextrin) daily with their regular meals for 12 weeks. Before and after this period, we collected data on peripheral and adipose tissue insulin sensitivity, fecal microbiota composition, plasma and fecal SCFA, energy expenditure and substrate oxidation, body composition, and hormonal and inflammatory responses. The primary outcome was the effect of GOS on peripheral insulin sensitivity, measured by the hyperinsulinemic-euglycemic clamp method. Results: Supplementation of diets with GOS, but not placebo, increased the abundance of Bifidobacterium species in feces by 5-fold (P = .009; q = 0.144). Microbial richness or diversity in fecal samples were not affected. We did not observe any differences in fecal or fasting plasma SCFA concentrations or in systemic concentrations of gut-derived hormones, incretins, lipopolysaccharide-binding protein, or other markers of inflammation. In addition, no significant alterations in peripheral and adipose tissue insulin sensitivity, body composition, and energy and substrate metabolism were found. Conclusions: Twelve-week supplementation of GOS selectively increased fecal Bifidobacterium species abundance, but this did not produce significant changes in insulin sensitivity or related substrate and energy metabolism in overweight or obese prediabetic men and women. ClincialTrials.gov number, NCT02271776.

Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: a Randomized Double-blind Placebo-controlled Trial
Reijnders, Dorien ; Goossens, Gijs H. ; Neis, Evelien P.J.G. ; Beek, Christina M. van der; Most, Jasper ; Holst, Jens J. ; Lenaerts, Kaatje ; Kootte, Ruud S. ; Nieuwdorp, Max ; Groen, Albert K. ; Boekschoten, Mark ; Hermes, Gerben ; Smidt, Hauke ; Zoetendal, Erwin ; Dejong, Cornelis H.C. ; Blaak, Ellen E. - \ 2016
Homo sapiens - GSE76003 - PRJNA305937
The gut microbiota has been implicated in obesity and cardiometabolic diseases, although evidence in humans is scarce. We investigated how gut microbiota manipulation by antibiotics (7-day administration of amoxicillin, vancomycin, or placebo) affects host metabolism in 57 obese, prediabetic men. Vancomycin, but not amoxicillin, decreased bacterial diversity and reduced Firmicutes involved in short-chain fatty acid and bile acid metabolism, concomitant with altered plasma and/or fecal metabolite concentrations. Adipose tissue gene expression of oxidative pathways was upregulated by antibiotics, whereas immune-related pathways were downregulated by vancomycin. Antibiotics did not affect tissue-specific insulin sensitivity, energy/substrate metabolism, postprandial hormones and metabolites, systemic inflammation, gut permeability, and adipocyte size. Importantly, energy harvest, adipocyte size, and whole-body insulin sensitivity were not altered at 8-week follow-up, despite a still considerably altered microbial composition, indicating that interference with adult microbiota by 7-day antibiotic treatment has no clinically relevant impact on metabolic health in obese humans.
Mining the human intestinal microbiota for biomarkers associated with metabolic disorders
Hermes, Gerben - \ 2016
Wageningen University. Promotor(en): Hauke Smidt; Erwin Zoetendal. - Wageningen : Wageningen University - ISBN 9789462579514 - 205
gastrointestinal microbiota - metabolic disorders - biomarkers - obesity - intestinal microorganisms - antibiotics - dna sequencing - rna - ribosomal rna - microbiota van het spijsverteringskanaal - stofwisselingsstoornissen - biomarkers - obesitas - darmmicro-organismen - antibiotica - dna-sequencing - rna - ribosomaal rna

After birth, our gastrointestinal (GI) tract is colonized by a highly complex assemblage of microbes, collectively termed the GI microbiota, that develop intimate interactions with our body. Recent evidence indicates that the GI microbiota and its products may contribute to the development of obesity and related diseases. This, coupled with the current worldwide epidemic of obesity, has moved microbiome research into the spotlight of attention. Although the main cause of obesity and its associated metabolic complications is excess caloric intake compared with expenditure, differences in GI tract microbial ecology between individuals might be an important biomarker, mediator or even new therapeutic target. Nevertheless, it is currently still unclear which bacterial groups play a role in the development of the metabolic syndrome in humans. This might partly be explained by: 1. Biological factors such as the heterogeneity in genotype, lifestyle, diet; and the often complex aetiology of human disease of which the metabolic syndrome is no exception. 2. Technological factors, such as the use of miscellaneous incompatible methods to assess the gut microbiota, often enumerating specific groups rather than using broad 16S rRNA gene surveys or metagenomics. 3. Studies vary greatly in the populations considered, their designs, and the degree of control for potential confounding factors such as lifestyle and diet. Nevertheless, recent research on this matter has shown a conceptual shift by focusing on more homogenous subpopulations, based on stricter control over variables such age range or through the use of both anthropometric (weight, total body fat) as well as biochemical variables (insulin resistance, hyperlipidaemia) to define groups.

Perturbations in microbial diversity and community structure in adults with overweight and obesity may be partly due to long-term dietary habits or physiological changes in these subjects. As such, exploring the association between the gut microbiota and variation in BMI and weight in early life, prior to or close to the onset of overweight, might provide additional insights into these processes. Therefore, we studied the fecal microbiota of 295 six-seven year old children from the KOALA Birth Cohort, living in the south of the Netherlands. This age range is relatively uncharted microbiota territory. We found that its composition seems to conform to tot same ecosystem rules as that of adults. The bimodal distribution pattern of several bacterial groups as well as their co-correlating groups that were reported previously, including Uncultured Clostridiales II (UCII), Prevotella spp. and Dialister were confirmed. Furthermore, one of the previously described bimodal groups (Uncultured Clostridiales I) was shown before to exhibit very clear shifting state probabilities associated with ageing, where the high abundance state was mainly observed above 40 years of age. This was corroborated as no support for bimodality of this group was observed in the children included in the study described here. A large part of the variation in microbiota composition was explained by the abundance of aforementioned groups in contrast to the anthropometric outcomes, suggesting that in this group of healthy children within a relatively normal weight range, weight and associated parameters were not major drivers of overall genus-level microbial composition or vice versa. Hereafter, multiple linear and logistic regression models with rigorous adjustment for confounders were applied to investigate individual microbiota features association with weight related anthropometric outcomes. Previously reported parameters such as diversity, richness and Bacteroidetes to Firmicutes ratio, were not significantly associated with any of the outcomes. Nevertheless, the abundance of several specific bacterial taxa; Akkermansia, Sutterella wadsworthia et rel. and Bryantella formatexigens et rel. and the dichotomous abundance state of the bi-modally distributed UCII was consistently associated with weight-related outcomes.

Other biochemical features of the metabolic syndrome have been associated with the gut microbiome. Mainly rodent studies have indicated that antibiotic treatment may improve glucose homeostasis and metabolic impairments. Therefore, the effects of gut microbiota manipulation by antibiotics (7d administration of amoxicillin, vancomycin or a placebo) on tissue-specific insulin sensitivity, energy metabolism, gut permeability and inflammation in 57 obese, pre-diabetic men from the same geographical region, were investigated. Vancomycin decreased bacterial diversity and significantly reduced well known butyrate- producing Firmicutes from Clostridium clusters IV and XIVa and bacterial groups involved in bile acid metabolism. These changes occurred concomitantly with altered plasma and fecal concentrations of these metabolites. In adipose tissue, gene expression of oxidative pathways was upregulated by antibiotics, whereas immune-related pathways were downregulated by vancomycin. However, antibiotic treatment had no significant effects on tissue-specific insulin sensitivity, energy/substrate metabolism, postprandial hormones and metabolites, systemic inflammation, gut permeability and adipocyte size. Importantly, despite a still considerably altered microbial composition at eight weeks follow-up, energy harvesting, adipocyte size and whole-body insulin sensitivity (HOMA-IR) remained unaltered. Overall these data indicate that interference with adult microbiota by antibiotic treatment for 7 days had no clinically relevant impact on metabolic health in obese humans. These data are in contrast with several rodent studies as well as a human intervention. The present study, which was well-powered and placebo-controlled, indicates that the previously reported vancomycin-induced effects on human peripheral insulin sensitivity are probably of minor physiological significance.

The aforementioned group that was relatively homogeneous with regards to phenotype was combined with another cohort with similar phenotypical characteristics (obese, male and pre-diabetic) from another region of the Netherlands, to investigate whether tissue specific insulin sensitivity, as measured by the golden standard hyperinsulinemic-euglycemic clamp technique, is related to a specific microbial pattern. Remarkably, despite the fact that both cohorts were constructed based on comparable recruitment strategies, the average microbiota composition in both cohorts showed pronounced differences. Firstly, we found no consistent and significant association between liver, adipose tissue or skeletal muscle insulin sensitivity and the microbiota in both cohorts. Nevertheless, Random Forests classifiers using microbiota composition as predictors revealed taxa associated with fasting glucose concentrations and HbAc1 but only in one cohort. The top microbial features distinguishing classes were different Proteobacteria and groups involved in butyrogenesis, such as Faecalibacterium prausnitzii, Roseburia intestinalis, and Eubacterium rectale and related species, for fasting glucose levels. For HbAc1 these taxa were Oscillospira guillermondii, Sporobacter termitidis, Lactobacillus gasseri and Peptococcus niger and related species. The striking cohort-specific observations suggest that the relation between microbiota composition and type 2 diabetes mellitus as well as other characteristics of the metabolic syndrome is very dependent on the selected cohort of patients and their respective baseline microbiota composition. Similar observations have been made by other researchers as well. It could be that differences in microbiota composition are not associated with the insulin resistance phenotype when the overweight and/or obese state of the patient is already established, as is the case for our metabolic syndrome patients. In the latter case we cannot exclude that the composition of the fecal microbiota may play a role in the worsening of insulin sensitivity in an early stage in the development from a lean towards an overweight/obese phenotype. Furthermore, the observation of a subgroup- specific microbiota only observed in one of the cohorts might indicate an alternative state of microbiota composition driven by yet unknown forces. Nevertheless, this study clearly demonstrated that cohort-specific microbiota differences hamper finding a consensus biological interpretation between cross-sectional studies. This, combined with the complexity of individual disease pathogenesis, as well as the individual-specific differences in microbiota composition, may explain the inconsistency in observations between different studies concerning the identification of signature microbes for obesity, irritable bowel syndrome and other diseases.

Besides the biological drivers for cohort specific inconsistencies in identified microbial biomarkers, there are also technological factors. Although high-throughput sequencing of short, hypervariable segments of the 16S ribosomal RNA (rRNA) gene has transformed the methodological landscape describing microbial diversity within and across complex biomes, evidence is increasing that methodology rather than the biological variation is responsible for observed sample composition and distribution. Large meta-analyses would aid in elucidating whether the basis for these observed inconsistencies is biological, technical or maybe a combination of both. To facilitate these meta-analyses of microbiota studies we developed NG-Tax, a pipeline for 16S rRNA gene amplicon sequence analysis that was validated with different Mock Communities (MC). NG-Tax demonstrated high robustness against choice of region and other technical biases associated with 16S rRNA gene amplicon sequencing studies. The analysis of α- and β-diversity of these MC confirmed conclusions guided by biology rather than the methodological aspects. This pipeline was applied to biological samples to monitor the developing communities an in vitro gut model (TIM-2) fed either with a normal diet, or modified versions from which the carbohydrate (MPLC) or protein fraction was diluted (LPMC) for 72h. In combination with global metatranscriptomics and metabolomics this revealed that each diet produced distinct microbial communities and temporal patterns and ratios of metabolites. The microbiota in reactors fed diets containing normal carbohydrate levels were enriched in members of the genera Prevotella, Subdoligranulum, Blautia and Bifidobacterium, all associated with carbohydrate fermentation. In turn, the microbiota in the reactors fed the MPLC diet, containing ten-fold less carbohydrates, was enriched in the genus Bacteroides, which is associated with diets rich in protein and animal fat. This setup allows researchers to study the (trophic) interactions and task division within a community and how they are impacted by diet-related factors under controlled conditions, which may assist in defining causal links between specific diet-derived parameters microbial groups and their activities.

In conclusion, currently it seems that GI microbiota based biomarkers associated with metabolic impairments and anthropometric variables associated with the metabolic syndrome are cohort specific or possibly individual, which could partly be due to the use of incompatible analytical approaches. Nevertheless, there is growing evidence that human health is a collective property of the human body and its associated microbiome and thus requires to study the interface of two very complex systems, i.e. on one side the extraordinary coding capacity, high inter-individuality and complex dynamics of the microbiome and on the other side the multifactorial individual nature of human disease. In light of these observations the manifestation of individual dynamics of the microbiota with the host when homeostasis is lost seems plausible and likely.

Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans : A Randomized Double-Blind Placebo-Controlled Trial
Reijnders, Dorien ; Goossens, Gijs H. ; Hermes, Gerben D.A. ; Neis, Evelien P.J.G. ; Beek, Christina M. van der; Most, Jasper ; Holst, Jens J. ; Lenaerts, Kaatje ; Kootte, Ruud S. ; Nieuwdorp, Max ; Groen, Albert K. ; Olde Damink, Steven W.M. ; Boekschoten, Mark V. ; Smidt, Hauke ; Zoetendal, Erwin G. ; Dejong, Cornelis H.C. ; Blaak, Ellen E. - \ 2016
Cell Metabolism 24 (2016)1. - ISSN 1550-4131 - p. 63 - 74.

The gut microbiota has been implicated in obesity and cardiometabolic diseases, although evidence in humans is scarce. We investigated how gut microbiota manipulation by antibiotics (7-day administration of amoxicillin, vancomycin, or placebo) affects host metabolism in 57 obese, prediabetic men. Vancomycin, but not amoxicillin, decreased bacterial diversity and reduced Firmicutes involved in short-chain fatty acid and bile acid metabolism, concomitant with altered plasma and/or fecal metabolite concentrations. Adipose tissue gene expression of oxidative pathways was upregulated by antibiotics, whereas immune-related pathways were downregulated by vancomycin. Antibiotics did not affect tissue-specific insulin sensitivity, energy/substrate metabolism, postprandial hormones and metabolites, systemic inflammation, gut permeability, and adipocyte size. Importantly, energy harvest, adipocyte size, and whole-body insulin sensitivity were not altered at 8-week follow-up, despite a still considerably altered microbial composition, indicating that interference with adult microbiota by 7-day antibiotic treatment has no clinically relevant impact on metabolic health in obese humans.

Trade credit use and competition in the value chain : Evidence from Vietnam
Hermes, Niels ; Lensink, Robert ; Lutz, Clemens ; Thu, Uyen Nguyen Lam - \ 2016
Economics of Transition 24 (2016)4. - ISSN 0967-0750 - p. 765 - 795.
Trade credit is a major source of finance in value chains in developed and emerging economies. Despite its ubiquitous use, this is one of the first empirical studies that analyzes why the use of trade credit varies along the value chain. We argue that competition faced by firms at different stages in the value chain and enforcement mechanisms that stimulate repayment jointly determine the use of trade credit. We distinguish two dimensions of competition, that is, rivalry and customer bargaining power. Competition may stimulate firms to provide trade credit to keep customers from switching to other suppliers. Yet, high contract enforcement costs relative to the value of the transactions, reduce the willingness to offer trade credit. We find empirical evidence showing that competition does not (strongly) influence the use of trade credit in the retail market, whereas it does in the markets for wholesalers and millers. We interpret these results as suggestive evidence that the retail, wholesale and milling market segments differ in terms of the enforcement costs involved in the provision of trade credit. Rivalry at the retail market segment makes switching easy for customers, even in case of default. As enforcement of repayment in this market segment is difficult and costly, trade credit appears to be a risky and less attractive marketing instrument for retailers. In contrast, in the wholesale and milling market segment, trade credit is widespread as stakeholders know each other, making informal mechanisms effective in supporting the enforcement of trade credit repayment.
The gut microbiota and host health : A new clinical frontier
Marchesi, Julian R. ; Adams, David H. ; Fava, Francesca ; Hermes, Gerben D.A. ; Hirschfield, Gideon M. ; Hold, Georgina ; Quraishi, Mohammed N. ; Kinross, James ; Smidt, Hauke ; Tuohy, Kieran M. ; Thomas, Linda V. ; Zoetendal, Erwin G. ; Hart, Ailsa - \ 2016
Gut 65 (2016)2. - ISSN 0017-5749 - p. 330 - 339.

Over the last 10-15 years, our understanding of the composition and functions of the human gut microbiota has increased exponentially. To a large extent, this has been due to new 'omic' technologies that have facilitated large-scale analysis of the genetic and metabolic profile of this microbial community, revealing it to be comparable in influence to a new organ in the body and offering the possibility of a new route for therapeutic intervention. Moreover, it might be more accurate to think of it like an immune system: a collection of cells that work in unison with the host and that can promote health but sometimes initiate disease. This review gives an update on the current knowledge in the area of gut disorders, in particular metabolic syndrome and obesity-related disease, liver disease, IBD and colorectal cancer. The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.

NG-Tax, a highly accurate and validated pipeline for analysis of 16S rRNA amplicons from complex biomes
Ramiro Garcia, J. ; Hermes, G.D.A. ; Giatsis, C. ; Sipkema, D. ; Zoetendal, E.G. ; Schaap, P.J. ; Smidt, H. - \ 2015
PRJEB11702 - ERP013110
Background Massive high-throughput sequencing of short, hypervariable segments of the 16S ribosomal RNA (rRNA) gene is transforming the methodological landscape describing microbial diversity within and across complex biomes. However, there is a strong need for standardisation as each new combination of experimental choices affects the results in different ways, restricting true meta-analyses. Results Here we present NG-Tax, a pipeline for 16S rRNA gene amplicon sequence analysis that was validated with different mock communities, specifically designed to challenge issues regarding optimization of routinely used filtering parameters. By sequencing two tandem variable 16S rRNA gene regions, V4 and V5-V6, in three separate sequencing runs on Illumina’s HiSeq2000 platform, the microbial composition of 49 independently amplified mock samples was characterized. This setup allowed for the evaluation of important factors of technical bias in taxonomic classification: 1) run-to-run sequencing variation 2) PCR – error 3) region/primer specific amplification bias. Despite the short read length (~140 nt) and all technical biases, the average specificity of the taxonomic assignment for the phylotypes included in the mock communities was 96%. On average 99.94% of the reads could be assigned to at least family level, while assignment to ‘spurious genera’ represented on average only 0.02% of the reads per sample. Pearson correlations between obtained and expected compositions at genus level were as high as 0.94, and Unifrac distance based PCoA plots confirmed biology guided clustering rather than the aforementioned technical aspects. Conclusions NG-Tax demonstrated improved qualitative and quantitative representation of the true sample composition. The high robustness of the pipeline against technical biases associated with 16S rRNA gene amplicon sequencing studies will additionally improve comparability between studies and facilitate efforts towards standardization.
Aid and microfinance
Hermes, Niels ; Lensink, Robert - \ 2015
In: Handbook on the Economics of Foreign Aid / Arvin, B.M., Lew, Byron, Edward Elgar Publishing Ltd. - ISBN 9781783474578 - p. 577 - 598.
Microfinance institutions (MFIs) focus on providing financial services to poor households who are excluded from the formal financial system. Having access to finance is crucial for the poor as this helps them to smooth their consumption, generate business opportunities, and improve their inclusion in the formal economy in the long run (Collins et al., 2009). Since the late 1970s, the poor in developing economies have increasingly gained access to financial services offered by MFIs. The market for microfinance has been booming, especially since the early 2000s. During 2000–2005, average annual growth rates in terms of the number of clients served by MFIs amounted to 50 per cent; during 2006–08 growth rates rose further to 70–100 per cent per year (Sinah, 2010). Although the global financial crisis led to a reduction of the growth of microfinance activities (Wagner and Winkler, 2013), microfinance has remained high on the agenda of policy makers as a potentially important instrument to reduce poverty. An important source for the high growth rates of microfinance has been the financial support MFIs have received from governments, development agencies and nongovernmental organizations (NGOs). In many cases, MFIs can only survive because they receive subsidies to cover their costs. Although an increasing number of institutions have been able to attract commercial funding and have become financially sustainable, the majority of these institutions is still dependent on subsidized funding from donor organizations.
The determinants of trade credit use : the case of the Tanzanian rice market
Hermes, Niels ; Kihanga, Ernest ; Lensink, Robert ; Lutz, Clemens - \ 2015
Applied Economics 47 (2015)30. - ISSN 0003-6846 - p. 3164 - 3174.
disequilibrium model - rice market - Tanzania - trade credit

Most small businesses in the developing economies suffer from a lack of access to formal external finance. One important alternative source of finance for these entrepreneurs is trade credit. Applying a unique data-set containing data on specific trade relations between rice wholesalers and rice retailers in Tanzania, we analyse the determinants of trade credit demand and supply in this market, using a simultaneous equation modelling approach. The analysis shows that while the demand for trade credit is primarily determined by the extent to which retailers need external funds, supply is mainly driven by wholesalers’ incentives to attract and keep clients. Moreover, wholesalers’ willingness to provide credit increases if they have better information about the possibility that the customer will fail to repay the credit.

Cohort profile: Lifelines DEEP, a prospective, general population cohort study in the northern Netherlands: study design and baseline characteristics
Tigchelaar, E.F. ; Zhernakova, A. ; Dekens, J.A.M. ; Hermes, G.D.A. ; Baranska, A. ; Mujagic, Z. ; Swertz, M.A. ; Munoz, A.M. ; Deelen, P. ; Cenit, M.C. ; Franke, L. ; Scholtens, S. ; Stolk, R.P. ; Wijmenga, C. ; Feskens, E.J.M. - \ 2015
BMJ Open 5 (2015). - ISSN 2044-6055 - 9 p.
Purpose There is a critical need for population-based prospective cohort studies because they follow individuals before the onset of disease, allowing for studies that can identify biomarkers and disease-modifying effects, and thereby contributing to systems epidemiology. Participants This paper describes the design and baseline characteristics of an intensively examined subpopulation of the LifeLines cohort in the Netherlands. In this unique subcohort, LifeLines DEEP, we included 1539 participants aged 18 years and older. Findings to date We collected additional blood (n=1387), exhaled air (n=1425) and faecal samples (n=1248), and elicited responses to gastrointestinal health questionnaires (n=1176) for analysis of the genome, epigenome, transcriptome, microbiome, metabolome and other biological levels. Here, we provide an overview of the different data layers in LifeLines DEEP and present baseline characteristics of the study population including food intake and quality of life. We also describe how the LifeLines DEEP cohort allows for the detailed investigation of genetic, genomic and metabolic variation for a wide range of phenotypic outcomes. Finally, we examine the determinants of gastrointestinal health, an area of particular interest to us that can be addressed by LifeLines DEEP. Future plans We have established a cohort of which multiple data levels allow for the integrative analysis of populations for translation of this information into biomarkers for disease, and which will offer new insights into disease mechanisms and prevention.
Molecular ecological tools to decipher the role of our microbial mass in obesity
Hermes, G.D.A. ; Zoetendal, E.G. ; Smidt, H. - \ 2014
Beneficial Microbes 6 (2014)1. - ISSN 1876-2883 - p. 61 - 81.
Genetics - Metabolism - Metagenomics - Microbiome - Proteome

After birth, our gastrointestinal (GI) tract is colonised by a highly complex assemblage of microbes, collectively termed the GI microbiota, that develops intimate interactions with our body. Recent evidence indicates that the GI microbiota and its products may contribute to the development of obesity and related diseases. This, coupled with the current worldwide epidemic of obesity, has moved microbiome research into the spotlight of attention. Although the main cause of obesity and its associated metabolic complications is excess caloric intake compared with expenditure, differences in GI tract microbial ecology between individuals might be an important biomarker, mediator or new therapeutic target. This can be investigated using a diverse set of complementary so called -omics technologies, such as 16S ribosomal RNA gene-targeted composition profiling, metabolomics, metagenomics, metatranscriptomics and metaproteomics. This review aims to describe the different molecular approaches and their contributions to our understanding of the role of the GI microbiota in host energy homeostasis. Correspondingly, we highlight their respective strengths, but also try to create awareness for their specific limitations. However, it is currently still unclear which bacterial groups play a role in the development of obesity in humans. This might partly be explained by the heterogeneity in genotype, lifestyle, diet and the complex ethology of obesity and its associated metabolic disorders (OAMD). Nevertheless, recent research on this matter has shown a conceptual shift by focusing on more homogenous subpopulations, through the use of both anthropometric (weight, total body fat) as well as biochemical variables (insulin resistance, hyperlipidaemia) to define categories. Combined with technological advances, recent data suggests that an OAMD associated microbiota can be characterised by a potential pro-inflammatory composition, with less potential for the production of short chain fatty acids and butyrate in particular.

Genetic mapping of semi-polar metabolites in pepper fruits (Capsicum sp.): towards unravelling the molecular regulation of flavonoid quantitative trait loci
Wahyuni, Y. ; Stahl-Hermes, V. ; Ballester, A.R. ; Vos, C.H. de; Voorrips, R.E. ; Maharijaya, A. ; Molthoff, J.W. ; Víquez Zamora, A.M. ; Sudarmonowati, E. ; Arisi, A.C.M. ; Bino, R.J. ; Bovy, A.G. - \ 2014
Molecular Breeding 33 (2014)3. - ISSN 1380-3743 - p. 503 - 518.
l. var. acuminatum - tomato fruit - frankliniella-occidentalis - capsaicinoid content - mass-spectrometry - annuum - expression - metabolomics - glycosides - biodiversity
Untargeted LCMS profiling of semi-polar metabolites followed by metabolite quantitative trait locus (mQTL) analysis was performed in ripe pepper fruits of 113 F2 plants derived from a cross between Capsicum annuum AC1979 (no. 19) and Capsicum chinense No. 4661 Selection (no. 18). The parental accessions were selected based on their variation in fruit morphological characteristics and fruit content of some target phytonutrients. Clear segregation of fruit colour and fruit metabolite profiles was observed in the F2 population. The F2 plants formed three clusters based on their metabolite profiles. Of the total of 542 metabolites, 52 could be annotated, including a range of flavonoids, such as flavone C-glycosides, flavonol O-glycosides and naringenin chalcone, as well as several phenylpropanoids, a capsaicin analogue, fatty acid derivatives and amino acid derivatives. Interval mapping revealed 279 mQTLs in total. Two mQTL hotspots were found on chromosome 9. These two chromosomal regions regulated the relative levels of 35 and 103 metabolites, respectively. Analysis also revealed an mQTL for a capsaicin analogue, located on chromosome 7. Confirmation of flavonoid mQTLs using a set of six flavonoid candidate gene markers and their corresponding expression data (expression QTLs) indicated the Ca-MYB12 transcription factor gene on chromosome 1 and the gene encoding flavone synthase (FS-2) on chromosome 6 as likely causative genes determining the variation in naringenin chalcone and flavone C-glycosides, respectively, in this population. The combination of large-scale metabolite profiling and QTL analysis provided valuable insight into the genomic regions and genes important for the production of (secondary) metabolites in pepper fruit. This will impact breeding strategies aimed at optimising the content of specific metabolites in pepper fruit
Financial Liberalization and Economic Growth
Bumann, S. ; Hermes, N. ; Lensink, B.W. - \ 2013
Journal of International Money and Finance 33 (2013). - ISSN 0261-5606 - p. 255 - 281.
capital account liberalization - meta-regression analysis - developing-countries - aid effectiveness - bias - markets - banking
This study provides a systematic analysis of the empirical literature on the relationship between financial liberalization and economic growth by conducting a meta-analysis, based on 441 t-statistics reported in 60 empirical studies. We focus on explaining the heterogeneity of results in our sample in terms of study-, data- and method-specific characteristics. Although our findings indicate that, on average, there is a positive effect of financial liberalization on growth, the significance of this effect is only weak. Moreover, we find that most of the variables that may help explain the heterogeneity of results are insignificant. There are two exceptions. First, studies carried out based on data from the 1970s on average find a statistically less significant relationship between financial liberalization policies and growth (i.e. they report lower t-statistics) as compared to studies using data from the 1980s. Second, studies controlling for the level of development of the financial system report lower t-statistics for the relationship between liberalization and growth.
The Impact of Trade Credit on Customer Switching Behaviour: Evidence from the Tanzanian Rice Market
Hermes, N. ; Kihanga, E. ; Lensink, B.W. ; Lutz, C. - \ 2012
Journal of Development Studies 48 (2012)3. - ISSN 0022-0388 - p. 363 - 376.
costs - determinants - satisfaction - competition - retention - services - barriers - industry
We use primary survey data to analyse the relationship between trade credit and customer switching in the context of trade transactions between wholesalers and retailers in the Tanzanian rice market. Results reveal a negative relation of trade credit and customer switching, that is, trade credit acts as a switching barrier; retailers are reluctant to move to another supplier if they depend on trade credit as a source of external finance. This interpretation fits with the underdeveloped financial markets in Tanzania, in which access to external finance is poor among rice retailers.
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