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Showing papers by "Jeroen Raes published in 2020"


Journal ArticleDOI
21 May 2020-Nature
TL;DR: A cross-sectional analysis of participants in the MetaCardis Body Mass Index Spectrum cohort finds that the higher prevalence of gut microbiota dysbiosis in individuals with obesity is not observed in those who take statin drugs, and statin therapy is identified as a key covariate of microbiome diversification.
Abstract: Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics. A cross-sectional analysis of participants in the MetaCardis Body Mass Index Spectrum cohort finds that the higher prevalence of gut microbiota dysbiosis in individuals with obesity is not observed in those who take statin drugs.

220 citations


Posted ContentDOI
Alexander Kurilshikov1, Carolina Medina-Gomez2, Rodrigo Bacigalupe3, Djawad Radjabzadeh2, Jun Wang4, Ayse Demirkan1, Ayse Demirkan5, Caroline I. Le Roy6, Juan Antonio Raygoza Garay7, Juan Antonio Raygoza Garay8, Casey T. Finnicum9, Xingrong Liu10, Daria V. Zhernakova11, Daria V. Zhernakova1, Marc Jan Bonder1, Tue H. Hansen12, Fabian Frost13, Malte C. Rühlemann14, Williams Turpin8, Williams Turpin7, Jee-Young Moon15, Han-Na Kim16, Kreete Lüll17, Elad Barkan18, Shiraz A. Shah19, Myriam Fornage20, Joanna Szopinska-Tokov, Zachary D. Wallen21, Dmitrii Borisevich12, Lars Agréus10, Anna Andreasson22, Corinna Bang14, Larbi Bedrani8, Jordana T. Bell6, Hans Bisgaard19, Michael Boehnke23, Dorret I. Boomsma24, Robert D. Burk15, Annique Claringbould1, Kenneth Croitoru7, Kenneth Croitoru8, Gareth E. Davies24, Cornelia M. van Duijn2, Cornelia M. van Duijn25, Liesbeth Duijts2, Gwen Falony3, Jingyuan Fu1, Adriaan van der Graaf1, Torben Hansen12, Georg Homuth13, David A. Hughes26, Richard G. IJzerman27, Matthew A. Jackson25, Matthew A. Jackson6, Vincent W. V. Jaddoe2, Marie Joossens3, Torben Jørgensen12, Daniel Keszthelyi28, Rob Knight29, Markku Laakso30, Matthias Laudes, Lenore J. Launer31, Wolfgang Lieb14, Aldons J. Lusis32, Ad A.M. Masclee28, Henriette A. Moll2, Zlatan Mujagic28, Qi Qibin15, Daphna Rothschild18, Hocheol Shin16, Søren J. Sørensen12, Claire J. Steves6, Jonathan Thorsen19, Nicholas J. Timpson26, Raul Y. Tito3, Sara Vieira-Silva3, Uwe Völker13, Henry Völzke13, Urmo Võsa1, Kaitlin H Wade26, Susanna Walter33, Kyoko Watanabe24, Stefan Weiss13, Frank Ulrich Weiss13, Omer Weissbrod34, Harm-Jan Westra1, Gonneke Willemsen24, Haydeh Payami21, Daisy Jonkers28, Alejandro Arias Vasquez35, Eco J. C. de Geus24, Katie A. Meyer36, Jakob Stokholm19, Eran Segal18, Elin Org17, Cisca Wijmenga1, Hyung Lae Kim37, Robert C. Kaplan38, Tim D. Spector6, André G. Uitterlinden2, Fernando Rivadeneira2, Andre Franke14, Markus M. Lerch13, Lude Franke1, Serena Sanna1, Serena Sanna39, Mauro D'Amato, Oluf Pedersen12, Andrew D. Paterson8, Robert Kraaij2, Jeroen Raes3, Alexandra Zhernakova1 
16 Dec 2020-bioRxiv
TL;DR: A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.
Abstract: To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P

210 citations



Journal ArticleDOI
TL;DR: An association between human host genotype and gut microbiome variation is shown and Mendelian randomization analysis was able to estimate associations between microbial traits and disease (including Bifidobacterium and body composition); however, in the absence of clear microbiome-driven effects, caution is needed in interpretation.
Abstract: Recent population-based1–4 and clinical studies5 have identified a range of factors associated with human gut microbiome variation. Murine quantitative trait loci6, human twin studies7 and microbiome genome-wide association studies1,3,8–12 have provided evidence for genetic contributions to microbiome composition. Despite this, there is still poor overlap in genetic association across human studies. Using appropriate taxon-specific models, along with support from independent cohorts, we show an association between human host genotype and gut microbiome variation. We also suggest that interpretation of applied analyses using genetic associations is complicated by the probable overlap between genetic contributions and heritable components of host environment. Using faecal 16S ribosomal RNA gene sequences and host genotype data from the Flemish Gut Flora Project (n = 2,223) and two German cohorts (FoCus, n = 950; PopGen, n = 717), we identify genetic associations involving multiple microbial traits. Two of these associations achieved a study-level threshold of P = 1.57 × 10−10; an association between Ruminococcus and rs150018970 near RAPGEF1 on chromosome 9, and between Coprococcus and rs561177583 within LINC01787 on chromosome 1. Exploratory analyses were undertaken using 11 other genome-wide associations with strong evidence for association (P < 2.5 × 10−8) and a previously reported signal of association between rs4988235 (MCM6/LCT) and Bifidobacterium. Across these 14 single-nucleotide polymorphisms there was evidence of signal overlap with other genome-wide association studies, including those for age at menarche and cardiometabolic traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease (including Bifidobacterium and body composition); however, in the absence of clear microbiome-driven effects, caution is needed in interpretation. Overall, this work marks a growing catalogue of genetic associations that will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis. A microbiome genome-wide association study using three large European cohorts identified several significant study-wide and genome-wide correlations between human genetic variants and microbial traits, and used Mendelian randomization to estimate causal relationships between microbial traits and disease.

121 citations


Journal ArticleDOI
TL;DR: The microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism, which likely reflects altered microbial metabolism of histidine, rather than histidine intake per se.
Abstract: Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.

99 citations


Journal ArticleDOI
TL;DR: It is indicated that chilling temperatures affect the bacterial community composition within the maize root endosphere, and two promising strains that promoted maize growth under chilling conditions were identified that belonged to the root endophytic bacterial families, from which the relative abundance remained unchanged by variations in the growth temperature.
Abstract: When maize (Zea mays L.) is grown in the Northern hemisphere, its development is heavily arrested by chilling temperatures, especially at the juvenile phase. As some endophytes are beneficial for plants under stress conditions, we analyzed the impact of chilling temperatures on the root microbiome and examined whether microbiome-based analysis might help to identify bacterial strains that could promote growth under these temperatures. We investigated how the maize root microbiome composition changed by means of 16S rRNA gene amplicon sequencing when maize was grown at chilling temperatures in comparison to ambient temperatures by repeatedly cultivating maize in field soil. We identified 12 abundant and enriched bacterial families that colonize maize roots, consisting of bacteria recruited from the soil, whereas seed-derived endophytes were lowly represented. Chilling temperatures modified the root microbiome composition only slightly, but significantly. An enrichment of several chilling-responsive families was detected, of which the Comamonadaceae and the Pseudomonadaceae were the most abundant in the root endosphere of maize grown under chilling conditions, whereas only three were strongly depleted, among which the Streptomycetaceae. Additionally, a collection of bacterial strains isolated from maize roots was established and a selection was screened for growth-promoting effects on juvenile maize grown under chilling temperatures. Two promising strains that promoted maize growth under chilling conditions were identified that belonged to the root endophytic bacterial families, from which the relative abundance remained unchanged by variations in the growth temperature. Our analyses indicate that chilling temperatures affect the bacterial community composition within the maize root endosphere. We further identified two bacterial strains that boost maize growth under chilling conditions. Their identity revealed that analyzing the chilling-responsive families did not help for their identification. As both strains belong to root endosphere enriched families, visualizing and comparing the bacterial diversity in these communities might still help to identify new PGPR strains. Additionally, a strain does not necessarely need to belong to a high abundant family in the root endosphere to provoke a growth-promoting effect in chilling conditions.

56 citations


Journal ArticleDOI
TL;DR: In this article, the authors assessed percentages of circulating peripheral blood mononuclear cells with focus on T helper cell subsets (memory T helper cells, Th1, Th2, Th17 and T regulatory cells) in a large and well-matched cohort of 153 patients diagnosed with Major Depressive Disorder and 153 age and sex matched controls.
Abstract: Background Previous research has demonstrated a strong link between immune system abnormalities and Major Depressive Disorder (MDD). High suicide risk is a major complication of MDD and has recently been linked to strong (neuro-)immune alterations, but little is known on the link between circulating immune cell composition and suicidal risk status. Methods Here, we assessed percentages of circulating peripheral blood mononuclear cells with focus on T helper cell subsets (memory T helper cells, Th1, Th2, Th17 and T regulatory cells) in a large and well-matched cohort of 153 patients diagnosed with MDD and 153 age and sex matched controls. We explored the association of these cell populations with suicide risk while accounting for age, sex, BMI, depression severity and childhood trauma. Results Patients with MDD had reduced percentages of NK cells, and higher percentages of B and T cells in line with current literature. Further exploration of T-cells revealed a robustly elevated number of memory T helper cells, regardless of age group. Patients at high risk for suicide had the highest memory T helper cells and additionally showed a robust increase of Th17 cells compared to other suicide risk groups. Conclusions The higher abundance of memory T helper cells points towards premature aging of the immune system in MDD patients, even during young adulthood. Patients at high risk for suicide show the clearest immune abnormalities and may represent a clinically relevant subtype of depression.

49 citations


Journal ArticleDOI
TL;DR: Diversity, enterotypes, and specific gut microbial taxa variation between MS and HC, and between MS subgroups are studied.
Abstract: Objective Multiple sclerosis (MS) is a heterogenous, inflammatory disease of the central nervous system. Microbiota alterations in MS versus healthy controls (HC) are observed, but results are inconsistent. We studied diversity, enterotypes, and specific gut microbial taxa variation between MS and HC, and between MS subgroups. Methods Amplicon sequencing of the 16S ribosomal RNA V4 region (Illumina MiSeq) was used to evaluate alpha and beta diversity, enterotypes, and relative taxa abundances on stool samples. MS subgroups were based on phenotype, disease course modifiers, and treatment status. Results were controlled for recently identified confounders of microbiota composition. Results Ninety-eight MS patients and 120 HC were included. Microbial richness was lower in interferon-treated (RRMS_I, N = 24) and untreated relapsing-remitting MS during relapse (RRMS_R, N = 4) when compared to benign (BMS, N = 20; Z = -3.07, Pcorr = 0.032 and Z = -2.68, Pcorr = 0.055) and primary progressive MS (PPMS, N = 26; Z = -2.39, Pcorr = 0.062 and Z = -2.26, Pcorr = 0.071). HC (N = 120) and active untreated MS (RRMS_U, N = 24) showed intermediate microbial richness. Enterotypes were associated with clinical subgroups (N = 218, chi(2) = 36.10, P = 0.002), with Bacteroides 2 enterotype being more prevalent in RRMS_I. Butyricicoccus abundance was lower in PPMS than in RRMS_U (Z = -3.00, Pcorr = 0.014) and BMS (Z = -2.56, Pcorr = 0.031), lower in RRMS_I than in BMS (Z = -2.50, Pcorr = 0.034) and RRMS_U (Z = -2.91, Pcorr = 0.013), and inversely correlated with self-reported physical symptoms (rho = -0.400, Pcorr = 0.001) and disease severity (rho = -0.223, P = 0.027). Interpretation These results emphasize the importance of phenotypic subcategorization in MS-microbiome research, possibly explaining previous result heterogeneity, while showing the potential for specific microbiome-based biomarkers for disease activity and severity.

44 citations


Journal ArticleDOI
TL;DR: It is concluded that dietary emulsifiers can severely impact the gut microbiota, and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin.
Abstract: The use of additives in food products has become an important public health concern. In recent reports, dietary emulsifiers have been shown to affect the gut microbiota, contributing to a pro-inflammatory phenotype and metabolic syndrome. So far, it is not yet known whether similar microbiome shifts are observable for a more diverse set of emulsifier types and to what extent these effects vary with the unique features of an individual's microbiome. To bridge this gap, we investigated the effect of five dietary emulsifiers on the fecal microbiota from 10 human individuals upon a 48 h exposure. Community structure was assessed with quantitative microbial profiling, functionality was evaluated by measuring fermentation metabolites, and pro-inflammatory properties were assessed with the phylogenetic prediction algorithm PICRUSt, together with a TLR5 reporter cell assay for flagellin. A comparison was made between two mainstream chemical emulsifiers (carboxymethylcellulose and P80), a natural extract (soy lecithin), and biotechnological emulsifiers (sophorolipids and rhamnolipids). While fecal microbiota responded in a donor-dependent manner to the different emulsifiers, profound differences between emulsifiers were observed. Rhamnolipids, sophorolipids, and soy lecithin eliminated 91 ± 0, 89 ± 1, and 87 ± 1% of the viable bacterial population after 48 h, yet they all selectively increased the proportional abundance of putative pathogens. Moreover, profound shifts in butyrate (-96 ± 6, -73 ± 24, and -34 ± 25%) and propionate (+13 ± 24, +88 ± 50, and +29 ± 16%) production were observed for these emulsifiers. Phylogenetic prediction indicated higher motility, which was, however, not confirmed by increased flagellin levels using the TLR5 reporter cell assay. We conclude that dietary emulsifiers can severely impact the gut microbiota, and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin. As biotechnological emulsifiers were especially more impactful than chemical emulsifiers, caution is warranted when considering them as more natural alternatives for clean label strategies.

25 citations


Posted ContentDOI
Alexander Kurilshikov1, Carolina Medina-Gomez2, Rodrigo Bacigalupe3, Djawad Radjabzadeh2, Jun Wang, Ayse Demirkan4, Caroline I. Le Roy5, Juan Antonio Raygoza Garay6, Casey T. Finnicum, Xingrong Liu7, Daria V. Zhernakova8, Marc Jan Bonder1, Tue H. Hansen9, Fabian Frost10, Malte C. Rühlemann11, Williams Turpin6, Jee-Young Moon12, Han-Na Kim13, Kreete Lüll14, Elad Barkan15, Shiraz A. Shah16, Myriam Fornage17, Joanna Szopinska-Tokov, Zachary D. Wallen18, Dmitrii Borisevich9, Lars Agréus7, Anna Andreasson19, Corinna Bang11, Larbi Bedrani6, Jordana T. Bell5, Hans Bisgaard16, Michael Boehnke20, Dorret I. Boomsma21, Robert D. Burk12, Annique Claringbould1, Kenneth Croitoru22, Gareth E. Davies, Cornelia M. van Duijn23, Liesbeth Duijts2, Gwen Falony3, Jingyuan Fu1, Adriaan van der Graaf1, Torben Hansen9, Georg Homuth10, David A. Hughes24, Richard G. IJzerman25, Matthew A Jackson4, Vincent W. V. Jaddoe2, Marie Joossens3, Torben Joergensen9, Daniel Keszthelyi26, Rob Knight27, Markku Laakso28, Matthias Laudes, Lenore J. Launer29, Wolfgang Lieb11, Aldons J. Lusis30, Ad A.M. Masclee26, Henriëtte A. Moll2, Zlatan Mujagic26, Qi Qibin12, Daphna Rothschild15, Hocheol Shin13, Søren J. Sørensen9, Claire J. Steves5, Jonathan Thorsen16, Nicholas J. Timpson24, Raul Y. Tito3, Sara Vieira-Silva3, Uve Voelker10, Henry Voelzke10, Urmo Võsa1, Kaitlin H Wade24, Susanna Walter, Kyoko Watanabe21, Stefan Weiss, Frank Ulrich Weiss10, Omer Weissbrod31, Harm-Jan Westra1, Gonneke Willemsen21, Haydeh Payami18, Daisy Jonkers26, Alejandro Arias Vasquez, Eco J. C. de Geus21, Katie A. Meyer32, Jakob Stokholm16, Eran Segal15, Elin Org14, Cisca Wijmenga1, Hyung Lae Kim33, Robert C. Kaplan12, Tim D. Spector5, André G. Uitterlinden2, Fernando Rivadeneira34, Andre Franke11, Markus M. Lerch10, Lude Franke1, Serena Sanna, Mauro D'Amato35, Oluf Pedersen9, Andrew D. Paterson6, Robert Kraaij2, Jeroen Raes3, Alexandra Zhernakova1 
28 Jun 2020-bioRxiv
TL;DR: A phenome-wide association study and Mendelian randomization analyses identified enrichment of microbiome trait loci SNPs in the metabolic, nutrition and environment domains and indicated food preferences and diseases as mediators of genetic effects.
Abstract: To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed whole-genome genotypes and 16S fecal microbiome data from 18,473 individuals (25 cohorts) Microbial composition showed high variability across cohorts: we detected only 9 out of 410 genera in more than 95% of the samples A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 30 loci affecting microbome taxa at a genome-wide significant (P

15 citations


Posted ContentDOI
28 Jun 2020-bioRxiv
TL;DR: It is concluded that dietary emulsifiers can severely impact the gut microbiota and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin.
Abstract: The use of additives in food products has become an important public health concern In recent reports, dietary emulsifiers have been shown to affect the gut microbiota, contributing to a pro-inflammatory phenotype and metabolic syndrome So far, it is not yet known whether similar microbiome shifts are observable for a more diverse set of emulsifier types and to what extent these effects vary with the unique features of an individual’s microbiome To bridge this gap, we investigated the effect of five dietary emulsifiers on the fecal microbiota from 10 human individuals upon a 48 hour exposure Community structure was assessed with quantative microbial profiling, functionality was evaluated by measuring fermentation metabolites and pro-inflammatory properties were assessed with the phylogenetic prediction algorythm PICRUSt, together with a TLR5 reporter cell assay for flagellin A comparison was made between two mainstream chemical emulsifiers (carboxymethylcellulose and P80), a natural extract (soy lecithin) and biotechnological emulsifiers (sophorolipids and rhamnolipids) While fecal microbiota responded in a donor-dependent manner to the different emulsifiers, profound differences between emulsifier were observed Rhamnolipids, sophorolipids and soy lecithin eliminated 91% ± 0%, 89% ± 1% and 87% ± 1% of the viable bacterial population after 48 hours, yet they all selectively increased the proportional abundance of putative pathogens Moreover, profound shifts in butyrate (−96% ± 6 %, −73% ± 24% and −34 ± 25% respectively) and propionate (+13% ± 24 %, +88% ± 50% and +29% ± 16% respectively) production were observed for these emulsifiers Phylogenetic prediction indicated higher motility, which was, however, not confirmed by increased flagellin levels using the TLR5 reporter cell assay We conclude that dietary emulsifiers can severely impact the gut microbiota and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin As biotechnological emulsifiers were especially more impactful than chemical emulsifiers, caution is warranted when considering them as more natural alternatives for clean label strategies

Journal ArticleDOI
TL;DR: Zinc modulates the gut microbiota, causing less induction of ISRE/IRF genes in crypt cells, less TNF‐induced necroptosis in Paneth cells, and less fatal evasion of gut bacteria into the system.
Abstract: The cytokine TNF drives inflammatory diseases, e.g., Crohn's disease. In a mouse model of TNF-induced systemic inflammatory response syndrome (SIRS), severe impact on intestinal epithelial cells (IECs) is observed. Zinc confers complete protection in this model. We found that zinc no longer protects in animals which lack glucocorticoids (GCs), or express mutant versions of their receptor GR in IECs, nor in mice which lack gut microbiota. RNA-seq studies in IECs showed that zinc caused reduction in expression of constitutive (STAT1-induced) interferon-stimulated response (ISRE) genes and interferon regulatory factor (IRF) genes. Since some of these genes are involved in TNF-induced cell death in intestinal crypt Paneth cells, and since zinc has direct effects on the composition of the gut microbiota (such as several Staphylococcus species) and on TNF-induced Paneth cell death, we postulate a new zinc-related anti-inflammatory mechanism. Zinc modulates the gut microbiota, causing less induction of ISRE/IRF genes in crypt cells, less TNF-induced necroptosis in Paneth cells, and less fatal evasion of gut bacteria into the system.

Journal ArticleDOI
TL;DR: To therapeutically modulate gut microbial ecosystems, a better understanding of gut ecology is key and high-throughput in vitro ecology provides a tool with the necessary power to address these needs and interpersonal treatment response variation.
Abstract: To therapeutically modulate gut microbial ecosystems, a better understanding of gut ecology is key. High-throughput in vitro ecology provides a tool with the necessary power to address these needs and interpersonal treatment response variation.

Posted ContentDOI
26 Dec 2020-medRxiv
TL;DR: In this paper, the authors examined potential confounders in COVID-19 microbiome studies by analyzing the upper and lower respiratory tract microbiome in well-phenotyped COVID19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling.
Abstract: Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 microbiome studies by analyzing the upper (n=58) and lower (n=35) respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We found that time in the intensive care unit and the type of oxygen support explained the most variation within the upper respiratory tract microbiome, dwarfing (non-significant) effects from viral load, disease severity, and immune status. Specifically, mechanical ventilation was linked to altered community structure, lower species- and higher strain-level diversity, and significant shifts in oral taxa previously associated with COVID-19. Single-cell transcriptomic analysis of the lower respiratory tract of ventilated COVID-19 patients identified increased oral microbiota compared to controls. These oral microbiota were found physically associated with proinflammatory immune cells, which showed higher levels of inflammatory markers. Overall, our findings suggest confounders are driving contradictory results in current COVID-19 microbiome studies and careful attention needs to be paid to ICU stay and type of oxygen support, as bacteria favored in these conditions may contribute to the inflammatory phenotypes observed in severe COVID-19 patients.

Journal ArticleDOI
TL;DR: In this paper, the host immune response in symptomatic COVID-19 patients seems ineffective in clearing SARS-CoV-2, yet excessive in causing local tissue damage and hypercytokinemia.
Abstract: The host immune response in symptomatic COVID-19 patients seems ineffective in clearing SARS-CoV-2, yet excessive in causing local tissue damage and hypercytokinemia. To elucidate the immunopathology underlying COVID-19 severity, cytokine profiling was performed in mild-moderate and critically-ill COVID-19 patients. Hypercytokinemia in COVID-19 differed from the IFN-γ-driven cytokine storm in macrophage activation syndrome, but was increased in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels followed by deep-immune profiling showed that classical monocytes drive this hyper-inflammatory phenotype and that both a quantitative and qualitative reduction in T-lymphocytes correlate with disease severity, with CD8+ cells being disproportionately affected. Expression of antigen presentation and co-stimulatory molecules was reduced in critical disease, while also neutrophils contributed to disease severity and local tissue damage by amplifying hypercytokinemia and neutrophil extracellular trap formation. We suggest a monocyte-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity. Funding: This work was funded by KU Leuven (internal fund and grant C14/17/084 and C16/17/010), VIB (Grand Challenge project), UZ Leuven (KOOR project), FWO grant I007418N, the Rega Foundation (research expert fellowship to G.M.) and ‘het Leuvens Kankerinstituut’. E.D. is a postdoctoral research fellow of the Research Foundation – Flanders (FWO), Belgium (grant number 12X9420N). J.G. holds a postdoctoral research fellowship granted by the clinical research and education council of the University Hospitals Leuven. Y.S. received funding from the Flemish Government (AI Research Program). L.V. is supported by an FWO PhD fellowship (grant number 11E9819N). P.V.M. is supported by an FWO PhD fellowship (grant number 1S66020N). S.V.G. is an ISAC Marylou Ingram Scholar and supported by an FWO postdoctoral research grant (Research Foundation – Flanders). E.W. is supported by Stichting tegen Kanker (Mandate for basic & clinical oncology research). J.W. is supported by an FWO Fundamental Clinical Mandate (1833317N). Conflict of Interest: The authors declare no competing interests. Ethical Approval: All study procedures were approved by the Ethics Committee of the University Hospitals Leuven. Informed consent was obtained from all individuals or their legal guardians.

Posted ContentDOI
19 Jun 2020-medRxiv
TL;DR: The demonstrated relevance of these findings to IBS warrants further study for the identification of actionable pathomechanisms in the dysmotility syndromes.
Abstract: Objective Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders (FGID) like irritable bowel syndrome (IBS) Its molecular underpinnings, and their anomalies in FGID disorders are poorly characterized, hence we sought to gain mechanistic insight through a large-scale genetic investigation Design We used stool frequency (STL-FRQ) as a (surrogate) quantitative trait to study the genetics of gut motility, exploiting questionnaire and genotype data from UK Biobank and four smaller population-based cohorts (LifeLines-Deep, Genes for Good, Flemish Gut Flora Project and PopCol), in a GWAS meta-analysis spanning 8,817,117 high-quality SNP markers and 167,875 individuals of European descent Results We identify 13 genome-wide significant loci (P≤50×10−8) harboring prioritized genes that are: i) involved in sensory perception and neurotransmitter/neuropeptide signaling; ii) enriched for their expression in enteric motor neurons associated with the control of peristalsis (P=70×10−8) iii) previously linked to other traits and conditions, including GI motility and dysmotility syndromes, and the response to their pharmacological treatment The genetic architecture of STL-FRQ most strongly correlates with that of IBS (rg=042; P=11×10−3) In UK Biobank, the risk of IBS with diarrhea was 4x higher in individuals from the top 1% of the distribution of polygenic scores (PGS) computed based on STL-FRQ GWAS summary statistics (ORs=414; P=12×10−97) Conclusion We identify loci harboring genes with a plausible role in GI motility, possibly acting via neurotransmission and similar pathways in specialized enteric neurons The demonstrated relevance of these findings to IBS warrants further study for the identification of actionable pathomechanisms in the dysmotility syndromes

Posted ContentDOI
05 Oct 2020-bioRxiv
TL;DR: Anuran, a toolbox for investigation of noisy networks with null models, for identification of non-random patterns in groups of association networks, is developed and it is demonstrated that different orders of sponges have a larger CAN than expected at random.
Abstract: Microbial network construction and analysis is an important tool in microbial ecology. As microbial interactions are challenging to infer experimentally, such networks are often constructed from statistically inferred associations and may not represent ecological interactions. Hence, microbial association networks contain a large number of errors and their derived properties do not necessarily reflect true community structure. Such errors can be identified with the use of appropriate null models. We have developed anuran, a toolbox for investigation of noisy networks with null models, for identification of non-random patterns in groups of association networks. This toolbox compares multiple networks to identify conserved subsets (core association networks, CANs) and other network properties that are shared across all networks. Such groups of networks can be generated from a collection of time series data or from cross-sectional sample sets. We use data from the Global Sponge Project to demonstrate that different orders of sponges have a larger CAN than expected at random.