Biology subjects

Raes, J.

Publications and source records attributed to Raes, J..

10 recordsLinked to original sources

bioRxiv2026

UNRAVELLING A HIDDEN SUBTYPE: MULTIOMICS REVEAL PSORIASIS-LIKE SIGNATURE WITH SURGICAL RELEVANCE IN A SUBSET OF PERIANAL FISTULIZING CROHN'S DISEASE

Background and aimsPerianal fistulizing Crohns disease (pCD) affects 20% of patients with Crohns disease (CD) and severely impacts quality of life. Current therapies fail to provide sustained relief, and the molecular underpinnings of pCD remain poorly understood. This study aimed to elucidate the molecular landscape of perianal fistulas through multiomic profiling. MethodsPaired fistula-tract and adjacent rectal mucosal biopsies were collected from 63 patients (48 with pCD, 15 with cryptoglandular fistula [CPTGL]). Longitudinal sampling generated 101 unique molecular profiles, comprising of both RNA sequencing (RNA-seq) and 16S rRNA sequencing from both tissue sites, followed by integrative multiomics and gene network analyses. ResultsUnsupervised clustering revealed three patient clusters primarily defined by host gene expression, with minimal contribution from microbial profiles. Fistulae in clusters 1 and 2 showed strong immune activation and epithelial-mesenchymal transition (EMT). In contrast, cluster 3 fistulae displayed keratinization and metabolic reprogramming resembling psoriatic skin, together with reduced JAK-STAT signalling. Cluster 3 was enriched for patients classified as TOpClass:2a, who are more suitable for surgical repair (p = 0.02). Conversely, cluster 2, characterized by rectal keratinization and EMT in both fistula and rectum, showed the highest MRI inflammatory-mass score (p = 0.02) and a greater risk of subsequent ileostomy (Kaplan-Meier; p = 0.008). An independent RNAseq dataset validated the keratinization signature in a subset of pCD fistulae. ConclusionIntegrated multiomic analysis identified distinct molecular subtypes of pCD with surgical and therapeutic relevance. These findings refine the molecular understanding of pCD and support a precision medicine approach. What You Need to Know?O_ST_ABSBACKGROUND AND CONTEXTC_ST_ABSO_LIPerianal fistulas affect 1 in 5 Crohns disease patients and have a severe negative impact on the quality of life of the patients. C_LIO_LIMost advanced IBD therapies are not efficacious for perianal Crohns disease. C_LIO_LISurgical repair is not suitable for all patients. C_LI NEW FINDINGSO_LIThis study is the first to delineate molecularly defined patient subtypes in perianal fistulizing Crohns disease. It further characterizes a psoriasis-like keratinization program in a subset of fistulas. Finally, it identifies molecular features and histological indicators that may explain-and potentially help predict-favorable surgical outcomes in selected patients C_LI LIMITATIONSO_LIFunctional and mechanistic studies will be required to further dissect the drivers and dynamics of the epithelial remodeling identified. C_LI CLINICAL RESEARCH RELEVANCEO_LIRaises the possibility of refining of existing clinical stratification using molecular markers for improved therapeutic management and outcome. C_LI BASIC RESEARCH RELEVANCEO_LIProposes keratinization as an opposing molecular process to EMT within the perianal fistula tract. C_LIO_LIIdentifies robust gene signatures associated with EMT and keratinization in the fistula for further experimental and clinical studies. C_LI

immunology↗

bioRxiv2024

Depletion of skin bacteria by topical antibiotic treatment accelerates onset of Zika virus disease in mice.

Mosquito-borne flaviviruses have emerged as global health threats due to their rapid spread and high disease burden. The initial site of virus replication is the mosquito biting site in the host skin, yet the role of host skin bacteria remains unclear. Here, we observed accelerated progression of Zika virus (ZIKV)-induced disease in mice with depleted skin bacteria by topical antibiotic treatment prior to ZIKV infection. Increased viral loads in the blood, draining lymph node, spleen and brain of antibiotic-treated mice suggested faster ZIKV dissemination. Flow cytometry revealed increased frequencies of T cells in the lymph nodes, along with enhanced activation of T cells in the brain upon antibiotic treatment. The antibiotic-induced phenotype was rescued by restoring the skin bacteria prior to infection. Our findings demonstrate an increased susceptibility to ZIKV infection in mice with depleted skin microbiomes, suggesting a potential role of skin bacteria in modulating the infection outcome.

microbiology↗

bioRxiv2024

Gut environmental factors explain variations in the gut microbiome composition and metabolism within and between healthy adults

The human gut microbiome is highly personal. However, the contribution of the gut environment to variations in the gut microbiome remains elusive. Here, we profiled the gut microbiome composition and metabolism over 9 consecutive days in 61 healthy adults and assessed gut environmental factors including segmental transit time and pH using a wireless motility capsule. Day-to-day fluctuations in gut environmental factors as well as segmental transit time and pH varied substantially between individuals. The gut environment explained more variations in gut microbiome and urine metabolome than dietary macronutrients or personal characteristics. Finally, we identified coffee-derived metabolites to be negatively correlated with small intestinal transit time and several microbial metabolites to be associated with colonic transit time including urinary proteolytic markers, faecal short-chain fatty acids, and breath methane. Our work suggests that the gut environment is key for understanding the individuality of the human gut microbiome composition and metabolism.

microbiology↗

bioRxiv2021

Disentangling environmental effects in microbial association networks

BackgroundEcological interactions among microorganisms are fundamental for ecosystem function, yet they are mostly unknown or poorly understood. High-throughput-omics can indicate microbial interactions through associations across time and space, which can be represented as association networks. Associations could result from either ecological interactions between microorganisms, or from environmental selection, where the associations are environmentally-driven. Therefore, before downstream analysis and interpretation, we need to distinguish the nature of the association, particularly if it is due to environmental selection or not. ResultsWe present EnDED (Environmentally-Driven Edge Detection), an implementation of four approaches as well as their combination to predict which links between microorganisms in an association network are environmentally-driven. The four approaches are Sign Pattern, Overlap, Interaction Information, and Data Processing Inequality. We tested EnDED on networks from simulated data of 50 microorganisms. The networks contained on average 50 nodes and 1087 edges, of which 60 were true interactions but 1026 false associations (i.e. environmentally-driven or due to chance). Applying each method individually, we detected a moderate to high number of environmentally-driven edges--87% Sign Pattern and Overlap, 67% Interaction Information, and 44% Data Processing Inequality. Combining these methods in an intersection approach resulted in retaining more interactions, both true and false (32% of environmentally-driven associations). After validation with the simulated datasets, we applied EnDED on a marine microbial network inferred from 10 years of monthly observations of microbial-plankton abundance. The intersection combination predicted that 8.3% of the associations were environmentally-driven, while individual methods predicted 24.8% (Data Processing Inequality), 25.7% (Interaction Information), and up to 84.6% (Sign Pattern as well as Overlap). The fraction of environmentally-driven edges among negative microbial associations in the real network increased rapidly with the number of environmental factors. ConclusionsTo reach accurate hypotheses about ecological interactions, it is important to determine, quantify, and remove environmentally-driven associations in marine microbial association networks. For that, EnDED offers up to four individual methods as well as their combination. However, especially for the intersection combination, we suggest using EnDED with other strategies to reduce the number of false associations and consequently the number of potential interaction hypotheses.

microbiology↗

bioRxiv2021

Successional stages in infant gut microbiota maturation

BackgroundDisturbances in the primary colonization of the infant gut can result in life-long consequences and have been associated with a range of host conditions. Although early life factors have been shown to affect the infant gut microbiota development, our current understanding of the human gut colonization in early life remains limited. To gain more insights in the unique dynamics of this rapidly evolving ecosystem, we investigated the microbiota over the first year of life in eight densely sampled infants (total number of samples, n=303). To evaluate gut microbiota maturation transition towards an adult configuration, we compared the microbiome composition of the infants to the Flemish Gut Flora Project population (n=1,106). ResultsWe observed the infant gut microbiota to mature through three distinct, conserved stages of ecosystem development. Across these successional gut microbiota maturation stages, genus predominance was observed to shift from Escherichia over Bifidobacterium to Bacteroides. Both disease and antibiotic treatment were observed to be associated occasionally with gut microbiota maturation stage regression, a transient setback in microbiota maturation dynamics. Although the studied microbiota trajectories evolved to more adult-like constellations, microbiome community typing against the background of the Flemish Gut Flora Project (FGFP) cohort clustered all infant samples within the (in adults) potentially dysbiotic Bact2 enterotype. ConclusionWe confirmed similarities between infant gut microbial colonization and adult dysbiosis. A profound knowledge about the primary gut colonization process in infants might provide crucial insights into how the secondary colonization of a dysbiotic adult gut can be redirected.

microbiology↗

bioRxiv2020

A framework for comparing microbial networks reveals core associations

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.

microbiology↗

bioRxiv2020

Dietary emulsifiers alter composition and activity of the human gut microbiota in vitro, irrespective of chemical or natural emulsifier origin.

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 individuals 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.

microbiology↗

bioRxiv2019

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

ObjectiveGut 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. DesignWe 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. ResultsIn-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 {beta}-cell mass and reduced liver inflammation and fibrosis, whereas benzoate treatment resulted in liver inflammation. ConclusionOur 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.

systems biology↗

bioRxiv2019

Metabolic Architecture of the Deep Ocean Microbiome

The deep sea, the largest compartment of the ocean, is an essential component of the Earth system, but the functional exploration of its microbial communities lags far behind that of other marine realms. Here we analyze 58 bathypelagic microbial metagenomes from the Atlantic, Indian, and Pacific Oceans in an unprecedented sampling effort from the Malaspina Global Expedition, to resolve the metabolic architecture of the deep ocean microbiome. The Malaspina Deep-Sea Gene Collection, 71% of which consists of novel genes, reveals a strong dichotomy between the functional traits of free-living and particle-attached microorganisms, and shows relatively patchy composition challenging the paradigm of a uniform dark ocean ecosystem. Metagenome Assembled Genomes uncovered 11 potential new phyla, establishing references for deep ocean microbial taxa, and revealed mixotrophy to be a widespread trophic strategy in the deep ocean. These results expand our understanding of the functional diversity, metabolic versatility, and carbon cycling in the largest ecosystem on Earth.\n\nOne Sentence SummaryA whole community genomic survey of the deep microbiome sheds light on the microbial and functional diversity of the dark ocean.

microbiology↗

bioRxiv2018

Integrated culturing, modeling and transcriptomics uncovers complex interactions and emergent behavior in a synthetic gut community

Whereas the composition of the human gut microbiome is relatively well resolved, predictive understanding of its response to perturbations such as diet shifts is still lacking. Here, we followed a bottom-up strategy to explore human gut community dynamics. We established a synthetic community composed of three representative human gut isolates in well-controlled conditions in vitro. We then explored species interactions by performing all mono- and pair-wise fermentation experiments and quantified with a mechanistic community model how well tri-culture dynamics was predicted from mono-culture data. With the model as a reference, we demonstrated that species grown in co-culture behaved differently than in mono-culture and confirmed their altered behavior at the transcriptional level. In addition, we showed with replicate tri-cultures and in simulations that dominance in tri-culture sensitively depends on initial conditions. Our work has important implications for gut microbial community modeling as well as ecological interaction detection from batch cultures.

bioinformatics↗