Biology subjects

Loeber, U.

Publications and source records attributed to Loeber, U..

7 recordsLinked to original sources

bioRxiv2025

Global analysis of infant gut microbiota revealed distinctive maturation dynamics across lifestyles

The infant gut microbiome develops during the first years of life and influences long-term health through its interaction with immune system development. However, our understanding of early-life microbiome assembly is biased by the predominance of infants with industrialized lifestyles from North America and Europe. Here, we address this bias by assembling a globally representative dataset of infant gut microbiomes to train a microbiome maturation model that can characterize lifestyle specific patterns of microbial maturation as a function of age. Models trained exclusively on industrialized infants perform poorly when applied to non-industrialized datasets. In contrast, more diverse models including individuals from both lifestyles achieve increased correlation between microbial and chronological age. We identified differences in relevant taxa associated with the maturation in the different lifestyles. Additionally, our modeling approach detects a delay in the microbial maturation of independent cohorts of severely malnourished and preterm infants compared to healthy ones. Our results underscore the relevance of global diversity in microbiome research and provide deeper insights into context-dependent maturation dynamics of the infant gut microbiome.

microbiology↗

bioRxiv2025

Environmental reservoir of resistance genes for the last resort antibiotic Cefiderocol.

Antibiotic resistance poses a global public health threat. Cefiderocol, a recently introduced siderophore cephalosporin, employs a "Trojan Horse" mechanism by exploiting bacterial iron uptake systems for cell entry. Yet, resistant clinical isolates are already observed in clinics and resistance mechanisms are difficult to characterize. Here, we applied functional metagenomics to identify cefiderocol resistance genes. Functional metagenomic DNA libraries from diverse environmental samples collected across several countries were expressed in a cefiderocol-sensitive Escherichia coli host. This yielded four resistant clones with DNA originating from wastewater or freshwater DNA libraries. The identified antibiotic resistance genes (ARGs) causing an increase in cefiderocol minimum inhibitory concentrations encoded for beta-lactamases (VEB-3, OXA-372 homolog and YbxI homolog) and a partial penicillin binding protein homolog. Three of four shared closest homologs in pathogenic bacteria. One ARG was associated with a mobile genetic element and was broadly distributed across all wastewater samples from every country surveyed. This study underscores the critical importance of environmental surveillance for ARGs, particularly for novel agents like cefiderocol with limited understanding of resistance mechanisms.

microbiology↗

bioRxiv2024

Identification and Mitigation of microbial contaminant reads from long-read metagenomic samples

Metagenomic sequencing of clinical samples has significantly enhanced our understanding of microbial communities. However, microbial contamination and host-derived DNA remain a major obstacle to accurate data interpretation. Here, we present a methodology called Stop-Check-Go for detecting and mitigating contaminants in metagenomic datasets obtained from neonatal patient samples (nasal and rectal swabs). This method incorporates laboratory and bioinformatics work combining a prevalence method, coverage estimation, and microbiological reports. We compared the Stop-Check-Go decontamination system with other published decontamination tools, and commonly found poor performance in decontaminating microbiologically negative patients (false positives). We emphasize that host DNA decreased by an average of 76% per sample using a lysis method and was further reduced during post-sequencing analysis. Microbial species were classified as putative contaminants and assigned to Stop in nearly 60% of the dataset. The Stop-Check-Go system was developed to address the specific need of decontaminating low-biomass samples, where existing tools primarily designed for short-read metagenomic data showed limited performance. Impact StatementMetagenomics has gained popularity due to its diverse applications in the multi-omics research field and the improvements in sequencing performance of technologies such as Nanopore. However, challenges in biological interpretation remain because of the complexity of the data structure and the potential of contamination occurring at multiple steps during sample processing, which can lead to incorrect conclusions. We aim to raise awareness of contamination, which can be host-associated, cross-contamination, or library-derived, any of which may be introduced at any stage from sample collection. Existing decontamination tools are largely designed for short-read sequencing and thus present limitations when applied to long-read datasets. We propose a direct comparison of species in samples with species in weekly negative controls that progressively accumulate both external and kit-reagent contaminants. Additionally, we recommend incorporating read-depth coverage and read-prevalence metrics, particularly in studies involving low-biomass or non-culturable microorganisms. Whenever possible, validation with microbiological reports is strongly advised. Our code is available on GitHub and can be executed locally in RStudio. It outputs species classifications labeled Stop, Check, or Go, as well as BIOM format files clean of identified contaminants, ready for downstream analysis with R packages such as phyloseq, vegan, or metagenomeSeq. Data summaryThe complete source code and documentation are available from GitHub (https://github.com/SAM81221/Stop-Check-Go_TAPIR). Metagenomic sequences including controls have been deposited in the ENA in project PRJEB82667; and isolate sequences of control samples in PRJEB95992. Information on samples and sequences can be found in Supplementary Table S1.

bioinformatics↗

bioRxiv2024

Baseline microbiome composition impacts resilience to and recovery following antibiotics

The gut microbiome of healthy individuals naturally undergoes temporal changes linked to the dynamics of its community components1. These dynamics are only observable in longitudinal studies; they are particularly relevant to understanding ecosystem responses to external environment disturbances. External exposures, such as antibiotic treatment, significantly reshape the gut microbiome, impacting both pathogen and commensal microbes2. The gut microbiome plays pivotal roles in digestion, nutrient absorption, and mental health, influencing immune systems, obesity, and various diseases3-6. Consequently, beyond the short-term effects on the host gut microbiome dynamics, alterations resulting from antibiotic exposure also have enduring repercussions on human health and physiological equilibrium7. Therefore, enhancing gut microbiome resilience during antibiotic treatment is essential, with the goal of mitigating prolonged adverse effects. Here, we explored the impact of pre-antibiotic microbial and functional profiles on resilience, suggesting that specific baseline features exhibit greater resilience to antibiotics-induced changes. Our results identified an uncultured Faecalibacterium prausnitzii taxon as a species at baseline associated with diminished resilience. We demonstrated that this association could be linked to the role of this F. prausnitzii taxon as a keystone species. Additionally, we observed the influence of other commensal bacteria, such as Bifidobacterium animalis and Lactobacillus acidophilus, as well as functional modules, such as multidrug resistance efflux pump, on resilience. This lays the foundations for designing targeted strategies to promote a resilient gut microbiome before antibiotic treatment, alleviating possible prolonged effects on human health.

microbiology↗

bioRxiv2021

Fungal biodiversity in Arctic paleoecosystems assessed by metabarcoding of lake sedimentary ancient DNA

Fungi are crucial organisms in most ecosystems as they exert ecological key functions and are closely associated with land plants. Fungal community changes may therefore help reveal biodiversity changes in past ecosystems. Lake sediments contain DNA of organisms in the catchment area, which allows reconstructing past biodiversity by using metabarcoding of ancient sedimentary DNA. We developed a novel PCR primer combination for fungal metabarcoding targeting a short amplicon to account for length bias of amplification due to ancient DNA degradation. In-silico PCRs showed higher diversity using this primer combination than using previously established fungal metabarcoding primers. We analyzed existing data from sediment cores from four artic and one boreal lake in Siberia. These cores had been stored for 2-22 years and examined degradation effects of ancient DNA and storage time-related bias in fungal communities. Amplicon size differed between fungal divisions, however, we observed no significant effect of sample age on amplicon length and GC content, suggesting robust results. We also found no indication of post-coring fungal growth during storage distorting ancient fungal communities. Terrestrial soil fungi, including mycorrhizal fungi and saprotrophs, were predominant in all lakes, which supports the use of lake sedimentary ancient DNA for reconstructing terrestrial communities.

ecology↗

bioRxiv2021

Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage

AimsHypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN. Methods and resultsFour-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44mg/kg/d) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory fecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice. ConclusionsMicrobial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN. Translation PerspectiveTo assess the potential of microbiota-targeted interventions to prevent organ damage in hypertension, an accurate quantification of microbial influence is necessary. We provide evidence that the development of hypertensive organ damage is dependent on colonization status and suggest that a healthy microbiota provides anti-hypertensive immune and metabolic signals to the host. In the absence of normal symbiotic host-microbiome interactions, hypertensive damage to the kidney in particular is exacerbated. We suggest that hypertensive patients experiencing perturbations to the microbiota, which are common in CVD, may be at a greater risk for target-organ damage than those with a healthy microbiome.

microbiology↗

bioRxiv2020

Dissecting the collateral damage of antibiotics on gut microbes

Antibiotics are used for fighting pathogens, but also target our commensal bacteria as a side effect, disturbing the gut microbiota composition and causing dysbiosis and disease1-3. Despite this well-known collateral damage, the activity spectrum of the different antibiotic classes on gut bacteria remains poorly characterized. Having monitored the activities of >1,000 marketed drugs on 38 representative species of the healthy human gut microbiome4, we here characterize further the 144 antibiotics therein, representing all major classes. We determined >800 Minimal Inhibitory Concentrations (MICs) and extended the antibiotic profiling to 10 additional species to validate these results and link to available data on antibiotic breakpoints for gut microbes. Antibiotic classes exhibited distinct inhibition spectra, including generation-dependent effects by quinolones and phylogeny-independence by {beta}-lactams. Macrolides and tetracyclines, two prototypic classes of bacteriostatic protein synthesis inhibitors, inhibited almost all commensals tested. We established that both kill different subsets of prevalent commensal bacteria, and cause cell lysis in specific cases. This species-specific activity challenges the long-standing divide of antibiotics into bactericidal and bacteriostatic, and provides a possible explanation for the strong impact of macrolides on the gut microbiota composition in animals5-8 and humans9-11. To mitigate the collateral damage of macrolides and tetracyclines on gut commensals, we exploited the fact that drug combinations have species-specific outcomes in bacteria12 and sought marketed drugs, which could antagonize the activity of these antibiotics in abundant gut commensal species. By screening >1,000 drugs, we identified several such antidotes capable of protecting gut species from these antibiotics without compromising their activity against relevant pathogens. Altogether, this study broadens our understanding of antibiotic action on gut commensals, uncovers a previously unappreciated and broad bactericidal effect of prototypical bacteriostatic antibiotics on gut bacteria, and opens avenues for preventing the collateral damage caused by antibiotics on human gut commensals.

microbiology↗