Biology subjects

Herrema, H.

Publications and source records attributed to Herrema, H..

10 recordsLinked to original sources

bioRxiv2026

Diversity-generating retroelements enable phages to expand their host range in the human gut.

Diversity-generating retroelements (DGRs) are genetic elements that use error-prone reverse transcription to hypermutate specific target genes, most often the receptor-binding proteins of phages. They are enriched in human gut viruses, where they are hypothesised to enable phages expand their host range. Yet DGR-mediated host-range expansion across bacterial species has so far only been predicted in silico and has not been examined directly within complex microbial communities. To test this hypothesis in situ, we tracked phage-host interactions in the human gut, combining bulk metagenomic, virus-like particle (VLP), and Hi-C sequencing of longitudinal faecal samples collected over a five-week period. This culture-independent approach identified 380 interactions between 97 phages and 76 bacterial hosts. Nearly a third of these phages (31 of 97) encoded a DGR, and DGR-encoding phages were more likely to interact with multiple bacterial species. Moreover, nucleotide diversity in DGR-targeted genes increased with the number of hosts a phage interacted with and was concentrated in the surface-exposed, DGR-targeted variable region of its receptor-binding proteins. Together, these results provide in situ evidence that DGRs enable phages to expand their host range in the human gut.

microbiology↗

bioRxiv2026

Ethnic differences in gut microbiota composition and functional capacity persist over six years in the HELIUS multi-ethnic longitudinal cohort

Background: Ethnic minority groups in Western Europe carry a disproportionate cardiometabolic disease burden not fully explained by conventional risk factors, and their gut microbiomes differ markedly from those of European-origin populations. Whether these differences persist over time has not been examined prospectively. Results: We followed 1,903 participants from six ethnic groups in the HELIUS cohort over 6 years, using faecal 16S rRNA sequencing across all groups and shotgun metagenomics in a matched Dutch and South-Asian Surinamese subset (N = 238 per group). The extent of microbiota compositional change over time differed between ethnic groups: Moroccan participants showed the largest change, while the Dutch and South-Asian Surinamese participants were most stable. Diabetes mellitus and medication use at baseline were associated with greater compositional drift. However, ethnic differences in composition were largely preserved across all six groups (16S: ethnicity R2 0.044 to 0.037; all 15 pairwise contrasts significant at follow-up) and in the shotgun subset (R2 0.047 to 0.037). At the species level, 61 of 78 ethnicity-associated species remained differentially abundant at follow-up. Alistipes putredinis, the species converging most strongly, was absent at baseline in 43% of South-Asian Surinamese participants, and the convergence was consistent with acquisition of this species by this group. At strain level, within-person strain sharing declined with follow-up duration but was similar between ethnic groups. Within hosts, 90% of A. putredinis populations were retained as the same or a closely related lineage, and within the retained subset, microdiversity increased in both groups. Ethnic differences in functional profiles persisted to a similar extent as those in composition, with limited convergence in fibre-degrading enzyme families (GH5_37, GH26). The total antibiotic resistance gene (ARG) burden in the gut microbiome declined similarly in both groups over time. Dutch participants showed higher baseline ARG diversity that converged toward South-Asian Surinamese levels, while class-level differences were predominantly stable. Conclusions: Six years of follow-up in a shared urban environment narrowed ethnic differences in the gut microbiome only modestly; assuming exponential decline, the observed change corresponds to a half-life of roughly two decades.

microbiology↗

bioRxiv2026

Sex-stratified adipose-liver circuits in human MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common, clinically heterogeneous condition associated with liver-related and cardiometabolic morbidity. Sex differences in MASLD prevalence and progression are well recognized, but how they extend across the liver and visceral adipose tissue (VAT), a major source of lipid and endocrine signals to the liver, remains unclear. Here, we profiled paired liver and VAT biopsies from women and men with and without MASLD, generating single-nucleus datasets of 34 liver samples and 40 VAT samples, including 32 patient-matched pairs. In liver, women with MASLD showed a higher Kupffer-cell triglyceride-catabolism score (1.30-SD female-male difference; FDR=0.0022), accompanied by directionally consistent hepatocyte and endothelial programs. In VAT, women with MASLD showed higher adipocyte lipid and oxidative metabolism (0.87-1.15 SD; FDR<0.05 across seven pathways) together with macrophage immune activation, whereas men with MASLD showed stronger stromal communication routes. Across matched patients, gene modules linked VAT adipocyte and macrophage states to liver hepatocyte stress and lipid-receipt states. Bulk RNA-seq module scoring and paired liver-VAT analyses in 293 patients supported hepatic stress in both sexes, lower adipocyte signaling in women with increasing steatosis, and cross-tissue adipocyte-hepatocyte coupling (r=0.30; FDR=2.1e-6). Together, these findings identify distinct sex-associated transcriptional states in liver and VAT in MASLD and show that these states are coordinated across both tissues within the same individuals.

physiology↗

bioRxiv2025

CLR-Seq: a pipeline to identify bacterial microbiota species with immunomodulatory potential through human C-type lectin receptor interaction

Bacterial glycans are key components in immune interactions. We lack insight into the diverse glycan landscape present in complex microbial communities since currentomics techniques do not capture this post-translational information. Here we employed C-type lectin receptors (CLRs), which are dedicated innate glycan-sensing receptors, as probes for bacterial cell sorting in combination with 16S rRNA gene sequencing to identify microbiota species with a specific CLR-reactive glycan profile. We established our experimental CLR-sequencing (CLR-seq) pipeline using soluble fluorescently-labeled human macrophage galactose C-type lectin (MGL, CD301) and langerin (CD207). Both receptors identified known langerin- or MGL-interacting Staphylococcus aureus strains in a synthetic microbial community even when present at low abundance. Subsequent application of CLR-seq on fecal microbiota samples from healthy donors identified specific langerin- and MGL-interacting bacterial species that were subsequently validated as monocultures. In summary, CLR-seq is a modular platform that allows identification of human microbiota species based on CLR-interacting glycans with easy expansion to other CLRs or microbiota samples from patients. Given that CLRs are densely expressed on dendrites of antigen-presenting cells, this pathway may play a role in cross-barrier recognition and sampling of the environment during homeostasis.

microbiology↗

bioRxiv2023

Phylogeny and disease links of a widespread and ancient gut phage lineage

Viruses are a core component of the human microbiome, impacting health and disease through interactions with gut bacteria1 and the immune system2. Most viruses in the human microbiome are bacteriophages, which exclusively infect bacteria. Individual gut bacteriophages can affect bacterial bile acid deconjugation3, and can alter their infection strategy based on dietary content4. Up to recently, most studies of the gut virome have focused on low taxonomic scales (e.g., viral operational taxonomic units), hampering population-level analyses. We previously identified the expansive and widespread Candidatus Heliusviridae bacteriophage family in a cohort with inhabitants of Amsterdam, the Netherlands. Here, we study their biodiversity and evolution in a wide variety of human populations. With a detailed phylogeny based on sequences from six viral genome databases, we now propose the Candidatus order Heliusvirales to accommodate these viruses. We identify Ca. Heliusvirales viruses in 80% of 5,441 individuals across 39 studies, and also in nine out of thirteen analyzed metagenomes from ancient humans that lived in Europe and North America between 1,000 and 5,000 years ago. We show that a large Ca. Heliusvirales lineage has diversified starting at the appearance of Homo sapiens some 200,000-300,000 years ago. Ancient peoples and modern hunter-gatherers further have distinct Ca. Heliusvirales populations that are characterized by lower richness than modern urbanized people. Within urbanized people, those suffering from type 1 and type 2 diabetes, as well as inflammatory bowel disease, have higher Ca. Heliusvirales richness than healthy controls. We thus conclude that these ancient core members of the human gut virome have thrived with increasingly westernized lifestyles of the human population.

microbiology↗

bioRxiv2022

High fat diet changes bacterial signatures in the murine pancreas

Hyperglycemia is caused by failure of pancreatic beta cells. Beta-cell inflammation contributes to beta-cell dysfunction, however (primary) immunogenic triggers are in large unknown. The gut microbiota is one potential source of pro-inflammatory molecules. A high-fat diet treatment increases pro-inflammatory bacteria in the gut microbiome, parts of which could migrate to the pancreatic beta-cell. In the present study, the bacterial DNA signature in the pancreas and intestine of C57BL6/J mice was analyzed. Mice were fed a high-fat diet (60% kcal fat) or a regular chow diet for 12 weeks. We took several precautions to avoid and map contamination. The gut microbiota was affected by high-fat diet as following: We observed several common intestinal ASVs in the pancreatic tissue. Although the pancreatic ASVs do not correlate exactly with the gut ASVs, our data implicate that the pancreas contains bacterial DNA and that this signature is altered in high-fat diet fed mice (PERMONOVA, p = 0.037; betadisper, p=0.029). Gut derived bacterial DNA might end up in the pancreas at some point in time. Hence, this work supports the concept of translocation of bacterial DNA to the pancreas, which might contribute to inflammation and dysfunction of pancreatic beta-cells.

microbiology↗

bioRxiv2022

Systems analysis of metabolic responses to a mixed meal test in an obese cohort reveals links between tissue metabolism and the gut microbiota

Individuals with prediabetes and type 2 diabetes mellitus (T2DM) have poor ability to adapt to diet-triggered perturbations. We investigated global metabolic responses to a mixed meal test (MMT) in morbidly obese individuals with different diabetic status by performing plasma metabolomic profiling. Abnormal metabolism of carbohydrates, (branched-chain) amino acids, fatty acids and acylcholines in individuals with (pre)diabetes was observed. Moreover, differences in metabolic responses were associated with altered fecal metagenomics and transcriptomes of liver, jejunum and adipose tissues, which revealed a modified gut microbiome and multi-tissue metabolism in individuals having insulin resistance. Finally, using integrative machine learning models, we built a predictive model based on metabolomics data after 2h MMT, and identified possible new biomarkers for glycemic control including N-acetylaspartate and phenylalanine-derived metabolites that may be useful for diagnosis, intervention and prevention of T2DM.

systems biology↗

bioRxiv2021

Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction

ObjectiveHyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied but causal links remain enigmatic. DesignObese individuals with or without T2D were included from two independent Dutch cohorts. Human data was translated in vitro and in vivo by using pancreatic islets from C57BL6/J mice and by injecting flagellin into obese mice. ResultsFlagellin is part of the bacterial locomotor appendage flagellum, present on gut bacteria including Enterobacteriaceae, which we show to be more abundant in the gut of individuals with T2D. Subsequently, flagellin induces a pro-inflammatory response in pancreatic islets mediated by the Toll-like receptor (TLR)-5 expressed on resident islet macrophages. This inflammatory response associated with beta-cell dysfunction, characterized by reduced insulin gene expression, impaired proinsulin processing and stress-induced insulin hypersecretion in vitro and in vivo in mice. ConclusionWe postulate that increased systemically disseminated flagellin in T2D is a contributing factor to beta cell failure in time and represents a novel therapeutic target. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/463317v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@b719aeorg.highwire.dtl.DTLVardef@f72958org.highwire.dtl.DTLVardef@bb7af5org.highwire.dtl.DTLVardef@859c70_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Drivers and Determinants of Strain Dynamics Following Faecal Microbiota Transplantation

Faecal microbiota transplantation (FMT) is an efficacious therapeutic intervention, but its clinical mode of action and underlying microbiome dynamics remain poorly understood. Here, we analysed the metagenomes associated with 142 FMTs, in a time series-based meta-study across five disease indications. We quantified strain-level dynamics of 1,089 microbial species based on their pangenome, complemented with 47,548 newly constructed metagenome-assembled genomes. Using subsets of procedural-, host- and microbiome-based variables, LASSO-regularised regression models accurately predicted the colonisation and resilience of donor and recipient microbes, as well as turnover of individual species. Linking this to putative ecological mechanisms, we found these sets of variables to be informative of the underlying processes that shape the post-FMT gut microbiome. Recipient factors and complementarity of donor and recipient microbiomes, encompassing entire communities to individual strains, were the main determinants of individual strain population dynamics, and mostly independent of clinical outcomes. Recipient community state and the degree of residual strain depletion provided a neutral baseline for donor strain colonisation success, in addition to inhibitive priority effects between species and conspecific strains, as well as putatively adaptive processes. Our results suggest promising tunable parameters to enhance donor flora colonisation or recipient flora displacement in clinical practice, towards the development of more targeted and personalised therapies.

microbiology↗

bioRxiv2021

Members of a highly widespread bacteriophage family are hallmarks of metabolic syndrome gut microbiomes

There is significant interest in altering the course of cardiometabolic disease development via the gut microbiome. Nevertheless, the highly abundant phage members -which impact gut bacteria- of the complex gut ecosystem remain understudied. Here, we characterized gut phageome changes associated with metabolic syndrome (MetS), a highly prevalent clinical condition preceding cardiometabolic disease. MetS gut phageome populations exhibited decreased richness and diversity, but larger inter-individual variation. These populations were enriched in phages infecting Bacteroidaceae and depleted in those infecting Ruminococcaeae. Differential abundance analysis identified eighteen viral clusters (VCs) as significantly associated with either MetS or healthy phageomes. Among these are a MetS-associated Roseburia VC that is related to healthy control-associated Faecalibacterium and Oscillibacter VCs. Further analysis of these VCs revealed the Candidatus Heliusviridae, a highly widespread gut phage lineage found in 90+% of the participants. The identification of the temperate Ca. Heliusviridae provides a novel starting point to a better understanding of the effect that phages have on their bacterial hosts and the role that this plays in MetS.

microbiology↗