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Abstract Neovaginas are surgically constructed to correct uterovaginal agenesis in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome or as part of gender-affirming surgery for transfeminine individuals. Understanding the assembly of the neovaginal microbiota is crucial for guiding its management. To address this, we conducted a longitudinal study on MRKH patients following laparoscopic peritoneal vaginoplasty. Our findings reveal that the early microbial assemblage exhibited stochastic characteristics, accompanied with a notable bloom of Enterococcus faecalis and genital Mycoplasmas. While both the pre-surgery dimple microbiota and the fecal microbiota constituted the primary species pool, the neovaginal microbiota developed into a microbiota that resembled that of a normal vagina at 6–12 months post-surgery, albeit with a bacterial vaginosis (BV)-like structure. By 2–4 years post-surgery, the neovaginal microbiota had further evolved into a structure closely resembling with the homeostatic pre-surgery dimple microbiota. This concords with the development of the squamous epithelium in the neovagina and highlights the pivotal roles of progressive selective forces imposed by the evolving neovaginal environment and the colonization tropism of vaginal species. Notably, we observed that strains of Lactobacillus crispatus colonizing the neovagina primarily originated from the dimple. Since L. crispatus is generally associated with vaginal health, this finding suggests potential avenues for future research to promote its colonization.

Abstract With climate change and anthropic influence on the coastal ecosystems, mangrove ecosystems are disappearing at an alarming rate. Accordingly, it becomes important to track, study, record and store the mangrove microbial community considering their ecological importance and potential for biotechnological applications. Here, we provide information on mangrove fungal community composition and diversity in mangrove ecosystems with different plant species and from various locations differing in relation to anthropic influences. We describe twelve newly assembled genomes, including four chromosomal-level genomes of fungal isolates from the mangrove ecosystems coupled with functional annotations. We envisage that these data will be of value for future studies including comparative genome analysis and large-scale temporal and/or spatial research to elucidate the potential mechanisms by which mangrove fungal communities assemble and evolve. We further anticipate that the genomes represent valuable resources for bioprospecting related to industrial or clinical uses.

Abstract Background Scavenging indigenous village chickens play a vital role in sub-Saharan Africa, sustaining the livelihood of millions of farmers. These chickens are exposed to vastly different environments and feeds compared to commercial chickens. In this study, we analysed the caecal microbiota of 243 Ethiopian village chickens living in different altitude-dependent agro-ecologies. Results Differences in bacterial diversity were significantly correlated with differences in specific climate factors, topsoil characteristics, and supplemental diets provided by farmers. Microbiota clustered into three enterotypes, with one particularly enriched at high altitudes. We assembled 9977 taxonomically and functionally diverse metagenome-assembled genomes. The vast majority of these were not found in a dataset of previously published chicken microbes or in the Genome Taxonomy Database. Conclusions The wide functional and taxonomic diversity of these microbes highlights their importance in the local adaptation of indigenous poultry, and the significant impacts of environmental factors on the microbiota argue for further discoveries in other agro-ecologies. Video Abstract

Abstract Detailed knowledge regarding the associations between intake of different types of seafood and meat and the risk of type 2 diabetes (T2D), and insight into possible mechanisms are warranted. In this study we aimed to evaluate the associations between intake of different types of seafood and meat and the subsequent risk of T2D using the Norwegian Mother, Father, and Child Cohort Study (MoBa), and furthermore, by using a mouse model to gain further insight into possible molecular mechanisms contributing to the associated metabolic changes. Women in MoBa who were free of pharmacologically treated diabetes at baseline (n = 60,777) were prospectively evaluated for incident T2D, identified on the basis of medication usages > 90 days after delivery, ascertained by the Norwegian Prescription Database. Dietary intake was obtained with a validated 255-item food frequency questionnaire which assessed habitual diet during the first 4–5 months of pregnancy. Metabolic phenotypes and plasma metabolome were investigated in female mice fed isocaloric diets with different types of seafood and meat mimicking the dietary intake in the human cohort. During maximum 10-year and mean (SD) 7.2 (1.6) years follow-up time, 681 (1.1%) women developed pharmacologically treated T2D. All statistical models identified a higher risk of T2D with increased shellfish intake, whereas no associations were observed for total seafood, fatty fish, total meat and red meat in the adjusted models. In mice, the shellfish-based western diet induced reduced glucose tolerance and insulin secretion compared to the diet based on lean fish, and we identified a number of metabolites elevated in plasma from shellfish-fed mice that correlated with glucose intolerance. Mice fed a western diet based on meat also exhibited reduced glucose tolerance in comparison to lean fish fed mice, whereas mice fed fatty fish, total seafood or red meat did not differ from lean fish fed mice. We observed a diet-specific metabolic signature in plasma demonstrating five distinct metabolite profiles in mice fed shellfish, fatty fish, total seafood/lean fish, a mixed diet and meat. In conclusion, these findings demonstrate that different types of seafood have different outcome on T2D risk. In women, intake of shellfish was associated with higher risk of T2D. In female mice, a shellfish enriched diet reduced glucose tolerance and altered the abundance of several distinct plasma metabolites correlating with glucose tolerance.

Abstract The oral cavity harbors complex communities comprising bacteria, archaea, fungi, protozoa, and viruses. The oral microbiota is establish at birth and develops further during childhood, with early life factors such as birth mode, feeding practices, and oral hygiene, reported to influence this development and the susceptibility to caries. We here analyzed the oral bacterial composition in saliva of 260 Swedish children at two, three and five years of age using 16S rRNA gene profiling to examine its relation to environmental factors and caries development at five years of age. We were able to assign the salivary bacterial community in each child at each time point to one of seven distinct clusters. We observed an individual dynamic in the development of the oral microbiota related to early life factors, such as being first born, born by C-section, maternal perinatal antibiotics use, with a distinct transition between three and five years of age. Different bacterial signatures depending on age were related to increased caries risk, while Peptococcus consistently linked to reduced risk of caries development.

Abstract Background Zoonotic viruses cause substantial public health and socioeconomic problems worldwide. Understanding how viruses evolve and spread within and among wildlife species is a critical step when aiming for proactive identification of viral threats to prevent future pandemics. Despite the many proposed factors influencing viral diversity, the genomic diversity and structure of viral communities in East Africa are largely unknown. Results Using 38.3 Tb of metatranscriptomic data obtained via ultradeep sequencing, we screened vertebrate-associated viromes from 844 bats and 250 rodents from Kenya and Uganda collected from the wild. The 251 vertebrate-associated viral genomes of bats (212) and rodents (39) revealed the vast diversity, host-related variability, and high geographic specificity of viruses in East Africa. Among the surveyed viral families, Coronaviridae and Circoviridae showed low host specificity, high conservation of replication-associated proteins, high divergence among viral entry proteins, and frequent recombination. Despite major dispersal limitations, recurrent mutations, cocirculation, and occasional gene flow contribute to the high local diversity of viral genomes. Conclusions The present study not only shows the landscape of bat and rodent viromes in this zoonotic hotspot but also reveals genomic signatures driven by the evolution and dispersal of the viral community, laying solid groundwork for future proactive surveillance of emerging zoonotic pathogens in wildlife. Video Abstract

Cetaceans play a crucial role in marine ecosystems; however, research on their gastrointestinal microbiota remains limited due to sampling constraints. In this study, we collected hindgut samples from 12 stranded cetaceans and performed 16S rRNA gene amplicon sequencing to investigate microbial composition and functional potentials. Analysis of ZOTUs profiles revealed that the phyla Firmicutes, Proteobacteria, and Bacteroidetes dominated all hindgut samples. However, unique microbial profiles were observed among different cetacean species, with significant separation of gut microbiota communities according to biological evolutionary lineages. Different genera that contain pathogens were observed distinguishing delphinids from physeteroids/ziphiids. Delphinid samples exhibited higher abundances of Vibrio, Escherichia, and Paeniclostridium, whereas physeteroid and ziphiid samples showed higher abundances of Pseudomonas, Enterococcus, and Intestinimonas. Functional analysis indicated convergence in the gut microbiota among all cetaceans, with shared bacterial infection pathways across hindgut samples. In addition, a comparison of the gastrointestinal microbial composition between a stranded short-finned pilot whale (Globicephala macrorhynchus) and a stranded rough-toothed dolphin (Steno bredanensis) using 16S rRNA gene sequencing revealed distinct microbial community structures and functional capacities. To the best of our knowledge, this study represents the first report on the gastrointestinal microbiota of the pantropical spotted dolphin (Stenella attenuata), Blainville’s beaked whale (Mesoplodon densirostris), and rough-toothed dolphin, with various comparisons conducted among different cetacean species. Our findings enhance the understanding of microbial composition and diversity in cetacean gastrointestinal microbiota, providing new insights into co-evolution and complex interactions between cetacean microbes and hosts.

Abstract Background Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking. Methods We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines. Results Here, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation. Conclusions Our findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis. Trial registration NCT02637167, registered December 22, 2015.

Abstract The Illumina HiSeq platform has been a commonly used option for bacterial genome sequencing. Now the BGI DNA nanoball (DNB) nanoarrays platform may provide an alternative platform for sequencing of bacterial genomes. To explore the impact of sequencing platforms on bacterial genome assembly, quality assessment, sequence alignment, functional annotation, mutation detection, and metagenome mapping, we compared genome assemblies based on sequencing of cultured bacterial species using the HiSeq 2000 and BGISEQ-500 platforms. In addition, simulated reads were used to evaluate the impact of insert size on genome assembly. Genome assemblies based on BGISEQ-500 sequencing exhibited higher completeness and fewer N bases in high GC genomes, whereas HiSeq 2000 assemblies exhibited higher N50. The majority of assembly assessment parameters, sequences of 16S rRNA genes and genomes, numbers of single nucleotide variants (SNV), and mapping to metagenome data did not differ significantly between platforms. More insertions were detected in HiSeq 2000 genome assemblies, whereas more deletions were detected in BGISEQ-500 genome assemblies. Insert size had no significant impact on genome assembly. Taken together, our results suggest that DNBSEQ platforms would be a valid substitute for HiSeq 2000 for bacterial genome sequencing.

Abstract Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few infection-related complications, raising the question if the more specific IgG may help IgM in compensating for the lack of IgA. Here we employ a cohort of IgA-deficient humans, each paired with IgA-sufficient household members, to investigate multi-Ig bacterial coating. In IgA-deficient humans, IgM alone, and together with IgG, recapitulate coating of most bacterial families, despite an overall 3.6-fold lower Ig-coating. Bacterial IgG coating is dominated by IgG1 and IgG4. Single-IgG2 bacterial coating is sparse and linked to enhanced Escherichia coli load and TNF-α. Although single-IgG2 coating is 1.6-fold more prevalent in IgA deficiency than in healthy controls, it is 2-fold less prevalent than in inflammatory bowel disease. Altogether we demonstrate that IgG assists IgM in coating of most bacterial families in the absence of IgA and identify single-IgG2 bacterial coating as an inflammatory marker.

Abstract The Lachnospiraceae family holds promise as a source of next‐generation probiotics, yet a comprehensive delineation of its diversity is lacking, hampering the identification of suitable strains for future applications. To address this knowledge gap, we conducted an in‐depth genomic and functional analysis of 1868 high‐quality genomes, combining data from public databases with our new isolates. This data set represented 387 colonization‐selective species‐level clusters, of which eight genera represented multilineage clusters. Pan‐genome analysis, single‐nucleotide polymorphism (SNP) identification, and probiotic functional predictions revealed that species taxonomy, habitats, and geography together shape the functional diversity of Lachnospiraceae. Moreover, analyses of associations with atherosclerotic cardiovascular disease (ACVD) and inflammatory bowel disease (IBD) indicated that several strains of potentially novel Lachnospiraceae species possess the capacity to reduce the abundance of opportunistic pathogens, thereby imparting potential health benefits. Our findings shed light on the untapped potential of novel species enabling knowledge‐based selection of strains for the development of next‐generation probiotics holding promise for improving human health and disease management.

Objective We investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate‐treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT). Methods This exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate‐to‐high peripheral PsA disease activity, despite at least 3 months of methotrexate‐treatment, were included in a 26‐week, double‐blind, 1:1 randomized, sham‐controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose‐to‐mannitol ratio (LMR) test at baseline (n = 31) and at week 26 (n = 26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1H Nuclear Magnetic Resonance. Results Trial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027 [0.017‐0.33]) vs. 0.012 [0‐0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (P

Abstract The oral cavity harbors highly diverse communities of microorganisms. However, the number of isolated species and high-quality genomes is limited. Here we present a Cultivated Oral Bacteria Genome Reference (COGR), comprising 1089 high-quality genomes based on large-scale aerobic and anaerobic cultivation of human oral bacteria isolated from dental plaques, tongue, and saliva. COGR covers five phyla and contains 195 species-level clusters of which 95 include 315 genomes representing species with no taxonomic annotation. The oral microbiota differs markedly between individuals, with 111 clusters being person-specific. Genes encoding CAZymes are abundant in the genomes of COGR. Members of the Streptococcus genus make up the largest proportion of COGR and many of these harbor entire pathways for quorum sensing important for biofilm formation. Several clusters containing unknown bacteria are enriched in individuals with rheumatoid arthritis, emphasizing the importance of culture-based isolation for characterizing and exploiting oral bacteria.

ABSTRACTAnimals and their associated microbiota share long evolutionary histories. However, it is not always clear how host genotype and microbiota interact to affect phenotype. We applied a hologenomic approach to explore how host–microbiota interactions shape lifetime growth and parasite infection in farmed Atlantic salmon (Salmo salar). Multi-omics data sets were generated from the guts of 460 salmon, 82% of which were naturally infected with an intestinal cestode. A single Mycoplasma bacterial strain, MAG01, dominated the gut metagenome of large, non-parasitized fish, consistent with previous studies showing high levels of Mycoplasma in the gut microbiota of healthy salmon. While small and/or parasitized salmon also had high abundance of MAG01, we observed increased alpha diversity in these individuals, driven by increased frequency of low-abundance Vibrionaceae and other Mycoplasma species that carried known virulence genes. Colonization by one of these cestode-associated Mycoplasma strains was associated with host individual genomic variation in long non-coding RNAs. Integrating the multi-omic data sets revealed coordinated changes in the salmon gut mRNA transcriptome and metabolome that correlated with shifts in the microbiota of smaller, parasitized fish. Our results suggest that the gut microbiota of small and/or parasitized fish is in a state of dysbiosis that partly depends on the host genotype, highlighting the value of using a hologenomic approach to incorporate the microbiota into the study of host–parasite dynamics.IMPORTANCEStudying host–microbiota interactions through the perspective of the hologenome is gaining interest across all life sciences. Intestinal parasite infections are a huge burden on human and animal health; however, there are few studies investigating the role of the hologenome during parasite infections. We address this gap in the largest multi-omics fish microbiota study to date using natural cestode infection of farmed Atlantic salmon. We find a clear association between cestode infection, salmon lifetime growth, and perturbation of the salmon gut microbiota. Furthermore, we provide the first evidence that the genetic background of the host may partly determine how the gut microbiota changes during parasite-associated dysbiosis. Our study therefore highlights the value of a hologenomic approach for gaining a more in-depth understanding of parasitism.

Objectives The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins.Methods This study relates to the FLORA trial cohort, where 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants were allocated to receive either one gastroscopic-guided healthy donor FMT (n=15) or sham (n=16). Patient plasma samples were collected at baseline, week 4, 12 and 26 while samples from 31 age-matched and sex-matched healthy controls (HC) were collected at baseline. Samples were analysed using proximity extension assay technology (Olink Target-96 Inflammation panel).Results Levels of 26 proteins differed significantly between PsA and HC pre-FMT (adjusted p

Abstract Intermittent fasting (IF) is a promising paradigm for weight loss which has been shown to modulate the gut microbiota based on 16S rRNA gene amplicon sequencing. Here, 72 Chinese volunteers with a wide range of body mass index (BMI) participated in a three-week IF program during which an average loss of 3.67 kg body weight accompanied with improved clinical parameters was observed irrespective of initial anthropometric and gut microbiota status. Fecal samples were collected before and after the intervention and subjected to shotgun metagenomic sequencing. De novo assembly yielded 2934 metagenome-assembled genomes (MAGs). Profiling revealed significant enrichment of Parabacteroides distasonis and Bacteroides thetaiotaomicron after the intervention, with inverse correlations between their relative abundances and parameters related to obesity and atherosclerotic cardiovascular diseases (ASCVD). MAGs enriched after the intervention showed high richness and diversity of carbohydrate-active enzymes, with an increased relative abundances of genes related to succinate production and glutamate fermentation.

Here, the authors present an expanded version of the Cultivated Genome Reference (CGR), termed CGR2, a catalog that includes 3324 high-quality draft genomes based on gut bacterial isolates from Chinese individuals, and classifies 527 species from 8 phyla, including 179 previously unidentified species, and provides information of secondary metabolite biosynthetic gene clusters and gut phage-bacteria interactions.

Summary: Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.

Summary: By a survey of metagenome-wide association studies (MWAS), we found a robust depletion of Bacteroides cellulosilyticus, Faecalibacterium prausnitzii, and Roseburia intestinalis in individuals with atherosclerotic cardiovascular disease (ACVD). From an established collection of bacteria isolated from healthy Chinese individuals, we selected B. cellulosilyticus, R. intestinalis, and Faecalibacterium longum, a bacterium related to F. prausnitzii, and tested the effects of these bacteria in an Apoe/− atherosclerosis mouse model. We show that administration of these three bacterial species to Apoe−/− mice robustly improves cardiac function, reduces plasma lipid levels, and attenuates the formation of atherosclerotic plaques. Comprehensive analysis of gut microbiota, plasma metabolome, and liver transcriptome revealed that the beneficial effects are associated with a modulation of the gut microbiota linked to a 7α-dehydroxylation–lithocholic acid (LCA)–farnesoid X receptor (FXR) pathway. Our study provides insights into transcriptional and metabolic impact whereby specific bacteria may hold promises for prevention/treatment of ACVD.

Abstract Background Increasing studies have demonstrated potential disproportionate functional and ecological contributions of rare taxa in a microbial community. However, the study of the microbial rare biosphere is hampered by their inherent scarcity and the deficiency of currently available techniques. Sample-wise cross contaminations might be introduced by sample index misassignment in the most widely used metabarcoding amplicon sequencing approach. Although downstream bioinformatic quality control and clustering or denoising algorithms could remove sequencing errors and non-biological artifact reads, no algorithm could eliminate high quality reads from sample-wise cross contaminations introduced by index misassignment, making it difficult to distinguish between bona fide rare taxa and potential false positives in metabarcoding studies. Results We thoroughly evaluated the rate of index misassignment of the widely used NovaSeq 6000 and DNBSEQ-G400 sequencing platforms using both commercial and customized mock communities, and observed significant lower (0.08% vs. 5.68%) fraction of potential false positive reads for DNBSEQ-G400 as compared to NovaSeq 6000. Significant batch effects could be caused by stochastically introduced false positive or false negative rare taxa. These false detections could also lead to inflated alpha diversity of relatively simple microbial communities and underestimated that of complex ones. Further test using a set of cow rumen samples reported differential rare taxa by different sequencing platforms. Correlation analysis of the rare taxa detected by each sequencing platform demonstrated that the rare taxa identified by DNBSEQ-G400 platform had a much higher possibility to be correlated with the physiochemical properties of rumen fluid as compared to NovaSeq 6000 platform. Community assembly mechanism and microbial network correlation analysis indicated that false positive or negative rare taxa detection could lead to biased community assembly mechanism and identification of fake keystone species of the community. Conclusions We highly suggest proper positive/negative/blank controls, technical replicate settings, and proper sequencing platform selection in future amplicon studies, especially when the microbial rare biosphere would be focused.

For the unmet need to choose the suitable doublet detection method, an ensemble machine learning algorithm called Chord was developed, which integrates multiple methods and achieves higher accuracy and stability on different scRNA-seq datasets.

The vagina contains at least a billion microbial cells, dominated by lactobacilli. Here we perform metagenomic shotgun sequencing on cervical and fecal samples from a cohort of 516 Chinese women of reproductive age, as well as cervical, fecal, and salivary samples from a second cohort of 632 women. Factors such as pregnancy history, delivery history, cesarean section, and breastfeeding were all more important than menstrual cycle in shaping the microbiome, and such information would be necessary before trying to interpret differences between vagino-cervical microbiome data. Greater proportion of Bifidobacterium breve was seen with older age at sexual debut. The relative abundance of lactobacilli especially Lactobacillus crispatus was negatively associated with pregnancy history. Potential markers for lack of menstrual regularity, heavy flow, dysmenorrhea, and contraceptives were also identified. Lactobacilli were rare during breastfeeding or post-menopause. Other features such as mood fluctuations and facial speckles could potentially be predicted from the vagino-cervical microbiome. Gut and salivary microbiomes, plasma vitamins, metals, amino acids, and hormones showed associations with the vagino-cervical microbiome. Our results offer an unprecedented glimpse into the microbiota of the female reproductive tract and call for international collaborations to better understand its long-term health impact other than in the settings of infection or pre-term birth.

The oral cavity of each person is home to hundreds of bacterial species. While taxa for oral diseases have been studied using culture-based characterization as well as amplicon sequencing, metagenomic and genomic information remains scarce compared to the fecal microbiome. Here, using metagenomic shotgun data for 3346 oral metagenomic samples together with 808 published samples, we obtain 56,213 metagenome-assembled genomes (MAGs), and more than 64% of the 3589 species-level genome bins (SGBs) contain no publicly available genomes. The resulting genome collection is representative of samples around the world and contains many genomes from candidate phyla radiation (CPR) that lack monoculture. Also, it enables the discovery of new taxa such as a genus Candidatus Bgiplasma within the family Acholeplasmataceae. Large-scale metagenomic data from massive samples also allow the assembly of strains from important oral taxa such as Porphyromonas and Neisseria. The oral microbes encode genes that could potentially metabolize drugs. Apart from these findings, a strongly male-enriched Campylobacter species was identified. Oral samples would be more user-friendly collected than fecal samples and have the potential for disease diagnosis. Thus, these data lay down a genomic framework for future inquiries of the human oral microbiome.

Abstract Background Animal protein production is increasingly looking towards microbiome-associated services such as the design of new and better probiotic solutions to further improve gut health and production sustainability. Here, we investigate the functional effects of bacteria-based pro- and synbiotic feed additives on microbiome-associated functions in relation to growth performance in the commercially important rainbow trout (Oncorhynchus mykiss). We combine complementary insights from multiple omics datasets from gut content samples, including 16S bacterial profiling, whole metagenomes, and untargeted metabolomics, to investigate bacterial metagenome-assembled genomes (MAGs) and their molecular interactions with host metabolism. Results Our findings reveal that (I) feed additives changed the microbiome and that rainbow trout reared with feed additives had a significantly reduced relative abundance of the salmonid related Candidatus Mycoplasma salmoninae in both the mid and distal gut content, (II) genome resolved metagenomics revealed that alterations of microbial arginine biosynthesis and terpenoid backbone synthesis pathways were directly associated with the presence of Candidatus Mycoplasma salmoninae, and (III) differences in the composition of intestinal microbiota among feed types were directly associated with significant changes of the metabolomic landscape, including lipids and lipid-like metabolites, amino acids, bile acids, and steroid-related metabolites. Conclusion Our results demonstrate how the use of multi-omics to investigate complex host-microbiome interactions enable us to better evaluate the functional potential of probiotics compared to studies that only measure overall growth performance or that only characterise the microbial composition in intestinal environments. Video Abstract

IntroductionThe gradual loss of motor neurons (MNs) in the brain and spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the mechanisms underlying neurodegeneration in ALS are still not fully understood.MethodsBased on 75 ALS-pathogenicity/susceptibility genes and large-scale single-cell transcriptomes of human/mouse brain/spinal cord/muscle tissues, we performed an expression enrichment analysis to identify cells involved in ALS pathogenesis. Subsequently, we created a strictness measure to estimate the dosage requirement of ALS-related genes in linked cell types.ResultsRemarkably, expression enrichment analysis showed that α- and γ-MNs, respectively, are associated with ALS-susceptibility genes and ALS-pathogenicity genes, revealing differences in biological processes between sporadic and familial ALS. In MNs, ALS-susceptibility genes exhibited high strictness, as well as the ALS-pathogenicity genes with known loss of function mechanism, indicating the main characteristic of ALS-susceptibility genes is dosage-sensitive and the loss of function mechanism of these genes may involve in sporadic ALS. In contrast, ALS-pathogenicity genes with gain of function mechanism exhibited low strictness. The significant difference of strictness between loss of function genes and gain of function genes provided a priori understanding for the pathogenesis of novel genes without an animal model. Besides MNs, we observed no statistical evidence for an association between muscle cells and ALS-related genes. This result may provide insight into the etiology that ALS is not within the domain of neuromuscular diseases. Moreover, we showed several cell types linked to other neurological diseases [i.e., spinocerebellar ataxia (SA), hereditary motor neuropathies (HMN)] and neuromuscular diseases [i.e. hereditary spastic paraplegia (SPG), spinal muscular atrophy (SMA)], including an association between Purkinje cells in brain and SA, an association between α-MNs in spinal cord and SA, an association between smooth muscle cells and SA, an association between oligodendrocyte and HMN, a suggestive association between γ-MNs and HMN, a suggestive association between mature skeletal muscle and HMN, an association between oligodendrocyte in brain and SPG, and no statistical evidence for an association between cell type and SMA.DiscussionThese cellular similarities and differences deepened our understanding of the heterogeneous cellular basis of ALS, SA, HMN, SPG, and SMA.

Summary: The oral microbiome has been implicated in a growing number of diseases; however, determinants of the oral microbiome and their roles remain elusive. Here, we investigated the oral (saliva and tongue dorsum) metagenome, the whole genome, and other omics data in a total of 4,478 individuals and demonstrated that the oral microbiome composition and its major contributing host factors significantly differed between sexes. We thus conducted a sex-stratified metagenome-genome-wide-association study (M-GWAS) and identified 11 differential genetic associations with the oral microbiome (psex-difference

Abstract The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.

Klebsiella pneumoniae (KP) is one of the microorganisms that can acquire carbapenem-resistance (CR), and few antimicrobial therapy options exist for infections caused by Carbapenem-Resistant KP (CRKP). In recent years, with the increase of carbapenem resistance rates, treating CRKP has become a serious public health threat in clinical practice. We have collected 2,035 clinical KP isolates from a tertiary hospital in China. Whole genome sequencing data coupled with their binary antimicrobial susceptibility testing data were obtained to conduct the genome-wide association study using a bayesian-based method, including single nucleotide polymorphisms (SNPs) and genes. We identified 28 and 37 potential maker genes associated with imipenem and meropenem resistance, respectively. Among which 19 of them were selected in both drugs by genome-wide association study (GWAS), 11 genes among them were simultaneously validated in independent datasets. These genes were likely related to biofilm formation, efflux pump, and DNA repairing. Moreover, we identified 13 significant CR related SNPs in imipenem or meropenem, with one SNP located in the non-coding region and validated in the independent datasets. Our study indicates complex mechanisms of carbapenems resistance and further investigation of CRKP-related factors are warranted to better understand their contributions to carbapenems resistance. These identified biomarkers may provide targets for future drug interventions or treatments.

BackgroundPreclinical studies have shown that maternal gut microbiota during pregnancy play a key role in prenatal immune development but the relevance of these findings to humans is unknown. The aim of this prebirth cohort study was to investigate the association between the maternal gut microbiota in pregnancy and the composition of the infant’s cord and peripheral blood immune cells over the first year of life.MethodsThe Barwon Infant Study cohort (n=1074 infants) was recruited using an unselected sampling frame. Maternal fecal samples were collected at 36 weeks of pregnancy and flow cytometry was conducted on cord/peripheral blood collected at birth, 6 and 12 months of age. Among a randomly selected sub-cohort with available samples (n=293), maternal gut microbiota was characterized by sequencing the 16S rRNA V4 region. Operational taxonomic units (OTUs) were clustered based on their abundance. Associations between maternal fecal microbiota clusters and infant granulocyte, monocyte and lymphocyte subsets were explored using compositional data analysis. Partial least squares (PLS) and regression models were used to investigate the relationships/associations between environmental, maternal and infant factors, and OTU clusters.ResultsWe identified six clusters of co-occurring OTUs. The first two components in the PLS regression explained 39% and 33% of the covariance between the maternal prenatal OTU clusters and immune cell populations in offspring at birth. A cluster in which Dialister, Escherichia, and Ruminococcus were predominant was associated with a lower proportion of granulocytes (p=0.002), and higher proportions of both central naïve CD4+ T cells (CD4+/CD45RA+/CD31−) (p

The incidence of the autoimmune disease type 1 diabetes is increasing, likely caused by environmental factors. A gluten-free diet has previously been shown to ameliorate autoimmune diabetes in non-obese diabetic (NOD) mice and humans. Although the exact mechanisms are not understood, interventions influencing the intestinal microbiota early in life affect the risk of type 1 diabetes. Here, we characterize how NOD mice that are fed a gluten-free (GF) diet differ from NOD mice that are fed a gluten-containing standard (STD) diet in terms of their microbiota composition by 16S rRNA gene amplicon sequencing and pancreatic immune environment by real-time quantitative PCR at the prediabetic stage at 6 and 13 weeks of age. Gut microbiota analysis revealed highly distinct microbiota compositions in both the cecum and the colon of GF-fed mice compared with STD-fed mice. The microbiotas of the GF-fed mice were characterized by an increased Firmicutes/Bacteroidetes ratio, an increased abundance of short chain fatty acid (particularly butyrate)-producing bacteria, and a reduced abundance of Lactobacilli compared with STD mice. We found that the insulitis score in the GF mice was significantly reduced compared with the STD mice and that the markers for regulatory T cells and T helper 2 cells were upregulated in the pancreas of the GF mice. In conclusion, a GF diet during pre- and early post-natal life induces shifts in the cecal and colonic microbiota compatible with a less inflammatory environment, providing a likely mechanism for the protective effect of a GF diet in humans.

Huang et al performed a genome-wide RNA editing investigation in the porcine brain in which they found over 680,000 A-to-I RNA editing sites. They identified conserved recoding events between pig and human brains thus providing an extensive resource to aid our understanding of the evolutionary importance of post-transcriptional RNA editing.

Antibodies targeting the programmed cell death protein-1 (PD-1) molecule have been reported to hold promising antitumor activities in patients with nasopharyngeal carcinoma (NPC). However, only a small subset of NPC patients benefits from the anti-PD-1 monotherapy and factors that affect the treatment response need further investigation. This study aimed to examine the impact of multiple genetic and environmental factors on outcome of anti-PD-1 immunotherapy by identifying tumor size, tumor mutation burden (TMB) based on whole exon sequencing, human leukocyte antigen class I (HLA-I) homo-/heterozygosity and supertypes, blood Epstein-Barr virus (EBV) DNA load, T cell proportions, and interferon-γ(IFN-γ) levels in a cohort of 57 NPC patients that received Nivolumab or Camrelizumab treatment. Moreover, we profiled the longitudinal changes in gut microbiota composition using shotgun metagenomics sequencing. We observed that high TMB combined with HLA-I heterozygosity was associated with improved clinical outcomes. In agreement with previous studies, we found that patients with higher plasma EBV DNA load showed worse progression-free survival. We found no evidence for an effect of gut bacterial diversity on the treatment response, but identified a higher abundance of seven specific gut bacteria at baseline of non-responders, including Blautia wexlera and Blautia obeum, as well as four other bacteria belonging to the Clostridiales order, and one Erysipelatoclostridium. Combined, this study provides insight into the influence of several genetic and environmental factors on anti-PD-1 immunotherapy responses in NPC patients.

Jacob Rasmussen et al. use metagenomic analyses to examine the diversity of Mycoplasma species among three commonly-fished species of salmonids. Their results establish a phylogeny of candidate salmonid related Mycoplasma species and suggest a mutualistic relationship between these microbial species and salmon hosts.

Abstract Exploiting a pure culture strategy to investigate the composition of the human gut microbiota, two novel anaerobes, designated strains AF52-21T and CM04-06T, were isolated from faeces of two healthy Chinese donors and characterized using a polyphasic approach. The two strains were observed to be gram-negative, non-motile, and rod-shaped. Both strains grew optimally at 37 °C and pH 7.0. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the two strains clustered with species of the genus Faecalibacterium and were most closely related to Faecalibacterium prausnitzii ATCC 27768T with sequence similarity of 97.18% and 96.87%, respectively. The two isolates shared a 16S rRNA gene sequence identity of 98.69%. Draft genome sequencing was performed for strains AF52-21T and CM04-06T, generating genome sizes of 2.85 Mbp and 3.01 Mbp. The calculated average nucleotide identity values between the genomes of the strains AF52-21T and CM04-06T compared to Faecalibacterium prausnitzii ATCC 27768T were 83.20% and 82.54%, respectively, and 90.09% when comparing AF52-21T and CM04-06T. Both values were below the previously proposed species threshold (95–96%), supporting their recognition as novel species in the genus Faecalibacterium. The genomic DNA G + C contents of strains AF52-21T and CM04-06T calculated from genome sequences were 57.77 mol% and 57.51 mol%, respectively. Based on the phenotypic, chemotaxonomic and phylogenetic characteristics, we conclude that both strains represent two new Faecalibacterium species, for which the names Faecalibacterium butyricigenerans sp. nov. (type strain AF52-21T = CGMCC 1.5206T = DSM 103434T) and Faecalibacterium longum sp. nov. (type strain CM04-06T = CGMCC 1.5208T = DSM 103432T) are proposed.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, the microbial composition of the respiratory tract and other infected tissues as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Between 27 January and 26 February 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients in Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. We identified distinct signatures of microbial dysbiosis among severely ill COVID-19 patients on broad spectrum antimicrobial therapy. Co-detection of other human respiratory viruses (including human alphaherpesvirus 1, rhinovirus B, and human orthopneumovirus) was demonstrated in 30.8% (4/13) of the severely ill patients, but not in any of the mildly affected patients. Notably, the predominant respiratory microbial taxa of severely ill patients were Burkholderia cepacia complex (BCC), Staphylococcus epidermidis, or Mycoplasma spp. (including M. hominis and M. orale). The presence of the former two bacterial taxa was also confirmed by clinical cultures of respiratory specimens (expectorated sputum or nasal secretions) in 23.1% (3/13) of the severe cases. Finally, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes was demonstrated in one severely ill patient, which might accelerate his disease deterioration and death occurring one month after ICU admission. Our findings point to SARS-CoV-2-related microbial dysbiosis and various antibiotic-resistant respiratory microbes/pathogens in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking strategies are needed to prevent the spread of antimicrobial resistance, improve the treatment regimen and clinical outcomes of hospitalized, severely ill COVID-19 patients.

Abstract While prolonged fasting induces significant metabolic changes in humans and mice, less is known about systems-wide metabolic changes in response to short-term feed deprivation, which is used in experimental animal studies prior to metabolic challenge tests. We here performed a systems biology-based investigation of connections between gut bacterial composition and function, inflammatory and metabolic parameters in the intestine, liver, visceral adipose tissue, blood and urine in high-fat fed, obese mice that were feed deprived up to 12 h. The systems-wide analysis revealed that feed deprivation linked to enhanced intestinal butyric acid production and expression of the gene encoding the pro-thermogenic uncoupling protein UCP1 in visceral adipose tissue of obese mice. Ucp1 expression was also positively associated with Il33 expression in ileum, colon and adipose tissue as well as with the abundance of colonic Porphyromonadaceae, the latter also correlating to cecal butyric acid levels. Collectively, the data highlighted presence of a multi-tiered system of inter-tissue communication involving intestinal, immune and metabolic functions which is affected by feed deprivation in obese mice, thus pointing to careful use of short-feed deprivation in metabolic studies using obese mice.

Abstract The gut microbiome has been established as a key environmental factor to health. Genetic influences on the gut microbiome have been reported, yet, doubts remain as to the significance of genetic associations. Here, we provide shotgun data for whole genome and whole metagenome from a Chinese cohort, identifying no

Abstract Background The human skin microbiota is considered to be essential for skin homeostasis and barrier function. Comprehensive analyses of its function would substantially benefit from a catalog of reference genes derived from metagenomic sequencing. The existing catalog for the human skin microbiome is based on samples from limited individuals from a single cohort on reference genomes, which limits the coverage of global skin microbiome diversity. Results In the present study, we have used shotgun metagenomics to newly sequence 822 skin samples from Han Chinese, which were subsequently combined with 538 previously sequenced North American samples to construct an integrated Human Skin Microbial Gene Catalog (iHSMGC). The iHSMGC comprised 10,930,638 genes with the detection of 4,879,024 new genes. Characterization of the human skin resistome based on iHSMGC confirmed that skin commensals, such as Staphylococcus spp, are an important reservoir of antibiotic resistance genes (ARGs). Further analyses of skin microbial ARGs detected microbe-specific and skin site-specific ARG signatures. Of note, the abundance of ARGs was significantly higher in Chinese than Americans, while multidrug-resistant bacteria (“superbugs”) existed on the skin of both Americans and Chinese. A detailed analysis of microbial signatures identified Moraxella osloensis as a species specific for Chinese skin. Importantly, Moraxella osloensis proved to be a signature species for one of two robust patterns of microbial networks present on Chinese skin, with Cutibacterium acnes indicating the second one. Each of such “cutotypes” was associated with distinct patterns of data-driven marker genes, functional modules, and host skin properties. The two cutotypes markedly differed in functional modules related to their metabolic characteristics, indicating that host-dependent trophic chains might underlie their development. Conclusions The development of the iHSMGC will facilitate further studies on the human skin microbiome. In the present study, it was used to further characterize the human skin resistome. It also allowed to discover the existence of two cutotypes on the human skin. The latter finding will contribute to a better understanding of the interpersonal complexity of the skin microbiome. Video abstract

Dietary changes can impact the microbial constitution of the gastrointestinal tract and modulate the local immune response. Here, the authors show supplementation using lysates of Methylococcus capsulatus Bath result in changes to the microbiota, modulate Treg populations and metabolic read outs in a dietary control murine model.

Abstract Ancient DNA research has developed rapidly over the past few decades due to improvements in PCR and next‐generation sequencing (NGS) technologies, but challenges still exist. One major challenge in relation to ancient DNA research is to recover genuine endogenous ancient DNA sequences from raw sequencing data. This is often difficult due to degradation of ancient DNA and high levels of contamination, especially homologous contamination that has extremely similar genetic background with that of the real ancient DNA. In this study, we collected whole‐genome sequencing (WGS) data from 6 ancient samples to compare different mapping algorithms. To further explore more effective methods to separate endogenous DNA from homologous contaminations, we attempted to recover reads based on ancient DNA specific characteristics of deamination, depurination, and DNA fragmentation with different parameters. We propose a quick and improved pipeline for separating endogenous ancient DNA while simultaneously decreasing homologous contaminations to very low proportions. Our goal in this research was to develop useful recommendations for ancient DNA mapping and for separation of endogenous DNA to facilitate future studies of ancient DNA.

BackgroundProgrammed death 1 (PD-1) and the ligand of PD-1 (PD-L1) are central targets for immune-checkpoint therapy (ICT) blocking immune evasion-related pathways elicited by tumor cells. A number of PD-1 inhibitors have been developed, but the efficacy of these inhibitors varies considerably and is typically below 50%. The efficacy of ICT has been shown to be dependent on the gut microbiota, and experiments using mouse models have even demonstrated that modulation of the gut microbiota may improve efficacy of ICT.MethodsWe followed a Han Chinese cohort of 85 advanced non-small cell lung cancer (NSCLC) patients, who received anti-PD-1 antibodies. Tumor biopsies were collected before treatment initiation for whole exon sequencing and variant detection. Fecal samples collected biweekly during the period of anti-PD-1 antibody administration were used for metagenomic sequencing. We established gut microbiome abundance profiles for identification of significant associations between specific microbial taxa, potential functionality, and treatment responses. A prediction model based on random forest was trained using selected markers discriminating between the different response groups.ResultsNSCLC patients treated with antibiotics exhibited the shortest survival time. Low level of tumor-mutation burden and high expression level of HLA-E significantly reduced progression-free survival. We identified metagenomic species and functional pathways that differed in abundance in relation to responses to ICT. Data on differential enrichment of taxa and predicted microbial functions in NSCLC patients responding or non-responding to ICT allowed the establishment of random forest algorithm-adopted models robustly predicting the probability of whether or not a given patient would benefit from ICT.ConclusionsOverall, our results identified links between gut microbial composition and immunotherapy efficacy in Chinese NSCLC patients indicating the potential for such analyses to predict outcome prior to ICT.

ABSTRACT Global dissemination of K. pneumoniae clones poses health hazards to the public. Genomic epidemiology studies with comprehensive data set further revealed clone divergence, showing a high complexity in evolution. Moreover, clones carrying both acquired virulent and antimicrobial-resistant genes emerged and might replace the carbapenem-resistant clones. Co-occurrence of virulence and resistance is emerging. An unbiased collection of 3,061 clinical K. pneumoniae isolates (January 5, 2013 to July 24, 2018) underwent whole-genome sequencing. Pairwise core-genome single-nucleotide polymorphism (cgSNP) distances identified clone divergence and transmission events. A sum of 2,193 nonduplicated genomes clustered into four phenotypically indistinguishable species complexes. 93% (n = 2,035) were KpI with its largest clonal group (CG) being CG11 (n = 406). Three hundred ninety-three were ST11 and three hundred seventy-four carried blaKPC-2. Noticeably, CG11 is divided into two main subclones based on the capsule synthesis K loci (KL). CG11-KL64 showed a clear hypervirulent plus antimicrobial-resistant (hv+AMR) characteristic. Besides, the phylogenetic structure revealed the clone divergence of CG25, and this is the first report with sufficient CG25 genomes to identify the divergence. The outcomes of the hv+AMR CG25 cluster 1 affected patients were poorer (P < 0.05). Moreover, two episodes of strain transmissions were associated with CG25 cluster 1. Other transmissions were associated with ST20 and ST307. Genomic epidemiology identified clone divergence of CG11 and CG25. The hv+AMR subclones pose greater threats on a global scale. Nosocomial transmissions of the high-risk clones raised our concerns about the evolution and transmission of emerging clones among newborns and critically ill patients. IMPORTANCE The convergence of AMR and acquired virulence posing higher risks to the public is a focusing point. With sufficient genomes and genotypes, we successfully identify the convergence in two subclones, the previously reported CG11-KL64, and the newly reported CG25 cluster 1. The novel finding of the CG25 divergence was not only revealed by the phylogenetic tree but also confirmed by the clinical outcome data and the accessory genome patterns. Moreover, the transmission subclones circulated in two clinically important wards highlights the deficiency of infection control program using conventional methods. Without the assistance of whole-genome sequencing, the transmissions of high-risk clones could not be identified.

We evaluated the possible protective effects of six polyphenols on benzo(a)pyrene (BaP)-induced cytotoxicity in Caco-2 cells. We show that treatment with quinic acid, ferulic acid, homovanillic acid, trolox and BaP decreased cell viability, whereas naringenin and eriodictyol affected viability in a bi-phasic manner with low concentrations decreasing viability whereas higher concentrations increase viability. Co-treatment with 20 μM eriodictyol or naringenin reduced BaP-induced cytotoxicity, including cell apoptosis, cell cycle progression, and oxidative stress. Our results show that the protective effect of eriodictyol was superior to that of naringenin. The potential protective mechanisms of eriodictyol on BaP-induced toxicity were investigated by proteomics. We identified 80 differentially expressed proteins (DEPs) with proteins associated with genetic information processing pathway representing the highest proportion and number of proteins responding to eriodictyol treatment, including key proteins such as RPA2, SNRPA, RAD23B, NUP155 and AARS. Our results provide new knowledge on how polyphenols may prevent BaP-induced carcinogenesis.

Gut microbiome has been linked to neurogenerative diseases. Here, the authors present a metagenome-wide association study of schizophrenia (SZ) in human cohorts and identify SZ-associated specific gut-brain functional modules and pathways including SCFAs and neurotransmitters.

In testicular germ cell tumor type II (TGCT), a seminoma subtype expresses an induced pluripotent stem cell (iPSC) panel with four upregulated genes, OCT4/POU5F1, SOX17, KLF4, and MYC, and embryonal carcinoma (EC) has four upregulated genes, OCT4/POU5F1, SOX2, LIN28, and NANOG. The EC panel can reprogram cells into iPSC, and both iPSC and EC can differentiate into teratoma. This review summarizes the literature on epigenetic regulation of the genes. Epigenetic mechanisms, such as methylations of cytosines on the DNA string and methylations and acetylations of histone 3 lysines, regulate expression of these driver genes between the TGCT subtypes. In TGCT, the driver genes contribute to well-known clinical characteristics and the driver genes are also important for aggressive subtypes of many other malignancies. In conclusion, epigenetic regulation of the driver genes are important for TGCT and for oncology in general.

Comprehensive analyses of multi-omics data may provide insights into interactions between different biological layers concerning distinct clinical features. We integrated data on the gut microbiota, blood parameters and urine metabolites of treatment-naive individuals presenting a wide range of metabolic disease phenotypes to delineate clinically meaningful associations. Trans-omics correlation networks revealed that candidate gut microbial biomarkers and urine metabolite feature were covaried with distinct clinical phenotypes. Integration of the gut microbiome, the urine metabolome and the phenome revealed that variations in one of these three systems correlated with changes in the other two. In a specific note about clinical parameters of liver function, we identified Eubacteriumeligens, Faecalibacteriumprausnitzii and Ruminococcuslactaris to be associated with a healthy liver function, whereas Clostridium bolteae, Tyzzerellanexills, Ruminococcusgnavus, Blautiahansenii, and Atopobiumparvulum were associated with blood biomarkers for liver diseases. Variations in these microbiota features paralleled changes in specific urine metabolites. Network modeling yielded two core clusters including one large gut microbe-urine metabolite close-knit cluster and one triangular cluster composed of a gut microbe-blood-urine network, demonstrating close inter-system crosstalk especially between the gut microbiome and the urine metabolome. Distinct clinical phenotypes are manifested in both the gut microbiome and the urine metabolome, and inter-domain connectivity takes the form of high-dimensional networks. Such networks may further our understanding of complex biological systems, and may provide a basis for identifying biomarkers for diseases. Deciphering the complexity of human physiology and disease requires a holistic and trans-omics approach integrating multi-layer data sets, including the gut microbiome and profiles of biological fluids. By studying the gut microbiome on carotid atherosclerosis, we identified microbial features associated with clinical parameters, and we observed that groups of urine metabolites correlated with groups of clinical parameters. Combining the three data sets, we revealed correlations of entities across the three systems, suggesting that physiological changes are reflected in each of the omics. Our findings provided insights into the interactive network between the gut microbiome, blood clinical parameters and the urine metabolome concerning physiological variations, and showed the promise of trans-omics study for biomarker discovery.

Most of the disease studies for the gut microbiome have collected cases and control samples from the elderly or the middle-aged. Despite general interest in microbiome health, it is not known how microbial biomarkers from metagenome-wide association studies (MWAS) would perform in a cohort of young individuals, who would be largely free of chronic diseases, as well as medication. Here we analyze high-depth fecal metagenomic shotgun sequencing for 2183 healthy adults with clinical parameters, diet, lifestyle, and metabolite measurements. We provide the first set of large-scale evidence for gut microbiome dysbiosis in hyperuricemia, which relates to meat intake. We build a cardiometabolic disease risk model based on gut microbes for initial screening in a young population and confirm the validity using external cohorts. Fecal bacteria that have been reported to be enriched in colorectal cancer (CRC) are found to correlate with methylhistidines, branched-chain amino acids (BCAA), aromatic amino acids and glutamic acid in these young individuals, which were validated by an additional cohort of 1404 individuals. Our comprehensive data suggest that the gut microbiome could show trends towards diseases years before onset, and the results lay the foundation for the design of larger screens for cardiometabolic diseases and CRC with clinically meaningful cutoffs.

Gut microbiome influenced many aspects of host physiology and psychology. Vice versa, lifestyles factors such as exercise and healthy diet are ways to shape the gut microbiota towards balance. We observed two distinct microbe groups characterized by physical fitness in a multi-omic cohort of 2183 young subjects with metagenomics, national physique comprehensive test, lifestyle and metabolome data. The panel of bacterial taxa including Clostridium bolteae, Escherichia coli, Ruminococcus gnavus, Clostridium clostridioforme, Clostridium innocuum, Bacteroides cellulosilyticus and Oscillospiraceae, were consistently associated with most of the physical fitness. Clostridium species and trace element both increased in the individuals those tend to stay up late. Yogurt consumption was associated with Streptococcus thermophilus and Bifidobacterium animalis subsp. lactis in feces, which differed from potentially endogenous Bifidobacterium species that was associated with milk intake. Our large-scale analyses were poised to advise for a healthy gut microbiome through behavioural changes.