Consumption of over-the-counter probiotics for promotion of health and well-being has increased worldwide in recent years. However, although probiotic use has been greatly popularized among the ...general public, there are conflicting clinical results for many probiotic strains and formulations. Emerging insights from microbiome research enable an assessment of gut colonization by probiotics, strain-level activity, interactions with the indigenous microbiome, safety and impacts on the host, and allow the association of probiotics with physiological effects and potentially useful medical indications. In this Perspective, we highlight key advances, challenges and limitations in striving toward an unbiased interpretation of the large amount of data regarding over-the-counter probiotics, and propose avenues to improve the quality of evidence, transparency, public awareness and regulation of their use.
Homopolymeric stretches of deoxyadenosine nucleotides (A's) on one strand of double-stranded DNA, referred to as poly(dA:dT) tracts or A-tracts, are overabundant in eukaryotic genomes. They have ...unusual structural, dynamic, and mechanical properties, and may resist sharp bending. Such unusual material properties, together with their overabundance in eukaryotes, raised the possibility that poly(dA:dT) tracts might function in eukaryotes to influence the organization of nucleosomes at many genomic regions. Recent genome-wide studies strongly confirm these ideas and suggest that these tracts play major roles in chromatin organization and genome function. Here we review what is known about poly(dA:dT) tracts and how they work.
The core components of the nuclear RNA export pathway are thought to be required for export of virtually all polyadenylated RNAs. Here, we depleted different proteins that act in nuclear export in ...human cells and quantified the transcriptome-wide consequences on RNA localization. Different genes exhibited substantially variable sensitivities, with depletion of NXF1 and TREX components causing some transcripts to become strongly retained in the nucleus while others were not affected. Specifically, NXF1 is preferentially required for export of single- or few-exon transcripts with long exons or high A/U content, whereas depletion of TREX complex components preferentially affects spliced and G/C-rich transcripts. Using massively parallel reporter assays, we identified short sequence elements that render transcripts dependent on NXF1 for their export and identified synergistic effects of splicing and NXF1. These results revise the current model of how nuclear export shapes the distribution of RNA within human cells.
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•Depletion of NXF1 and TREX retains in the nucleus different transcript groups•Transcripts with few or long exons are preferentially dependent on NXF1•G/C-rich, 5′-biased, and m6A-modified regions drive single-exon transcript export•Splicing efficiency affects export in a largely NXF1-independent manner
Zuckerman et al. study the consequences of depletion of core components of the nuclear RNA export pathway in human cells. Different components are required for nuclear export of distinct transcript sets. Gene architecture, sequence composition, RNA secondary structure, RNA modifications, and certain sequence motifs are associated with this selective dependency.
The genomic revolution promises to transform our approach to treat patients by individualizing treatments, reducing adverse events, and decreasing health care costs. The early advances using this ...have been realized primarily by optimizing preventive and therapeutic approaches in cancer using human genome sequencing. The ability to characterize the microbiome, which includes all the microbes that reside within and upon us and all their genetic elements, using next-generation sequencing allows us to now incorporate this important contributor to human disease into developing new preventive and therapeutic strategies. In this review we highlight the importance of the microbiome in all aspects of human disease, including pathogenesis, phenotype, prognosis, and response to treatment, as well as their role as diagnostic and therapeutic biomarkers. We provide a role for next-generation sequencing in both precise microbial identification of infectious diseases and characterization of microbial communities and their function. Taken together, the microbiome is emerging as an integral part of precision medicine approach as it not only contributes to interindividual variability in all aspects of a disease but also represents a potentially modifiable factor that is amenable to targeting by therapeutics.
Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal ...host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.
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•Murine gut mucosal probiotic colonization is only mildly enhanced by antibiotics•Human gut mucosal probiotic colonization is significantly enhanced by antibiotics•Post antibiotics, probiotics delay gut microbiome and transcriptome reconstitution•In contrast, aFMT restores mucosal microbiome and gut transcriptome reconstitution
Probiotics perturb rather than aid in microbiota recovery back to baseline after antibiotic treatment in humans.
MicroRNAs are key regulators of gene expression, but the precise mechanisms underlying their interaction with their mRNA targets are still poorly understood. Here, we systematically investigate the ...role of target-site accessibility, as determined by base-pairing interactions within the mRNA, in microRNA target recognition. We experimentally show that mutations diminishing target accessibility substantially reduce microRNA-mediated translational repression, with effects comparable to those of mutations that disrupt sequence complementarity. We devise a parameter-free model for microRNA-target interaction that computes the difference between the free energy gained from the formation of the microRNA-target duplex and the energetic cost of unpairing the target to make it accessible to the microRNA. This model explains the variability in our experiments, predicts validated targets more accurately than existing algorithms, and shows that genomes accommodate site accessibility by preferentially positioning targets in highly accessible regions. Our study thus demonstrates that target accessibility is a critical factor in microRNA function.
Abstract
The gut is the richest ecosystem of microbes in the human body and has great influence on our health. Despite many efforts, the set of microbes inhabiting this environment is not fully ...known, limiting our ability to identify microbial content and to research it. In this work, we combine new microbial metagenomic assembled genomes from 51,052 samples, with previously published genomes to produce a curated set of 241,118 genomes. Based on this set, we procure a new and improved human gut microbiome reference set of 3594 high quality species genomes, which successfully matches 83.65% validation samples’ reads. This improved reference set contains 310 novel species, including one that exists in 19% of validation samples. Overall, this study provides a gut microbial genome reference set that can serve as a valuable resource for further research.
Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited ...efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences.
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•High interpersonal variability in post-meal glucose observed in an 800-person cohort•Using personal and microbiome features enables accurate glucose response prediction•Prediction is accurate and superior to common practice in an independent cohort•Short-term personalized dietary interventions successfully lower post-meal glucose
People eating identical meals present high variability in post-meal blood glucose response. Personalized diets created with the help of an accurate predictor of blood glucose response that integrates parameters such as dietary habits, physical activity, and gut microbiota may successfully lower post-meal blood glucose and its long-term metabolic consequences.
Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and ...beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.
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