Culture-independent analyses of microbial communities have progressed dramatically in the last decade, particularly due to advances in methods for biological profiling via shotgun metagenomics. ...Opportunities for improvement continue to accelerate, with greater access to multi-omics, microbial reference genomes, and strain-level diversity. To leverage these, we present bioBakery 3, a set of integrated, improved methods for taxonomic, strain-level, functional, and phylogenetic profiling of metagenomes newly developed to build on the largest set of reference sequences now available. Compared to current alternatives, MetaPhlAn 3 increases the accuracy of taxonomic profiling, and HUMAnN 3 improves that of functional potential and activity. These methods detected novel disease-microbiome links in applications to CRC (1262 metagenomes) and IBD (1635 metagenomes and 817 metatranscriptomes). Strain-level profiling of an additional 4077 metagenomes with StrainPhlAn 3 and PanPhlAn 3 unraveled the phylogenetic and functional structure of the common gut microbe
, previously described by only 15 isolate genomes. With open-source implementations and cloud-deployable reproducible workflows, the bioBakery 3 platform can help researchers deepen the resolution, scale, and accuracy of multi-omic profiling for microbial community studies.
The gastrointestinal tract of mammals hosts a high and diverse number of different microorganisms, known as intestinal microbiota. Many probiotics were originally isolated from the gastrointestinal ...tract, and they were defined by the Food and Agriculture Organization of the United Nations (FAO)/WHO as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.” Probiotics exert their beneficial effects on the host through four main mechanisms: interference with potential pathogens, improvement of barrier function, immunomodulation and production of neurotransmitters, and their host targets vary from the resident microbiota to cellular components of the gut–brain axis. However, in spite of the wide array of beneficial mechanisms deployed by probiotic bacteria, relatively few effects have been supported by clinical data. In this regard, different probiotic strains have been effective in antibiotic‐associated diarrhea or inflammatory bowel disease for instance. The aim of this review was to compile the molecular mechanisms underlying the beneficial effects of probiotics, mainly through their interaction with the intestinal microbiota and with the intestinal mucosa. The specific benefits discussed in this paper include among others those elicited directly through dietary modulation of the human gut microbiota.
Probiotics exert health benefits on the host through interaction with specific components of the host (mostly epithelial and immune cells), notably at the mucosa level, involving different mechanisms of action and biological effects
Akkermansia muciniphila is a human gut microbe with a key role in the physiology of the intestinal mucus layer and reported associations with decreased body mass and increased gut barrier function ...and health. Despite its biomedical relevance, the genomic diversity of A. muciniphila remains understudied and that of closely related species, except for A. glycaniphila, unexplored.
We present a large-scale population genomics analysis of the Akkermansia genus using 188 isolate genomes and 2226 genomes assembled from 18,600 metagenomes from humans and other animals. While we do not detect A. glycaniphila, the Akkermansia strains in the human gut can be grouped into five distinct candidate species, including A. muciniphila, that show remarkable whole-genome divergence despite surprisingly similar 16S rRNA gene sequences. These candidate species are likely human-specific, as they are detected in mice and non-human primates almost exclusively when kept in captivity. In humans, Akkermansia candidate species display ecological co-exclusion, diversified functional capabilities, and distinct patterns of associations with host body mass. Analysis of CRISPR-Cas loci reveals new variants and spacers targeting newly discovered putative bacteriophages. Remarkably, we observe an increased relative abundance of Akkermansia when cognate predicted bacteriophages are present, suggesting ecological interactions. A. muciniphila further exhibits subspecies-level genetic stratification with associated functional differences such as a putative exo/lipopolysaccharide operon.
We uncover a large phylogenetic and functional diversity of the Akkermansia genus in humans. This variability should be considered in the ongoing experimental and metagenomic efforts to characterize the health-associated properties of A. muciniphila and related bacteria.
FLT3 mutation is present in 25-30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront ...treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs.
We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher's test.
A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants.
We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.
Abstract
Diarrhoea is one of the most burdensome and common adverse events of chemotherapeutics, and has no standardised therapy to date. Increasing evidence suggests that the gut microbiome can ...influence the development of chemotherapy-induced diarrhoea. Here we report findings from a randomised clinical trial of faecal microbiota transplantation (FMT) to treat diarrhoea induced by tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (ClinicalTrials.gov number: NCT04040712). The primary outcome is the resolution of diarrhoea four weeks after the end of treatments. Twenty patients are randomised to receive FMT from healthy donors or placebo FMT (vehicle only). Donor FMT is more effective than placebo FMT in treating TKI-induced diarrhoea, and a successful engraftment is observed in subjects receiving donor faeces. No serious adverse events are observed in both treatment arms. The trial meets pre-specified endpoints. Our findings suggest that the therapeutic manipulation of gut microbiota may become a promising treatment option to manage TKI-dependent diarrhoea.
Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that ...fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.
This work describes a new procedure that allows the targeted modification of the human gut microbiota by using antibodies raised against bacterial surface-associated proteins specific to the ...microorganism of interest. To this end, a polyclonal antibody recognising the surface-associated protein Surface Layer Protein A of Lactobacillus acidophilus DSM20079
was developed. By conjugating this antibody with fluorescent probes and magnetic particles, we were able to specifically identify this bacterium both in a synthetic, and in real gut microbiotas by means of a flow cytometry approach. Further, we demonstrated the applicability of this antibody to deplete complex human gut microbiotas from L. acidophilus in a single step. L. acidophilus was found to interact with other bacteria both in synthetic and in real microbiotas, as reflected by its concomitant depletion together with other species. Further optimization of the procedure including a trypsin step enabled to achieve the selective and complete isolation of this species. Depleting a single species from a gut microbiota, using antibodies recognizing specific cell surface elements of the target organism, will open up novel ways to tackle research on the specific immunomodulatory and metabolic contributions of a bacterium of interest in the context of a complex human gut microbiota, including the investigation into therapeutic applications by adding/depleting a key bacterium. This represents the first work in which an antibody/flow-cytometry based application enabled the targeted edition of human gut microbiotas, and represents the basis for the design of precision microbiome-based therapies.
Chemoprevention is the use of natural and/or synthetic substances to block, reverse, or retard the process of carcinogenesis. In this field, the use of antitumor peptides is of interest as, (i) these ...molecules are small in size, (ii) they show good cell diffusion and permeability, (iii) they affect one or more specific molecular pathways involved in carcinogenesis, and (iv) they are not usually genotoxic. We have checked the Web of Science Database (23/11/2015) in order to collect papers reporting on bioactive peptide (1691 registers), which was further filtered searching terms such as “antiproliferative,” “antitumoral,” or “apoptosis” among others. Works reporting the amino acid sequence of an antiproliferative peptide were kept (60 registers), and this was complemented with the peptides included in CancerPPD, an extensive resource for antiproliferative peptides and proteins. Peptides were grouped according to one of the following mechanism of action: inhibition of cell migration, inhibition of tumor angiogenesis, antioxidative mechanisms, inhibition of gene transcription/cell proliferation, induction of apoptosis, disorganization of tubulin structure, cytotoxicity, or unknown mechanisms. The main mechanisms of action of those antiproliferative peptides with known amino acid sequences are presented and finally, their potential clinical usefulness and future challenges on their application is discussed.
At the end of the 2nd century AD the urban network of the Roman Empire was subject to weakness and crisis. We know this on one hand through decrees from the Flavian era, comments of Pliny the Younger ...on the financial problems of some cities and on the other hand through notices in the Historia Augusta reporting the existence of oppida labentia –"cities in decline".In this volume, we discuss some of these issues with the following questions: was the municipal system, at least in the Roman West and, particularly in Roman Spain, a useful and sustainable model of managing local autonomy? Was it a durable system? Were new cities more fragile than others in terms of financial sustainability? What were the causes and the indicators signalling the lack of strength of many urban centres from the 2nd century AD onwards?
This paper explores how to rank social allocations when individuals have other-regarding preferences (ORPs). Unlike the few existing studies on this issue, we focus on two different private goods, ...only one of which generates ORPs concerns. Specifically, individuals exhibit other-regarding views about the social health state but have standard self-centered preferences over other goods, namely consumption. Our social evaluation also incorporates a fairness view that aims to reduce inequalities that originate from factors for which individuals should not be deemed responsible. By resorting to a
non-resourcist
approach, we derive social preferences that seek to reduce individual well-being inequalities. Such differences are assessed by means of an interpersonal comparable measure that is related to an ideal situation which involves neither externalities nor unfair inequalities. We obtain that the use of the state of perfect health as the reference value leads society to give a higher priority to those who exhibit more altruistic preferences.
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