Explore the vast range of titles available.

The gut microbiota is composed of bacteria, archaea, phages, and protozoa. It is now well known that their mutual interactions and metabolism influence host organism pathophysiology. Over the years, there has been growing interest in the composition of the gut microbiota and intervention strategies in order to modulate it. Characterizing the gut microbial populations represents the first step to clarifying the impact on the health/illness equilibrium, and then developing potential tools suited for each clinical disorder. In this review, we discuss the current gut microbiota manipulation strategies available and their clinical applications in personalized medicine. Among them, FMT represents the most widely explored therapeutic tools as recent guidelines and standardization protocols, not only for intestinal disorders. On the other hand, the use of prebiotics and probiotics has evidence of encouraging findings on their safety, patient compliance, and inter-individual effectiveness. In recent years, avant-garde approaches have emerged, including engineered bacterial strains, phage therapy, and genome editing (CRISPR-Cas9), which require further investigation through clinical trials.

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

Fecal microbiota transplantation (FMT) consists of infusion of feces from a donor to a recipient patient in order to restore the resident microbial population. FMT has shown to be a valid clinical option for Clostridioides difficile infections (CDI). However, this approach shows several criticalities, such as the recruiting and screening of voluntary donors. Our aim was to evaluate the therapeutic efficacy of a synthetic bacterial suspension defined “Bacterial Consortium” (BC) infused in the colon of CDI patients. The suspension was composed by 13 microbial species isolated by culturomics protocols from healthy donors’ feces. The efficacy of the treatment was assessed both clinically and by metagenomics typing. Fecal samples of the recipient patients were collected before and after infusion. DNA samples obtained from feces at different time points (preinfusion, 7, 15, 30, and 90 days after infusion) were analyzed by next-generation sequencing. Before infusion, patient 1 showed an intestinal microbiota dominated by the phylum Bacteroidetes. Seven days after the infusion, Bacteroidetes decreased, followed by an implementation of Firmicutes and Verrucomicrobia. Patient 2, before infusion, showed a strong abundance of Proteobacteria and a significant deficiency of Bacteroidetes and Verrucomicrobia. Seven days after infusion, Proteobacteria strongly decreased, while Bacteroidetes and Verrucomicrobia increased. Metagenomics data revealed an “awakening” by microbial species absent or low concentrated at time T0 and present after the infusion. In conclusion, the infusion of selected bacteria would act as a trigger factor for “bacterial repopulation” representing an innovative treatment in patients with Clostridioides difficile infections.

Gut microbiota is a complex ecosystem composed by trillions of microorganisms that are crucial for human health or disease status. Currently, there are two methodological options to explore its complexity: metagenomics and culturomics. Culturomics is an approach that uses multiple culture conditions (days of incubation, enrichment factors and growth temperature) and MALDI-TOF mass spectrometry for the identification of bacterial species and sequencing when this method fails. In this paper, we describe how Colturomic’s protocol has allowed the first isolation in human sample of Rummeliibacillus suwonensis, a Gram positive, facultative anaerobe bacterium. The bacterium was isolated from feces of a 69 years old male with amyotrophic lateral sclerosis (ALS) recruited for a clinical trial assessing safety and efficacy of fecal microbiota transplantation in ALS. The first isolation of the microorganism dates back to 2013 from the soil of a South Korean mountain area. In this report, morphological description, biochemical characterization and antibiotic susceptibility tests were performed to outline the bacterial properties.

The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant ( P -value < 5.0 × 10 −8 ) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold ( P -value = 5.19 × 10 −8 ). A total of 113 variants were associated with survival at P -value < 1.0 × 10 −5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways.

Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 ( www.clinicaltrial.org )

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k -fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome. A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients.

The severity of coronavirus disease 2019 (COVID‐19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine‐1‐phosphate (S1P) along with severity markers, in COVID‐19 patients. One hundred eleven COVID‐19 patients and forty‐seven healthy subjects were included. The severity of COVID‐19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil‐to‐lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C‐reactive protein (CRP), and D‐dimer. Serum S1P level was inversely associated with COVID‐19 severity, being significantly correlated with CRP, LDH, ferritin, and D‐dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient’s outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID‐19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID‐19. Synopsis The study demonstrates that patients with COVID‐19 experience a significant reduction of serum sphingosine‐1‐phosphate (S1P). The decrease of S1P associates with the number of erythrocytes, a major source of circulating S1P, as well as with the levels of high‐density lipoprotein (HDL)/apolipoprotein M (apoM) and albumin, the most important transporters of circulating S1P. The serum levels of S1P, erythrocytes, apoM and albumin are lower in COVID‐19 patients admitted to intensive care unit (ICU) than in no‐ICU patients. Serum S1P negatively correlates with clinical parameters including Pneumonia Severity Index and days of hospitalization. S1P levels exhibit a strong power in predicting both ICU admission and mortality. Graphical Abstract The study demonstrates that patients with COVID‐19 experience a significant reduction of serum sphingosine‐1‐phosphate (S1P). The decrease of S1P associates with the number of erythrocytes, a major source of circulating S1P, as well as with the levels of high‐density lipoprotein (HDL)/apolipoprotein M (apoM) and albumin, the most important transporters of circulating S1P.

Background Proximal femur fractures have a negative impact on loss of functional autonomy and mortality. Objective The aim of this retrospective study was to evaluate functional autonomy and mortality in a group of older adults with hip fractures managed in an orthogeriatric setting 12 months after discharge and to determine if gender affected outcome. Methods In all participants, we assessed clinical history, functional pre-fracture status using activities of daily living (ADL) and in-hospital details. At 12 months after discharge, we evaluated functional status, place of residence, hospital readmissions and mortality. Results We studied 361 women and 124 men and we observed a significant reduction in the ADL score at 6 months (1.15 ± 1.58/p < 0.001 in women and 1.45 ± 1.66/p < 0.001 in men). One-year mortality (33.1% in men and 14.7% in women) was associated with pre-fracture ADL score and reduction in ADL at 6 months (HR 0.68/95%, CI 0.48–0.97/p < 0.05 and HR 1.70/95%, CI 1.17–2.48/p < 0.01, respectively) in women, and new hospitalisations at 6 months and polypharmacy in men (HR 1.65/95%, CI 1.07–2.56/p < 0.05 and HR 1.40/95%, CI 1.00–1.96/p = 0.05, respectively) in Cox's regression model. Discussion and Conclusions Our study suggests that functional loss in older adults hospitalised for proximal femur fractures is greatest in the first 6 months after discharge, and this increases the risk of death at 1 year. Cumulative mortality at 12 months is higher in men and appears to be related to polypharmacy and new hospital admissions 6 months after discharge.

Skeletal muscle regeneration occurs through the finely timed activation of resident muscle stem cells (MuSC). Following injury, MuSC exit quiescence, undergo myogenic commitment, and regenerate the muscle. This process is coordinated by tissue microenvironment cues, however the underlying mechanisms regulating MuSC function are still poorly understood. Here, we demonstrate that the extracellular matrix protein Tenascin-C (TnC) promotes MuSC self-renewal and function. Mice lacking TnC exhibit reduced number of MuSC, and defects in MuSC self-renewal, myogenic commitment, and repair. We show that fibro-adipogenic progenitors are the primary cellular source of TnC during regeneration, and that MuSC respond through the surface receptor Annexin A2. We further demonstrate that TnC declines during aging, leading to impaired MuSC function. Aged MuSC exposed to soluble TnC show a rescued ability to both migrate and self-renew in vitro. Overall, our results highlight the pivotal role of TnC during muscle repair in healthy and aging muscle. Tenascin-C (TnC) produced by the fibro-adipogenic progenitors (FAPs) is required for MuSC maintenance and function. FAP-secreted TnC signals through Annexin-A2 on the MuSC surface to promote self-renewal and regeneration potential.