Dynamic change of the human gastrointestinal microbiome in relation to mucosal barrier effects during chemotherapy and immune ablative intervention

Numerous studies have demonstrated that the gastrointestinal tract (GIT) microbiota plays important roles for the human host. Since the GIT microbiota interfaces with the immune system and represents a first line of defense against infectious agents, interest has grown in whether the GIT microbiota may influence the outcome of different anticancer treatments. In this study, the GIT of pediatric patients with different cancer types as well as adult patients with hematologic malignancies undergoing an allogeneic hematopoietic stem cell transplantation were sampled throughout their treatment. In order to deeply profile not only the composition of the community, but also the functional capacity and expression, recently developed wet- and dry-lab methodologies for integrated multi-omic analyses were applied. The trajectories of the prokaryotic and microeukaryotic GIT communities of the patients were described in detail using 16S, 18S rRNA gene amplicon sequencing, as well as metagenomic and metatranscriptomic shotgun sequencing. Indeed, changes in the GIT microbiome in response to treatment were detected. Some changes that are generally thought to be detrimental for human health were detected during treatment, such as a decrease in alpha-diversity, a decrease in relative abundance of bacteria associated with health-promoting properties (such as Blautia spp., Roseburia spp. and Faecalibacterium spp.), as well as an increase in the relative abundance of antibiotic resistance genes. These changes were more pronounced in the adult hematology patients than in the pediatric patients, which is likely due to the more intensive treatment. Some observations need further investigation in order to explain their implication in human health. For example, in the pediatric patients, lower relative abundance of Akkermansia muciniphila was associated with mucositis and functional gene categories that are linked to bacteriophages or the bacterial defense mechanism against bacteriophages were associated with the overall status of the patient and mucositis development. Importantly, in both cohorts, high inter-individual but also high intra-individual variation in the prokaryotic communities were detected while the microeukaryotic community did not exhibit drastic changes. In conclusion, the employed integrated multi-omics analysis allowed detailed profiling of the GIT community including archaea, bacteria, eukaryotes and viruses as well as the functional potential including antibiotic resistance genes. In the future, analysis of the individual-specific processes within the GIT microbial community of patients throughout treatment might allow to adjust therapy regimens accordingly and improve the overall outcome of the therapy

The Gut Microbiota and Hematopoietic Stem Cell Transplantation: Challenges and Potentials.

The human gut microbiota gained tremendous importance in the last decade as next-generation technologies of sequencing and multiomics analyses linked the role of the microbial communities to host physiology and pathophysiology. A growing number of human pathologies and diseases are linked to the gut microbiota. One of the main mechanisms by which the microbiota influences the host is through its interactions with the host immune system. These interactions with both innate and adaptive host intestinal and extraintestinal immunity, although usually commensalistic even mutualistic with the host, in some cases lead to serious health effects. In the case of allogenic hematopoietic stem cell transplantation (allo-HSCT), the disruption of the intestinal microbiota diversity is associated with acute graft-versus-host disease (GvHD). Causing inflammation of the liver, skin, lungs, and the intestine, GvHD occurs in 40-50% of patients undergoing allo-HSCT and results in significant posttransplantation mortality. In this review, we highlight the impact of the gut microbiota on the host immunity in GvHD and the potential of microbiota in alleviation or even prevention of GvHD

Small RNA profiling of low biomass samples: identification and removal of contaminants

Background Sequencing-based analyses of low-biomass samples are known to be prone to misinterpretation due to the potential presence of contaminating molecules derived from laboratory reagents and environments. DNA contamination has been previously reported, yet contamination with RNA is usually considered to be very unlikely due to its inherent instability. Small RNAs (sRNAs) identified in tissues and bodily fluids, such as blood plasma, have implications for physiology and pathology, and therefore the potential to act as disease biomarkers. Thus, the possibility for RNA contaminants demands careful evaluation. Results Herein, we report on the presence of small RNA (sRNA) contaminants in widely used microRNA extraction kits and propose an approach for their depletion. We sequenced sRNAs extracted from human plasma samples and detected important levels of non-human (exogenous) sequences whose source could be traced to the microRNA extraction columns through a careful qPCR-based analysis of several laboratory reagents. Furthermore, we also detected the presence of artefactual sequences related to these contaminants in a range of published datasets, thereby arguing in particular for a re-evaluation of reports suggesting the presence of exogenous RNAs of microbial and dietary origin in blood plasma. To avoid artefacts in future experiments, we also devise several protocols for the removal of contaminant RNAs, define minimal amounts of starting material for artefact-free analyses, and confirm the reduction of contaminant levels for identification of bona fide sequences using ‘ultra-clean’ extraction kits. Conclusion This is the first report on the presence of RNA molecules as contaminants in RNA extraction kits. The described protocols should be applied in the future to avoid confounding sRNA studies. Keywords: RNA sequencing; Artefact removal; Exogenous RNA in human blood plasma; Contaminant RNA; Spin column

Integrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation.

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment-induced changes to the gastrointestinal tract (GIT) microbiome have been linked to adverse outcomes, most notably graft-versus-host disease (GvHD). However, it is presently unknown whether this relationship is causal or consequential. Here, we performed an integrated meta-omic analysis to probe deeper into the GIT microbiome changes during allo-HSCT and its accompanying treatments. We used 16S and 18S rRNA gene amplicon sequencing to resolve archaea, bacteria, and eukaryotes within the GIT microbiomes of 16 patients undergoing allo-HSCT for the treatment of hematologic malignancies. These results revealed a major shift in the GIT microbiome after allo-HSCT including a marked reduction in bacterial diversity, accompanied by only limited changes in eukaryotes and archaea. An integrated analysis of metagenomic and metatranscriptomic data was performed on samples collected from a patient before and after allo-HSCT for acute myeloid leukemia. This patient developed severe GvHD, leading to death 9 months after allo-HSCT. In addition to drastically decreased bacterial diversity, the post-treatment microbiome showed a higher overall number and higher expression levels of antibiotic resistance genes (ARGs). One specific Escherichia coli strain causing a paravertebral abscess was linked to GIT dysbiosis, suggesting loss of intestinal barrier integrity. The apparent selection for bacteria expressing ARGs suggests that prophylactic antibiotic administration may adversely affect the overall treatment outcome. We therefore assert that such analyses including information about the selection of pathogenic bacteria expressing ARGs may assist clinicians in "personalizing" regimens for individual patients to improve overall outcomes

Birth mode is associated with earliest strain-conferred gut microbiome functions and immunostimulatory potential

The effects of caesarean section delivery on mother-to-neonate transmission of microbiota are unclear. Here the authors show that caesarean section delivery can affect the transmission of specific microbial strains and the immunomodulatory potential of the microbiota

Programme Dementia Prevention (pdp): A Nationwide Program for Personalized Prevention in Luxembourg.

peer reviewedBACKGROUND: With continuously aging societies, an increase in the number of people with cognitive decline is to be expected. Aside from the development of causative treatments, the successful implementation of prevention strategies is of utmost importance to reduce the high societal burden caused by neurodegenerative diseases leading to dementia among which the most common cause is Alzheimer's disease. OBJECTIVE: The aim of the Luxembourgish "programme dementia prevention (pdp)" is to prevent or at least delay dementia in an at-risk population through personalized multi-domain lifestyle interventions. The current work aims to provide a detailed overview of the methodology and presents initial results regarding the cohort characteristics and the implementation process. METHODS: In the frame of the pdp, an extensive neuropsychological evaluation and risk factor assessment are conducted for each participant. Based on the results, individualized multi-domain lifestyle interventions are suggested. RESULTS: A total number of 450 participants (Mean age = 69.5 years; SD = 10.8) have been screened at different recruitment sites throughout the country, among whom 425 participants (94.4%) met the selection criteria. CONCLUSIONS: We provide evidence supporting the feasibility of implementing a nationwide dementia prevention program and achieving successful recruitment of the target population by establishing a network of different healthcare providers.3. Good health and well-bein

Fibroblast Growth Factor 23 is Associated With Adiposity in Patients Receiving Hemodialysis: Possible Cross Talk Between Bone and Adipose Tissue.

OBJECTIVE:Fibroblast growth factor 23 (FGF-23) may be involved in signaling between bone and adipose tissue in dialysis patients, but its role is uncertain. We sought to examine the association between FGF-23 and adiposity and whether this association is mediated in part by leptin. DESIGN/SETTING:We performed univariate and multivariate linear regression analyses using data from 611 participants in a cohort of prevalent hemodialysis patients recruited from dialysis centers in Atlanta, GA and San Francisco, CA from 2009 to 2011. We also investigated the role of leptin in these relationships. SUBJECTS:Participants were aged ≥18 years, English or Spanish speaking, and receiving hemodialysis for at least 3 months. MAIN OUTCOME MEASURES:Outcome measures of adiposity included body mass index, waist circumference, and body fat measured by bioelectrical impedance spectroscopy. RESULTS:Mean age was 56 ± 14 years, 39.8% were female, and median serum FGF-23 was 807 pg/mL. In fully adjusted models, FGF-23 was inversely associated with body mass index (-0.24 kg/m2 per 50% higher FGF-23, 95% confidence interval [CI]: -0.38 to -0.10), waist circumference (-0.44 cm per 50% higher FGF-23, 95% CI: -0.79 to -0.08), and percent body fat (-0.58% per 50% higher FGF-23, 95% CI: -0.79 to -0.37). Leptin was inversely associated with FGF-23. Addition of leptin to body composition models attenuated the associations between FGF-23 and measures of adiposity, but FGF-23 remained significantly associated with percent body fat (-0.17% per 50% higher FGF-23, 95% CI: -0.32 to -0.02). CONCLUSION:We found a negative association between FGF-23 and adiposity that appears to be mediated in part by leptin. As adipose tissue provides a "protective energy depot" for patients with chronic illness, a decrease in adipose tissue may be one mechanism in which higher FGF-23 levels may contribute to increased mortality in dialysis patients

Development of RESTORE: an online intervention to improve mental health symptoms associated with COVID-19-related traumatic and extreme stressors

Background: Frontline healthcare workers, recovered COVID+ patients who had severe illness, and close others of COVID+ patients who have recovered or died are at risk for clinical levels of mental health symptoms in the context of the COVID-19 pandemic. RESTORE (Recovering from Extreme Stressors Through Online Resources and E-health) was specifically designed for this context. RESTORE is a transdiagnostic guided online intervention adapted from evidence-based cognitive-behavioural therapies. Objectives: RESTORE was designed to address depression, anxiety, and posttraumatic stress disorder symptoms associated with exposure to COVID-19-related traumatic and extreme stressors, and to overcome multiple barriers to accessing psychotherapies. Method: This paper describes the intervention components and platform, as well as the principles used to develop RESTORE. Current research and future directions in developing and testing RESTORE are outlined. Results: Preliminary data from an initial uncontrolled trial evaluating RESTORE in frontline healthcare workers is highly promising. Conclusion: We believe RESTORE has great potential to provide accessible, evidence-based psychological intervention to those in great need

Unmet Needs of People With Parkinson's Disease and Their Caregivers During COVID-19-Related Confinement: An Explorative Secondary Data Analysis.

Self-perceived unmet needs in people with typical and atypical parkinsonism (PwP) and their caregivers, support network, personalized ways to address self-perceived unmet needs during confinement, as well as the prevalence of self-reported COVID-19 related symptoms, confirmed SARS-CoV-2 infection, and self-reported COVID-19 related hospitalization in Luxembourg and the Greater Region were assessed. From 18th March to 10th April 2020, 679 PwP were contacted by phone. Data was collected in the form of a semi-structured interview. The thematic synthesis identified 25 themes where PwP need to be supported in order to cope with consequences of the pandemic, and to adapt their daily and health-related activities. The present work highlights that in the context of personalized medicine, depending on the individual needs of support of the patient the identified self-perceived unmet needs were addressed in various ways ranging from one-directed information over interaction up to proactive counseling and monitoring. Family and health professionals, but also other support systems were taking care of the unmet needs of PwP (e.g., shopping, picking-up medication, etc.) during the pandemic. 7/606 PwP (1.15%) reported COVID-19 related symptoms, 4/606 (0.66%) underwent a rRT-PCR-based diagnostic test and 2/606 (0.33%) were confirmed as SARS-CoV-2 positive. None of these PwP reported being hospitalized due to COVID-19. Our results will allow health professionals to expand their services in a meaningful way i.e., personalize their support in the identified themes and thus improve the healthcare of PwP in times of crisis