The 5D Framework: A Clinical Primer for Fecal Microbiota Transplantation to Treat Clostridium difficile infection

Clostridium difficile infection is the most common health care–associated infection in the United States. Recently, fecal microbiota transplantation (FMT) has emerged as an effective and safe therapy for recurrent C difficile infection; however, despite rapid adoption there is no standardized clinical approach. Given the rapid adoption of FMT, in part because of stool banks, there is a need for a practical primer for clinicians to safely perform FMT. Accordingly, we aim to provide a simple approach entitled the 5D FMT framework to guide physicians. The 5D FMT framework includes: decision (selecting appropriate patient for FMT), donor (selection and screening), discussion (risk, benefits, alternatives), delivery (selecting appropriate modality for FMT administration), and discharge (counseling at discharge and follow-up). We aim to help clinicians take a simple but evidence-based approach to FMT to optimize efficacy and safety. This primer navigates how to decide whether a patient with C difficile infection is appropriate for FMT and how to select and screen stool donors, identify the ideal delivery modality, and provide follow-up care after FMT

Fecal microbiota transplantation in HIV: A pilot placebo-controlled study

Changes in the microbiota have been linked to persistent inflammation during treated HIV infection. In this pilot double-blind study, we study 30 HIV-infected subjects on antiretroviral therapy (ART) with a CD4/CD8 ratio < 1 randomized to either weekly fecal microbiota capsules or placebo for 8 weeks. Stool donors were rationally selected based on their microbiota signatures. We report that fecal microbiota transplantation (FMT) is safe, not related to severe adverse events, and attenuates HIV-associated dysbiosis. FMT elicits changes in gut microbiota structure, including significant increases in alpha diversity, and a mild and transient engraftment of donor’s microbiota during the treatment period. The greater engraftment seems to be achieved by recent antibiotic use before FMT. The Lachnospiraceae and Ruminococcaceae families, which are typically depleted in people with HIV, are the taxa more robustly engrafted across time-points. In exploratory analyses, we describe a significant amelioration in the FMT group in intestinal fatty acid-binding protein (IFABP), a biomarker of intestinal damage that independently predicts mortality. Gut microbiota manipulation using a non-invasive and safe strategy of FMT delivery is feasible and deserves further investigation. Trial number: NCT03008941.This work was supported by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013–2016, project PI18/00154, a Gilead Fellowship (GLD16-00030), the SPANISH AIDS Research Network RD16/0025/0001project), and co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (ERDF). The present investigation was also funded by the Instituto de Salud Carlos III and the Fundación Asociación Española contra el Cáncer within the ERANET TRANSCAN-2 program, grant number AC17/00022, a crowdfunding project from the precipita platform of the Fundación Española para la Ciencia y la Tecnología (FECYT) and a restricted grant from Finch Therapeutics. The SEIMC-GESIDA Foundation supported this study with safety and data monitoring (GESIDA 9116).Peer reviewe

Framework for rational donor selection in fecal microbiota transplant clinical trials

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact

Framework for rational donor selection in fecal microbiota transplant clinical trials.

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact

Gut microbial dysbiosis in individuals with Sjögren’s disease

Abstract Purpose To evaluate the gut microbiome in individuals with Sjögrens and correlate bacterial profiles to dry eye (DE) measures. Methods Prospective case series of individuals with confirmed (n=13) and unconfirmed (n=8) Sjögrens (n=21; total cases) as compared to healthy controls (n=10). Stool was analyzed by 16S pyrosequencing and associations between bacterial classes and DE symptoms and signs were examined. Results Firmicutes was the dominant phylum in the gut, comprising 40-60% of all phyla. On a phyla level, subjects with Sjögrens (confirmed and unconfirmed) had depletion of Firmicutes (1.1- fold) and an expansion of Proteobacteria (3.0-fold), Actinobacteria (1.7-fold), and Bacteroidetes (1.3-fold) compared to controls. Shannon’s diversity index showed no differences between groups with respect to the numbers of different operational taxonomic units (OTUs) encountered (diversity) and the instances these unique OTUs were sampled (evenness). On the other hand, Faith’s phylogenetic diversity showed increased diversity in cases vs controls, which reached significance when comparing confirmed Sjögrens and controls (13.57 ± 0.89 and 10.96 ± 0.76, p=0.02). Using Principle Co-ordinate Analysis, qualitative differences in microbial composition were noted with differential clustering of cases and controls. Dimensionality reduction and clustering of complex microbial data further showed differences between the three groups, with regard to microbial composition, association and clustering. Finally, differences in certain classes of bacteria correlated with DE symptoms and signs. Conclusions Individuals with Sjögrens have gut microbiome alterations as compared to healthy controls. Certain classes of bacteria were associated with DE measures

HIV-exposure, early life feeding practices and delivery mode impacts on faecal bacterial profiles in a South African birth cohort

CITATION: Claassen-Weitz, S., et al. 2018. HIV-exposure, early life feeding practices and delivery mode impacts on faecal bacterial profiles in a South African birth cohort. Scientific Reports, 8:5078, doi:10.1038/s41598-018-22244-6.The original publication is available at https://www.nature.comThere are limited data on meconium and faecal bacterial profiles from African infants and their mothers. We characterized faecal bacterial communities of infants and mothers participating in a South African birth cohort. Stool and meconium specimens were collected from 90 mothers and 107 infants at birth, and from a subset of 72 and 36 infants at 4–12 and 20–28 weeks of age, respectively. HIV-unexposed infants were primarily exclusively breastfed at 4–12 (49%, 26/53) and 20–28 weeks (62%, 16/26). In contrast, HIV-exposed infants were primarily exclusively formula fed at 4–12 (53%; 10/19) and 20–28 weeks (70%, 7/10). Analysis (of the bacterial 16S rRNA gene sequences of the V4 hypervariable region) of the 90 mother-infant pairs showed that meconium bacterial profiles [dominated by Proteobacteria (89%)] were distinct from those of maternal faeces [dominated by Firmicutes (66%) and Actinobacteria (15%)]. Actinobacteria predominated at 4–12 (65%) and 20–28 (50%) weeks. HIV-exposed infants had significantly higher faecal bacterial diversities at both 4–12 (p = 0.026) and 20–28 weeks (p = 0.002). HIV-exposed infants had lower proportions of Bifidobacterium (p = 0.010) at 4–12 weeks. Maternal faecal bacterial profiles were influenced by HIV status, feeding practices and mode of delivery. Further longitudinal studies are required to better understand how these variables influence infant and maternal faecal bacterial composition.https://www.nature.com/articles/s41598-018-22244-6Publisher's versio