The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
Fecal microbiota transplantation (FMT) from healthy donor to patient is a treatment for microbiome-associated diseases. Although the success of FMT requires donor bacteria to engraft in the patient's ...gut, the forces governing engraftment in humans are unknown. Here we use an ongoing clinical experiment, the treatment of recurrent Clostridium difficile infection, to uncover the rules of engraftment in humans. We built a statistical model that predicts which bacterial species will engraft in a given host, and developed Strain Finder, a method to infer strain genotypes and track them over time. We find that engraftment can be predicted largely from the abundance and phylogeny of bacteria in the donor and the pre-FMT patient. Furthermore, donor strains within a species engraft in an all-or-nothing manner and previously undetected strains frequently colonize patients receiving FMT. We validated these findings for metabolic syndrome, suggesting that the same principles of engraftment extend to other indications.
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•Gut microbiota of 18 C. difficile patients profiled during fecal transplantation•Developed Strain Finder, a method to infer strain genotypes and track them over time•Bacterial abundance and phylogeny are the strongest determinants of engraftment•Unlike bacterial species, closely related strains engraft in an all-or-nothing pattern
Smillie et al. profile the gut microbiota of recurrent Clostridium difficile patients during fecal microbiota transplantation (FMT) and uncover the principles of microbiota engraftment in humans. They validate their findings across several FMT datasets and in another disease context, metabolic syndrome.
Background. Recurrent Clostridium difficile infection (CDI) with poor response to standard antimicrobial therapy is a growing medical concern. We aimed to investigate the outcomes of fecal microbiota ...transplant (FMT) for relapsing CDI using a frozen suspension from unrelated donors, comparing colonoscopic and nasogastric tube (NGT) administration. Methods. Healthy volunteer donors were screened and a frozen fecal suspension was generated. Patients with relapsing/refractory CDI were randomized to receive an infusion of donor stools by colonoscopy or NGT. The primary endpoint was clinical resolution of diarrhea without relapse after 8 weeks. The secondary endpoint was self-reported health score using standardized questionnaires. Results. A total of 20 patients were enrolled, 10 in each treatment arm. Patients had a median of 4 (range, 2–16) relapses prior to study enrollment, with 5 (range, 3–15) antibiotic treatment failures. Resolution of diarrhea was achieved in 14 patients (70%) after a single FMT (8 of 10 in the colonoscopy group and 6 of 10 in the NGT group). Five patients were retreated, with 4 obtaining cure, resulting in an overall cure rate of 90%. Daily number of bowel movements changed from a median of 7 (interquartile range IQR, 5–10) the day prior to FMT to 2 (IQR, 1–2) after the infusion. Self-ranked health score improved significantly, from a median of 4 (IQR, 2–6) before transplant to 8 (IQR, 5–9) after transplant. No serious or unexpected adverse events occurred. Conclusions. In our initial feasibility study, FMT using a frozen inoculum from unrelated donors is effective in treating relapsing CDI. NGT administration appears to be as effective as colonoscopic administration. Clinical Trials Registration. NCT01704937.
Abstract
Background
Maternal influenza and pertussis vaccinations have been proven safe and effective in reducing maternal and infant morbidity and mortality. Though recommended, not all pregnant ...women receive these important vaccines. We aimed to evaluate the vaccine coverage of maternal immunization in pregnancy for seasonal influenza and acellular pertussis and elucidate the reasons for non-vaccination among pregnant women. The secondary objective was to describe factors that affect vaccine uptake.
Methods
A cross sectional observational study using anonymous questionnaires distributed to women in the maternity ward or pregnant women hospitalized in the high-risk ward, between Nov 2017 and June 2018, In an Israeli tertiary hospital.
Results
Of 321 women approached, 313 were eligible, with a total of 290 women completing the questionnaire (92.6%). We found a 75.9% (95% CI 71–81) and 34.5% (95% CI 29–40) vaccination rate for pertussis and influenza vaccines, respectively. The most prominent reason for not receiving the pertussis vaccine was being under-informed (24%). Influenza vaccine was not received mainly due to concerns about vaccine efficacy (28%). Other factors influencing vaccine uptake included education, prior childbirth and vaccine recommendations made by the provider.
Conclusion
Although maternal vaccination of pertussis and influenza is officially recommended, vaccine uptake is suboptimal. Our study suggests a central role for medical providers in diminishing the concerns about safety and efficacy, and presents novel factors influencing compliance rates, like seasonality and number of prior births.
Immune thrombocytopenia (ITP) is an isolated autoimmune condition, often preceded by a viral infection. Vaccines, mainly the measles-mumps-rubella vaccine, have also been associated with an increased ...risk of developing the disease. Although some case reports of ITP after influenza immunization in adults have been published, epidemiologic studies examining the role of the influenza vaccine as a trigger of ITP have not conclusively proven causality. We report a child with 3 occurrences of ITP, each within 1 week of receiving the influenza trivalent inactivated vaccine. He recovered fully in-between the episodes, and no further episodes have occurred since discontinuation of seasonal influenza vaccination. To the best of our knowledge, this report is the first showing, with high probability, the influenza vaccine as a cause for ITP in a pediatric patient.
Fecal microbiota transplantation (FMT) has been shown to be safe and effective in treating refractory or relapsing C. difficile infection (CDI), but its use has been limited by practical barriers. We ...recently reported a small preliminary feasibility study using orally administered frozen fecal capsules. Following these early results, we now report our clinical experience in a large cohort with structured follow-up.
We prospectively followed a cohort of patients with recurrent or refractory CDI who were treated with frozen, encapsulated FMT at our institution. The primary endpoint was defined as clinical resolution whilst off antibiotics for CDI at 8 weeks after last capsule ingestion. Safety was defined as any FMT-related adverse event grade 2 or above.
Overall, 180 patients aged 7-95 years with a minimal follow-up of 8 weeks were included in the analysis. CDI resolved in 82 % of patients after a single treatment, rising to a 91 % cure rate with two treatments. Three adverse events Grade 2 or above, deemed related or possibly related to FMT, were observed.
We confirm the effectiveness and safety of oral administration of frozen encapsulated fecal material, prepared from unrelated donors, in treating recurrent CDI. Randomized studies and FMT registries are still needed to ascertain long-term safety.
Previous studies have linked the Mediterranean diet (MED) with improved cardiometabolic health, showing preliminary evidence for a mediating role of the gut microbiome. We recently suggested the ...Green-Mediterranean (Green-MED) diet as an improved version of the healthy MED diet, with increased consumption of plant-based foods and reduced meat intake. Here, we investigated the effects of MED interventions on the gut microbiota and cardiometabolic markers, and the interplay between the two, during the initial weight loss phase of the DIRECT-PLUS trial.
In the DIRECT-PLUS study, 294 participants with abdominal obesity/dyslipidemia were prospectively randomized to one of three intervention groups: healthy dietary guidelines (standard science-based nutritional counseling), MED, and Green-MED. Both isocaloric MED and Green-MED groups were supplemented with 28g/day walnuts. The Green-MED group was further provided with daily polyphenol-rich green tea and Mankai aquatic plant (new plant introduced to a western population). Gut microbiota was profiled by 16S rRNA for all stool samples and shotgun sequencing for a select subset of samples.
Both MED diets induced substantial changes in the community structure of the gut microbiome, with the Green-MED diet leading to more prominent compositional changes, largely driven by the low abundant, "non-core," microorganisms. The Green-MED diet was associated with specific microbial changes, including enrichments in the genus Prevotella and enzymatic functions involved in branched-chain amino acid degradation, and reductions in the genus Bifidobacterium and enzymatic functions responsible for branched-chain amino acid biosynthesis. The MED and Green-MED diets were also associated with stepwise beneficial changes in body weight and cardiometabolic biomarkers, concomitantly with the increased plant intake and reduced meat intake. Furthermore, while the level of adherence to the Green-MED diet and its specific green dietary components was associated with the magnitude of changes in microbiome composition, changes in gut microbial features appeared to mediate the association between adherence to the Green-MED and body weight and cardiometabolic risk reduction.
Our findings support a mediating role of the gut microbiome in the beneficial effects of the Green-MED diet enriched with Mankai and green tea on cardiometabolic risk factors.
The study was registered on ClinicalTrial.gov ( NCT03020186 ) on January 13, 2017.
Multiple studies suggest a key role for gut microbiota in IgE-mediated food allergy (FA) development, but to date, none has studied it in the persistent state.
To characterize the gut microbiota ...composition and short-chain fatty acid (SCFAs) profiles associated with major food allergy groups, we recruited 233 patients with FA including milk (N = 66), sesame (N = 38), peanut (N = 71), and tree nuts (N = 58), and non-allergic controls (N = 58). DNA was isolated from fecal samples, and 16S rRNA gene sequences were analyzed. SCFAs in stool were analyzed from patients with a single allergy (N = 84) and controls (N = 31).
The gut microbiota composition of allergic patients was significantly different compared to age-matched controls both in α-diversity and β-diversity. Distinct microbial signatures were noted for FA to different foods. Prevotella copri (P. copri) was the most overrepresented species in non-allergic controls. SCFAs levels were significantly higher in the non-allergic compared to the FA groups, whereas P. copri significantly correlated with all three SCFAs. We used these microbial differences to distinguish between FA patients and non-allergic healthy controls with an area under the curve of 0.90, and for the classification of FA patients according to their FA types using a supervised learning algorithm. Bacteroides and P. copri were identified as taxa potentially contributing to KEGG acetate-related pathways enriched in non-allergic compared to FA. In addition, overall pathway dissimilarities were found among different FAs.
Our results demonstrate a link between IgE-mediated FA and the composition and metabolic activity of the gut microbiota.
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