Culturomics: bacterial species isolated in 3 healthy donors for faecal microbiota transplantation in Clostridium difficile infection

Background. Clostridium difficile infections are the main cause of nosocomial acquired diarrhea, because of prolonged antibiotic regimens. In the last years, mortality has increased due to recurrent infections caused by metronidazole and vancomicin resistant hypervirulent C. difficile strain 027. Faecal Microbiota Transplantation (FMT) is an infusion of faecal material obtained from healthy donors. This procedure reduces mortality in recurrent C. difficile infections (CDI). In this study we identified bacterial species obtained from donors' stool samples using culturomics. Materials and methods. Three donors were selected for FMT in three recipients affected by CDI. Faces obtained for FMT underwent culturomics, applying 17 different culture methods. Results and conclusions. Several different bacteria were isolated from donors. In two donors 4 potentially pathogenic bacteria were isolated; this suggests the use of culturomics for donors' screening or for selection of bacteria to infuse

Prevention and treatment of Clostridium difficile infection

Clostridium difficile infection (CDI) is one of the most common intestinal infection often requiring hospitalization. Several risk factors are associated with the development of CDI with antibiotic treatments being the most common. Diagnosis is based on clinical suspicion, (typical symptoms associated with risk factors) and confirmatory tests, both of which are often inadequate leading to underestimation of the disease. The management of CDI is based on fluid and nutritional support, avoidance of predisposing conditions and therapeutic interventions. Therapy consists mainly in antibiotics with vancomycin and metronidazole being the most used, the former is usually reserved for severe cases or when metronidazole cannot be used. Evidence is increasing about the use of fidaxomicin, which is as effective as vancomycin but associated with lower rates of recurrences. Lastly, fecal microbiota transplantation is now recommended by most guidelines for recurrent CDI obtaining extremely higher efficacy in comparison to standard treatments

Current and future targets for faecal microbiota transplantation

The human gastrointestinal tract is home to the most diverse microbial ecosystem in the human body and is made up of bacteria, viruses and eukarya. Collectively known as the gut microbiota, our knowledge of these microbial communities has historically been restricted by the relative limitations of culturing techniques. However, the recent development and utilisation of next-generation sequencing techniques has enhanced our understanding of its structure, diversity and function.There is emerging evidence that the gut microbiota plays a pivotal role in both health and disease. Perturbations to the structure and function of the gut microbiota are known to be associated with certain disease states. Therefore, manipulating the gut microbiota in an attempt to restore structure and function represents a promising therapeutic strategy. Recently, there has been a surge in clinical and scientific interest in manipulating the gut microbiota using a method called faecal microbiota transplantation. This increase in interest has gathered after it was shown in randomised controlled trials to be highly effective in treating recurrent Clostridium difficile infection.Despite success in treating recurrent Clostridium difficile, there remain many unknowns about how best to optimise its preparation, regulation, mode of delivery and safety. This review aims to summarise the literature surrounding the current knowledge regarding faecal microbiota transplantation and explore potential future research avenues that aim to enhance the safety, efficacy and utilisation of faecal microbiota transplantation

Atopic dermatitis and ulcerative colitis successfully treated with upadacitinib

Background and Objectives: JAK inhibitors entered current clinical practice as treatment for several immune-related diseases and, recently, for atopic dermatitis. These drugs target the Janus Kinase intracellular cascade, rendering them suitable for treating both Th1 and Th2 immune-mediated responses. Materials and Methods: We report the case of a 36-year-old male patient presenting an overlap of ulcerative colitis, a Th1-related disease, and atopic dermatitis, a Th2-mediated condition. Treatment with upadacitinib was initiated, and laboratory and instrumental follow-ups were carried out for 8 months. Results: The complete and persistent clinical remission of both conditions was observed at a low dose of 15 mg of upadacitinib, even though ulcerative colitis guidelines usually recommend a dosage of 45 mg. No serious adverse responses to therapy were reported. Conclusions: Upadacitinib may be the most suitable management strategy in subjects with coexisting severe conditions mediated by Th1 inflammation, such as ulcerative colitis, and by Th2 cytokines, such as atopic dermatitis

Gut Microbiota as a Driver of Inflammation in Nonalcoholic Fatty Liver Disease

The prevalence of nonalcoholic fatty liver disease and the consequent burden of metabolic syndrome have increased in recent years. Although the pathogenesis of nonalcoholic fatty liver disease is not completely understood, it is thought to be the hepatic manifestation of the dysregulation of insulin-dependent pathways leading to insulin resistance and adipose tissue accumulation in the liver. Recently, the gut-liver axis has been proposed as a key player in the pathogenesis of NAFLD, as the passage of bacteria-derived products into the portal circulation could lead to a trigger of innate immunity, which in turn leads to liver inflammation. Additionally, higher prevalence of intestinal dysbiosis, larger production of endogenous ethanol, and higher prevalence of increased intestinal permeability and bacterial translocation were found in patients with liver injury. In this review, we describe the role of intestinal dysbiosis in the activation of the inflammatory cascade in NAFLD

Role of Microbiota and Innate Immunity in Recurrent Clostridium difficile

Recurrent Clostridium difficile infection represents a burdensome clinical issue whose epidemiology is increasing worldwide. The pathogenesis is not yet completely known. Recent observations suggest that the alteration of the intestinal microbiota and impaired innate immunity may play a leading role in the development of recurrent infection. Various factors can cause dysbiosis. The causes most involved in the process are antibiotics, NSAIDs, acid suppressing therapies, and age. Gut microbiota impairment can favor Clostridium difficile infection through several mechanisms, such as the alteration of fermentative metabolism (especially SCFAs), the alteration of bile acid metabolism, and the imbalance of antimicrobial substances production. These factors alter the intestinal homeostasis promoting the development of an ecological niche for Clostridium difficile and of the modulation of immune response. Moreover, the intestinal dysbiosis can promote a proinflammatory environment, whereas Clostridium difficile itself modulates the innate immunity through both toxin-dependent and toxin-independent mechanisms. In this narrative review, we discuss how the intestinal microbiota modifications and the modulation of innate immune response can lead to and exacerbate Clostridium difficile infection

Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic

The COVID-19 pandemic has led to an exponential increase in SARS-CoV-2 infections and associated deaths, and represents a significant challenge to healthcare professionals and facilities. Individual countries have taken several prevention and containment actions to control the spread of infection, including measures to guarantee safety of both healthcare professionals and patients who are at increased risk of infection from COVID-19. Faecal microbiota transplantation (FMT) has a well-established role in the treatment of Clostridioides difficile infection. In the time of the pandemic, FMT centres and stool banks are required to adopt a workflow that continues to ensure reliable patient access to FMT while maintaining safety and quality of procedures. In this position paper, based on the best available evidence, worldwide FMT experts provide guidance on issues relating to the impact of COVID-19 on FMT, including patient selection, donor recruitment and selection, stool manufacturing, FMT procedures, patient follow-up and research activities.Peer reviewe

Impact evaluation of a Critical Pathway for patients with Clostridium difficile infection: a pre-post analysis in a Third Level Referral Center

Background: Clostridium Difficile Infections (CDIs) have been increasing both in incidence and in severity, representing a big public health concern. Aim: The aim of this study was to evaluate the impact of a recently implemented Critical Pathway (CP) focused on patients with CDI in an Italian Teaching Hospital. Methods: The CP implementation consisted of intervention aimed to faster diagnosis and appropriateness in admission and discharge point of care; activation of a multidisciplinary team; staff training; information to patients and caregivers.In a pre-post retrospective observational study, volume, process and outcome indicators were analyzed. Findings: A total of 228 patients (128 in 2013 and 100 in 2016) were included. A decrease in the absolute number of access to the Emergency Department (p = 0.02) and an increase in hospitalization in more appropriate ward (ie gastroenterology ward, p < 0.001) were found. The median hospital length of stay decreased from 20.5 (12.5–31) days in 2013 to 16.5 (7–31) days in 2016 (p = 0.05). With regards to outcome indicators, an increase of discharge to home and a decrease of discharge to long term facilities were showed (p = 0.01 both). Despite a reduction, no statically significant differences in mortality between 2013 and 2016 were revealed by the analysis. Conclusion: In conclusion, we found quality improvement in patient hospital management. Our experience confirms that the implementation of the CP increases the appropriateness in hospital quality of care. Keywords: Patient centeredness, Critical pathways, Clostridium Difficile infection, "Patient centered" analytic

Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO trial)

Background: Renal cell carcinoma (RCC) is the 6° most common cancer in men and the 8° in women in the USA. In Italy RCC incidence was 11,500 new cases in 2017, while mortality was 3,371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel treatment option aimed to restore healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection. Preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a double-blinded placebo-controlled randomized clinical trial, the efficacy of targeted FMT (from donors who are responding to ICIs) in improving response rates to ICIs in subjects with aRCC. Methods: 50 patients who are about to receive, or have started by &lt;8 weeks, pembrolizumab + axitinib as first-line therapy for aRCC will be enrolled. Exclusion criteria include major comorbidities, concomitant GI or autoimmune disorders, or HIV, HBV, HCV infection, continuative corticosteroid therapy, previous treatment with systemic immune-suppressants or immune-modulatory drugs, antibiotic therapy within 4 weeks prior to enrollment. Stool samples and clinical data will be collected at baseline. Then, patients will be randomized to donor FMT or placebo FMT. They will receive the first infusion by colonoscopy and then oral frozen fecal or placebo capsules (8 capsules t.i.d.) 90 and 180 days after the first FMT. Stool donors will be searched among long-term (&gt;12 months) responders to ICIs, and will be selected by following protocols recommended by international guidelines. Patients in the FMT group will always receive feces from the same donor throughout the three fecal transplants. Frozen fecal batches and frozen fecal capsules will be manufactured according to international guidelines. Patients will be followed-up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of stool samples. Patients will also undergo radiological assessment at 90, 180, 270 and 360 days after randomization. Microbiome analysis will be performed with shotgun metagenomics. The primary endpoint is the progression-free survival (PFS) at 12 months. Secondary endpoints are: objective response rate at 12 months; overall survival at 12 months; adverse events after FMT; microbiome changes after FMT. Sample size calculation was based on the hypothesis that FMT can improve the 1-year PFS rate from 60% (reported 1-year PFS for SOC) to 80% wen associated to SOC. Clinical trial information: NCT04758507

Letter: faecal microbiota transplantation in combination with fidaxomicin to treat severe complicated recurrent Clostridium difficile infection

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