Safety and feasibility of faecal microbiota transplant for major depressive disorder: study protocol for a pilot randomised controlled trial.

BACKGROUND: Mental disorders, including major depressive disorder (MDD), are a leading cause of non-fatal burden of disease globally. Current conventional treatments for depression have significant limitations, and there have been few new treatments in decades. The microbiota-gut-brain-axis is now recognised as playing a role in mental and brain health, and promising preclinical and clinical data suggest Faecal Microbiota Transplants (FMT) may be efficacious for treating a range of mental illnesses. However, there are no existing published studies in humans evaluating the efficacy of FMT for MDD. METHODS AND DESIGN: This protocol describes an 8-week, triple-blind, 2:1 parallel group, randomised controlled pilot trial (n = 15), of enema-delivered FMT treatment (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. There will be a further 26-week follow-up to monitor longer-term safety. Participants will receive four FMT or placebo enemas over four consecutive days. The primary aims of the study are to evaluate feasibility and safety of FMT as an adjunctive treatment for MDD in adults. Changes in gut microbiota will be assessed as a secondary outcome. Other data will be collected, including changes in depression and anxiety symptoms, and safety parameters. DISCUSSION: Modification of the microbiota-gut-brain axis via FMT is a promising potential treatment for MDD, but there are no published rigorous clinical trials evaluating its use. If this study finds that our FMT strategy is safe and feasible, a larger fully powered RCT is planned. Further high-quality research in this field is urgently needed to address unmet need. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12621000932864.

Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial.

OBJECTIVES: Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD. METHODS: The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial (n = 15) of enema-delivered FMT (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. RESULTS: Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD. CONCLUSIONS: All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.

Efficacy and safety of fecal microbiota transplantation for the treatment of diseases other than Clostridium difficile infection: a systematic review and meta-analysis.

The intestinal microbiome has been identified as a key modifier for a variety of health conditions. Fecal Microbiota Transplantation (FMT) has emerged as a fast, safe, and effective means by which to modify the intestinal microbiome and potentially treat a variety of health conditions. Despite extensive research of FMT for CDI, there is a lack of clarity informed by systematic synthesis of data regarding the safety and efficacy of FMT for other health conditions. This systematic review used PRISMA guidelines and was prospectively registered with PROSPERO (CRD42018104243). In March 2020, a search of MEDLINE, EMBASE, and PsycINFO was conducted. We identified 26 eligible studies. A meta-analysis of FMT for active Ulcerative Colitis (UC) showed that FMT significantly improved rates of clinical remission (OR = 3.634, 95% CI = 1.940 to 6.808, I2 = 0%, p < .001), clinical response (OR = 2.634, 95% CI = 1.441 to 4.815, I2 = 33%, p = .002) and endoscopic remission (OR = 4.431, 95% CI = 1.901 to 10.324, I2 = 0%, p = .001). With respect to Irritable Bowel Syndrome, a meta-analysis showed no significant change in symptoms following FMT (p = .739). Hepatic disorders, metabolic syndrome, and antibiotic-resistant organisms were conditions with emerging data on FMT. Serious adverse events (AE) were more often reported in control group participants (n = 43) compared with FMT group participants (n = 26). There were similar rates of mild to moderate AE in both groups. Preliminary data suggest that FMT is a potentially safe, well-tolerated and efficacious treatment for certain conditions other than CDI, with evidence for active UC being the most compelling.

Never underestimate inflammatory bowel disease: High prevalence rates and confirmation of high incidence rates in Australia.

BACKGROUND AND AIMS: Regional variations in inflammatory bowel disease (IBD) rates have been observed. Limited epidemiological data are available from Australasia. IBD prevalence rates have never been assessed in an Australian population-based setting. In addition, there are few historical IBD incidence data to allow assessment of rate changes. The aims were to calculate Australia's first population-based IBD prevalence rates, to reassess local IBD incidence rates, and to establish a population-based inception cohort. METHODS: An observational, prospective population-based epidemiological study was performed to assess IBD prevalence and incidence rates from July 2010 to June 2011 in a geographically defined Australian population (Barwon, Victoria). RESULTS: There were 1011 prevalent IBD cases identified, representing a crude point prevalence rate of 344.6 per 100,000 on June 30, 2011. Crohn's disease was the most common prevalent subtype. Seventy-one incident cases of IBD were identified, with a crude incidence rate of 24.2 per 100,000. Crohn's disease was again more common. Local incidence rates have not changed between 2007 and the present study. All incident cases were successfully incorporated into an inception cohort. CONCLUSION: The burden of IBD in our local region is high. Demographic similarities allow these results to be applied to the broader Australian community. We propose that the number of existing and new cases each year in Australia has been previously underestimated. These revised figures will be important when planning the provision of health resources for these patients in the future and when assessing need for research funding priorities.

Health Care Cost Analysis in a Population-based Inception Cohort of Inflammatory Bowel Disease Patients in the First Year of Diagnosis.

BACKGROUND: There are limited prospective population-based data on the health care cost of IBD in the post-biologicals era. A prospective registry that included all incident cases of inflammatory bowel disease [IBD] was established to study disease progress and health cost. AIM: To prospectively assess health care costs in the first year of diagnosis among a well-characterised cohort of newly diagnosed IBD patients. METHOD: Incident cases of IBD were prospectively identified in 2007-2008 and 2010-2013 from multiple health care providers, and enrolled into the population-based registry. Health care resource utilisation for each patient was collected through active surveillance of case notes and investigations including specialist visits, diagnostic tests, medications, medical hospitalisation, and surgery. RESULTS: Off 276 incident cases of IBD, 252 [91%] were recruited to the registry, and health care cost was calculated for 242 (146 Crohn's disease [CD] and 96 ulcerative colitis [UC] patients). The median cost in CD was higher at A$5905 per patient (interquartile range [IQR]: A$1571-$91,324) than in UC at A$4752 [IQR: A$1488-A$58,072]. In CD, outpatient resources made up 55% of all cost, with medications accounting for 32% of total cost [15% aminosalicylates, 15% biological therapy], followed by surgery [31%], and diagnostic testing [21%]. In UC, medications accounted for 39% of total cost [of which 37% was due to 5-aminosalicylates, and diagnostics 29%; outpatient cost contributed 71% to total cost. CONCLUSION: In the first year of diagnosis, outpatient resources account for the majority of cost in both CD and UC. Medications are the main cost driver in IBD.

Gastroduodenal outlet obstruction and palliative self-expandable metal stenting: a dual-centre experience.

Background. Self-expandable metal stents (SEMs) are increasingly being utilised instead of invasive surgery for the palliation of patients with malignant gastroduodenal outlet obstruction. Aim. To review two tertiary centres' experience with placement of SEMs and clinical outcomes. Methods. Retrospective analysis of prospectively collected data over 12 years. Results. Ninety-four patients (mean age, 68; range 28-93 years) underwent enteral stenting during this period. The primary tumour was gastric adenocarcinoma in 27 (29%) patients, pancreatic adenocarcinoma in 45 (48%), primary duodenal adenocarcinoma in 8 (9%), and cholangiocarcinoma and other metastatic cancers in 14 (16%). A stent was successfully deployed in 95% of cases. There was an improvement in gastric outlet obstruction score (GOOS) in 84 (90%) of patients with the ability to tolerate an enteral diet. Median survival was 4.25 months (range 0-49) without any significant differences between types of primary malignancy. Mean hospital stay was 3 days (range 1-20). Reintervention rate for stent related complications was 5%. Conclusion. The successful deployment of enteral stents achieves excellent palliation often resulting in the prompt reintroduction of enteral diet and early hospital discharge with minimal complications and reintervention.

High incidence of inflammatory bowel disease in Australia: a prospective population-based Australian incidence study.

BACKGROUND: To date, there have been no population-based epidemiological studies published from Australia concerning the incidence of inflammatory bowel disease (IBD). Our hypothesis was that the incidence of IBD in Australia is at least as high as other industrialized countries, given similar genetic and environmental risk factors. METHODS: A prospective, population-based IBD incidence study was conducted between April 2007 and March 2008 in Greater Geelong, Victoria, Australia. According to 2006 Australian Census data, this comprises an at-risk population of 259,015. Cases were ascertained from multiple overlapping sources. All local general practitioners, gastroenterologists, surgeons, and pediatricians were contacted every 2 months to identify new IBD cases. The Royal Children's Hospital in Melbourne, local endoscopy and pathology centers were also searched to ensure completeness of case capture. Standard IBD case definitions were used with clinical, endoscopic, and histological criteria. RESULTS: In all, 76 new cases of IBD were identified during the 1-year period. There were 45 cases of Crohn's disease, 29 of ulcerative colitis, and 2 of indeterminate colitis. The crude annual incidence rates for IBD overall, Crohn's disease, ulcerative colitis, and indeterminate colitis were 29.3 per 100,000 (95% confidence interval [CI] 23.5-36.7 per 100,000), 17.4 per 100,000, 11.2 per 100,000, and 0.8 per 100,000, respectively. When directly age-standardized to the World Health Organization standard population the overall IBD incidence rate was 29.6 per 100,000. CONCLUSIONS: This is the first prospective, Australian population-based IBD incidence study. The incidence rates are among the highest reported in the literature of IBD.

Resection of right atrial metastatic large-cell neuroendocrine carcinoma.

The incidence of cardiac metastases is rising due to increasingly sensitive diagnostic investigations and longer patient survival as a result of improved treatment for malignancies. We report a rare case of right atrial metastasis from a large cell neuroendocrine carcinoma successfully resected with cardiopulmonary bypass. The surgical management of advanced cardiac malignancy is discussed. In appropriately selected cases surgical resection of cardiac metastases can be beneficial, allowing improvement in quality of life, and prolongation of life.