The microbiome: current and future view of an ancient paradigm.

Current perspectives on the microbiome in health and disease

https://pubmed.ncbi.nlm.nih.gov/28660775/

Ethical Considerations in Microbial Therapeutic Clinical Trials.

As understanding of the human microbiome improves, novel therapeutic targets to improve human health with microbial therapeutics will continue to expand. We outline key considerations of balancing risks and benefits, optimising access, returning key results to research participants, and potential conflicts of interest.

https://pubmed.ncbi.nlm.nih.gov/29039256/

Durability and Long-term Clinical Outcomes of Fecal Microbiota Transplant Treatment in Patients With Recurrent Clostridium difficile Infection.

Fecal microbiota transplant (FMT) appears safe and effective for treatment of recurrent Clostridium difficile infection (RCDI). However, durability, long-term clinical outcomes, and patient satisfaction after FMT are not well described. In this follow-up survey of outcomes after FMT at a median of 22 months follow-up, 82% of patients had durable cure of CDI. Patients with recurrence had more post-FMT antibiotic exposure, underscoring the need for thoughtful antibiotic use and a potential role for prophylactic microbiome enrichment to reduce recurrence.

https://pubmed.ncbi.nlm.nih.gov/29272401/

Fecal Microbiota Transplant for Multidrug-Resistant Organism Decolonization Administered During Septic Shock.

Antibiotic resistance (AR) is a growing crisis fueled by globalization and widespread antibiotic use.1 The development of new antibiotics has not matched the emergence of MDROs,2 making it further necessary to explore other avenues to combat this issue. Fecal microbiota transplantation (FMT) is one such option that needs further exploration in the acute-care setting in cases with therapeutic limitations associated with AR such as the following.

https://pubmed.ncbi.nlm.nih.gov/29343312/

Tacrolimus concentration to dose ratio in solid organ transplant patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection.

Fecal microbiota transplantation (FMT) is increasingly being performed for Clostridium difficile infection in solid organ transplant (SOT) patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 SOT patients from September 2012-December 2016 who were taking tacrolimus at time of FMT for recurrent C. difficile infection. We compared the differences in tacrolimus concentration/dose ratio (C/D ratio) 3 months prior to FMT vs 3 months after FMT. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/kg/d) was -17.65 (95% CI -1.25 to 0.58) (ng/mL)/(mg/kg/d), P-value .43 by Wilcoxon signed-rank test. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/d) was -0.33 (95% CI -1.25 to 0.58) (ng/mL)/(mg/d), P-value .28 by Wilcoxon signed-rank test. Of these patients, 2/10 underwent allograft biopsy for allograft dysfunction in the year after FMT, with no evidence of allograft rejection on pathology. These preliminary data suggest that FMT may not predictably alter tacrolimus levels and support its safety for SOT patients however further study in randomized trials is needed.

https://pubmed.ncbi.nlm.nih.gov/29446866/

Fecal Microbiota Transplant for Refractory Clostridium difficile Infection Interrupts 25-Year History of Recurrent Urinary Tract Infections.

Here, we describe resolution of recurrent symptomatic UTI after FMT for RCDI in a woman who had been treated with nearly continuous antibiotics in the preceding 2 years. As common sources of morbidity, UTIs make significant contributions toward antibiotic resistance and antibiotic-associated infections. Though FMT may have changed provider behavior, post-FMT urine cultures were not indicated in the absence of further symptoms. Pre- or post-FMT stool cultures were not obtained for microbiota analysis. However, our case adds evidence for FMT as a safe and potentially efficacious intervention for the prevention and treatment of infections outside of C. difficile, suggesting a possible role for FMT in combatting antimicrobial resistance.

https://pubmed.ncbi.nlm.nih.gov/29450212/

Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience.

Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti-CDI antibiotics, respectively. Ninety-four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT-related adverse events (AE) occurred in 22.3% of cases, mainly comprising self-limiting conditions including nausea, abdominal pain, and FMT-related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT-related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus-seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non-CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.

https://pubmed.ncbi.nlm.nih.gov/30085388/

The Use of Microbiome Restoration Therapeutics to Eliminate Intestinal Colonization With Multidrug-Resistant Organisms.

Antibiotic resistance (AR) has been described by the World Health Organization as an increasingly serious threat to global public health. Many mechanisms of AR have become widespread due to global selective pressures such as widespread antibiotic use. The intestinal tract is an important reservoir for many multidrug-resistant organisms (MDROs), and next-generation sequencing has expanded understanding of the resistome, defined as the comprehensive sum of genetic determinants of AR. Intestinal decolonization has been explored as a strategy to eradicate MDROs with selective digestive tract decontamination and probiotics being notable examples with mixed results. This review focuses on fecal microbiota transplantation and the early evidence supporting its efficacy in decolonizing MDROs and potential mechanisms of action to reduce AR genes. Current evidence suggests that fecal microbiota transplantation may have promise in restoring healthy microbial diversity and reducing AR, and clinical trials are underway to better characterize its safety and efficacy.

https://pubmed.ncbi.nlm.nih.gov/30384952/

Fecal Microbiota Transplantations: Where Are We, Where Are We Going, and What Is the Role of the Clinical Laboratory?

Fecal microbiota transplantation (FMT) is a medical procedure by which intestinal microorganisms are transferred to a patient as a therapeutic. FMTs can use microbiota from donors or from an autologous supply; these are referred to as allo- and auto-FMTs, respectively. FMTs are most commonly used for medically refractory or recurrent infections of Clostridioides (formerly Clostridium) difficile. C. difficile infections (CDIs) usually develop after broad-spectrum antibiotic usage that disrupts the normal intestinal microbiota, creating a niche permissive for C. difficile to flourish and cause a toxin-mediated illness. CDIs are routinely treated with oral antimicrobial therapy; however, relapse, and even multiple relapses, can occur after antimicrobials are stopped. An adjunct treatment option is FMT. While FMTs have been used to treat CDIs for over a decade, questions remain regarding their effectiveness, safety, regulatory oversight, and best practices. We have asked 5 experts with different roles in the field (including infectious diseases, laboratory medicine, industry, and public health) to share their thoughts on this important topic.

https://pubmed.ncbi.nlm.nih.gov/32232453/

The gut microbiome's role in the development, maintenance, and outcomes of sepsis.

The gut microbiome regulates a number of homeostatic mechanisms in the healthy host including immune function and gut barrier protection. Loss of normal gut microbial structure and function has been associated with diseases as diverse as Clostridioides difficile infection, asthma, and epilepsy. Recent evidence has also demonstrated a link between the gut microbiome and sepsis. In this review, we focus on three key areas of the interaction between the gut microbiome and sepsis. First, prior to sepsis onset, gut microbiome alteration increases sepsis susceptibility through several mechanisms, including (a) allowing for expansion of pathogenic intestinal bacteria, (b) priming the immune system for a robust pro-inflammatory response, and (c) decreasing production of beneficial microbial products such as short-chain fatty acids. Second, once sepsis is established, gut microbiome disruption worsens and increases susceptibility to end-organ dysfunction. Third, there is limited evidence that microbiome-based therapeutics, including probiotics and selective digestive decontamination, may decrease sepsis risk and improve sepsis outcomes in select patient populations, but concerns about safety have limited uptake. Case reports of a different microbiome-based therapy, fecal microbiota transplantation, have shown correlation with gut microbial structure restoration and decreased inflammatory response, but these results require further validation. While much of the evidence linking the gut microbiome and sepsis has been established in pre-clinical studies, clinical evidence is lacking in many areas. To address this, we outline a potential research agenda for further investigating the interaction between the gut microbiome and sepsis.

https://pubmed.ncbi.nlm.nih.gov/32487252/

Fecal Microbiota Transplantation Is Safe and Effective in Patients With Clostridioides difficile Infection and Cirrhosis.

Clostridioides difficile infection (CDI) harms a large proportion of patients with cirrhosis. Fecal microbiota transplantation (FMT) is recommended for recurrent CDI, but its effects in patients with cirrhosis have not been established. We performed a multicenter observational study to evaluate the efficacy and safety of FMT for CDI in patients with cirrhosis.

https://pubmed.ncbi.nlm.nih.gov/32645451/

Fecal Microbiota Transplantation: Tales of Caution.

Microbiota-based therapies are generally considered safe and are the cornerstone of management of patients with recurrent Clostridioides difficile infection, with high success rates to prevent future recurrences. These therapies have evolved with several emerging modalities of delivering a diverse microbial consortium to a patient with reduced microbiome diversity. The most widely use modality is fecal microbiota transplantation (FMT). Despite more than a decade of discovery and research, FMT is still dependent on procurement of donor stool from well-screened healthy donors. A detailed informed consent with patients is of absolute necessity as unforeseen complications have happened, and this has been a longstanding aspect of the US Food and Drug Administration’s (FDA’s) enforcement discretion.

https://pubmed.ncbi.nlm.nih.gov/32991697/