Durable coexistence of donor and recipient strains after fecal microbiota transplantation.

Fecal Microbiota Transplantation for Ulcerative Colitis: Not Just Yet

Results of the First Pilot Randomized Controlled Trial of Fecal Microbiota Transplant In Pediatric Ulcerative Colitis: Lessons, Limitations, and Future Prospects

Methodology, Not Concept of Fecal Microbiota Transplantation, Affects Clinical Findings

A child, L.B., born at term, the third child whose older sister has juvenile idiopathic arthritis successfully treated with azathioprine, presented at 3 months with 6 to 8 bloody diarrheal stools per day, resolving spontaneously within 1 week. She was breast-fed for 4 months, when solid food was started. Formula was introduced at 6 months. She was asymptomatic between 4 and 10 months, but then presented again with bloody diarrhea, up to 10 stools per day, with mucus and bright red blood in her diapers. Upper endoscopy and histology were normal. Lower endoscopy showed pancolitis with loss of colonic haustrations, friability, absent vascular pattern, and some small ulcerations (Fig. 1). Histology was consistent with an ulcerative colitis (UC)–like phenotype; additionally, perinuclear anti-neutrophil cytoplasmic antibody was positive (1/160). Oral (50–60 mg · kg−1 · day−1) and rectal (333 mg/day) mesalamine was initiated. Following a good initial response, she relapsed 2 months later. At 13 months, azathioprine (2.0 mg · kg−1 · day−1) and prednisolone (2 mg · kg−1 · day−1) were initiated. Although she responded with decreased severity of symptom, stools remained frequent, bloody, and liquid. General condition, weight, and linear growth remained acceptable. The use of an amino acid–based formula for several months had no effect. Iron supplements failed to compensate for the rectal bleeding, and transfusion of packed red blood cells was needed every 3 to 4 weeks. Several probiotics, including VSL-3, proved unsuccessful. Infliximab treatment (5 mg/kg at 0–2–6–10 weeks) had no effect. An adverse reaction to sirolimus (Rapamune; Pfizer Pharmaceutical, New York, NY) made further administration impossible. Intravenous broad-spectrum antibiotics and total parental nutrition were administered for severe flares. Repeat biopsies with histology including electron microscopy did not reveal etiologies other than the "UC-like image." Antigen detection for Clostridium difficile was negative. An immunodeficiency was suspected because of L.B.'s young age at onset. Lymphocyte numbers and subsets were normal. Immunoglobulin levels were within the normal range for age. B-cell subsets for common variable immunodeficiency were analyzed and showed no decrease in switched memory B cells. Vaccination response against tetanus was adequate. Normal dihydrorhodamine flow cytometric assay made chronic granulomatous disease unlikely. Signaling-lymphocytic-activation-molecule–associated protein (SAP), X-linked inhibitor of apoptosis protein, and Wiskott-Aldrich syndrome protein deficiency was not tested as the child was female and the parents were not genetically related. Foxp3 was normal, excluding immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. No mutations were detected in the NOD2/CARD15 or in the STAT3 genes. The IL-10 (interleukin 10) gene was not completely sequenced; however, evaluation of known single nucleotide polymorphisms in the IL-10 gene showed a wild-type sequence for exons 1–4 and the coding region in exon 5 and a homozygous single nucleotide polymorphism that is also found in the healthy population (rs3024496 in the 3′UTR in exon 5). Both the IL-10RA and IL-10RB gene were sequenced. A heterozygous unclassified variant was found in the IL-10RA gene. This heterozygous silent c.180G>A p.(=) is not predicted to lead to abnormal function of the protein. Coding exons 1–7 of the IL-10RB gene were sequenced and showed no mutations. Functional testing of the IL-10 pathway at 9 months showed normal function. In particular, in vitro T-cell stimulation with anti-CD3 yielded normal IL-17 secretion. At 20 hours after culture, IL-12p70, tumor necrosis factor-α, and IL-8 concentrations were normal in stimulation assays of peripheral blood mononuclear leukocytes with lipopolysaccharide; however, after lipopolysaccharide stimulation, IL-6 and IL-1-β were increased as observed in auto-inflammatory syndromes. Concentrations of IL-1-β, IL-6, and IL-12p70 were increased in plasma.FIGURE 1: Histology just before (A) and 4 months after (B) the last fecal transplantation. A, Colitis: distortion of the normal architecture; regenerative changes of the epithelium; presence of crypt abscesses; dense stromal inflammation. Absence of granulomas. A, Normal mucosa: crypts are arranged parallel to each other; they are covered by a normal epithelium; total restoration of the mucin content; the lamina propria contains no inflammatory infiltrate.The patient was seen almost every 2 weeks at the outpatient clinic and more frequently as needed (Fig. 2: growth chart). The attempted treatments did not result in a sufficient clinical improvement. The Pediatric Ulcerative Colitis Activity Index (PUCAI) (1) varied between 60 and 75 (Table 1).FIGURE 2: Growth chart of the patient. The growth chart illustrates faltering growth during the active disease and (ineffective) prednisolone treatment (growth below P3) and the recovery growth when the patient was asymptomatic and when prednisolone was stopped, again reaching P3 (genetically, she should be on P25). Weight has returned to P50, where it was at the beginning of the disease.TABLE 1: Evolution of the Pediatric Ulcerative Colitis Activity IndexBecause of limited experience with alternative medical treatment options and the invasiveness of total colectomy, the possibility of fecal transplantation was discussed with the parents, who consented for fecal transplantation. The approval of the ethical committee at UZ Brussel was obtained for the procedure. The first fecal microbial transplantation was attempted at the age of 18 months, 5 months after the start of prednisolone and azathioprine. Donor stools were screened (2). Approximately 100 g of fresh fecal material was homogenized in 100 mL of sterile saline and filtered through gauze to remove larger particles. The first 2 infusions were administered into the cecum through a colonoscope, whereas the next 5 were infused by nasoduodenal tube. The first 4 fecal transplantations, with fresh stools from an age-related niece, led to transitory improvement and normal defecation for 7 to 14 days. The last 3 infusions contained fresh stool from the patient's older brother. Interestingly, L.B. tolerated the fecal transplants from the niece well, but she reacted to the first fecal transplant from the brother with profuse sweating, vomiting, paleness, tachycardia (blood pressure remained at 70/40), and transitory fever for an hour. She recovered spontaneously within an hour, and no active intervention was needed. Normalization of the stools lasted for 1 month. Because of the observed but transient clinical improvement, further fecal transplant using the brother's stools was discussed with the parents. She had a similar but smaller reaction after the second transplant 6 weeks later, followed by remission for 2 months. A much lesser reaction occurred again at the third infusion, and 6 months later L.B. still had normal stools. Prednisolone and azathioprine were initially continued, but were gradually decreased during 6 weeks (first prednisolone, then azathioprine) when the patient had been symptom-free for 2 months. The histology of the last colonoscopy, performed during anesthesia to remove the Port-a-Cath (Smiths Medical, Gary, IN) 6 months after the last fecal infusion and approximately 3 months after stopping all medication, showed normal histology and thus a resting phase or inactive UC. To our knowledge, this is the first report of a successful fecal transplant in a child with early-onset colitis (3). Consideration of fecal transplant should be made in the context of whether it is safer than continuing ineffective regimens that may be detrimental to the patient. We observed that a patient receiving fecal transplantation may develop systemic reactions that may be related specifically to the fecal content of an individual donor. As this case documents potential intolerance to infusion of foreign fecal material, we recommend careful monitoring of these patients as we learn more about the safety and efficacy of this recently applied treatment. Bacteremia following fecal microbiota transplantation has been reported (4). Further investigations may help determine whether the host intestinal and/or systemic immune responses to infused feces are related to disease activity.

Syngeneic Fecal Microbiota Transplant Effectively Attenuated Graft-Versus-Host Disease after Bone Marrow Transplantation in Mice

Faecal microbiota transplantations and urinary tract infections

BackgroundClostridium difficile is an opportunistic human intestinal pathogen, and C. difficile infection (CDI) is one of the main causes of antibiotic-induced diarrhea and colitis. One successful approach to combat CDI, particularly recurrent form of CDI, is through transplantation of fecal microbiota from a healthy donor to the infected patient. In this study we investigated the distal gut microbial communities of three CDI patients before and after fecal microbiota transplantation, and we compared these communities to the composition of the donor’s fecal microbiota. We utilized phylogenetic Microbiota Array, high-throughput Illumina sequencing, and fluorescent in situ hybridization to profile microbiota composition down to the genus and species level resolution.ResultsThe original patients’ microbiota had low diversity, was dominated by members of Gammaproteobacteria and Bacilli, and had low numbers of Clostridia and Bacteroidia. At the genus level, fecal samples of CDI patients were rich in members of the Lactobacillus, Streptococcus, and Enterobacter genera. In comparison, the donor community was dominated by Clostridia and had significantly higher diversity and evenness. The patients’ distal gut communities were completely transformed within 3 days following fecal transplantation, and these communities remained stable in each patient for at least 4 months. Despite compositional differences among recipients’ pre-treatment gut microbiota, the transplanted gut communities were highly similar among recipients post-transplantation, were indistinguishable from that of the donor, and were rich in members of Blautia, Coprococcus, and Faecalibacterium. In each case, the gut microbiota restoration led to a complete patient recovery and symptom alleviation.ConclusionWe conclude that C. difficile infection can be successfully treated by fecal microbiota transplantation and that this leads to stable transformation of the distal gut microbial community from the one abundant in aerotolerant species to that dominated by members of the Clostridia.

Fecal microbiota transplantation with ruxolitinib as a treatment modality for steroid-refractory/dependent acute, gastrointestinal graft-versus-host disease: A case series.

Fecal microbiota transplantation (FMT) is a therapy that involves the transplantation of healthy human fecal microorganisms into the gut of patients to rebuild or consolidate the intestinal microecology. It has been utilized in many diseases. However, FMT had a limited effect on patients with small intestinal diseases because of the unique ecological characteristics of the microorganisms. Thus, we proposed a new microecology transplantation therapy called human intestinal fluid transplantation (HIFT). Human intestinal fluid can be collected through a nasojejunal tube and be made into capsules using the freeze-dried powder method. In addition, strict standards for donor screening and management have been established. We are currently developing a high-standard HIFT preparation system and conducting high-quality clinical studies to validate the safety and efficacy of HIFT combined with FMT.

Faecal microbiota transplantation (FMT) has been used for centuries and was initially employed to combat acute gastrointestinal infections.1 The procedure involves transferring faecal material from a healthy donor to an infected individual. Our understanding of gut microbiota has significantly evolved during the 21st century. Researchers now acknowledge the pivotal role played by this complex ecosystem in overall health and disease.2 Broader applications are now being explored for FMT, which was once limited to treating infections. The gastrointestinal tract harbours a diverse community of microorganisms, including archaea, bacteria, viruses and fungi. Disturbances in this delicate balance, which are collectively known as intestinal dysbiosis, can lead to the qualitative, quantitative and functional microbial alterations associated with diseases. Dysbiosis may exacerbate existing conditions or precipitate new ones.2 Recurrent Clostridioides difficile infections are still the primary recognised indication for FMT,3 but there has been considerable research into its potential in other contexts. Dysbiosis is implicated in both inflammatory bowel disease and irritable bowel syndrome, making FMT an intriguing avenue for investigation. There has also been research on conditions beyond the gut, such as hepatic encephalopathy, obesity and metabolic syndrome. FMT has also extended into neurological and neuropsychiatric diseases, based on the gut–brain theory,4 although establishing a causal link between dysbiosis and these conditions remains challenging. The use of FMT has been well established as part of the treatment algorithm for recurrent C. difficile infections in adults, as proposed by the North American and European societies for paediatric gastroenterology, hepatology and nutrition.5 They recommend that FMT is used for cases that relapse within 8 weeks of treatment for at least two severe episodes requiring hospitalisation or for three mild-to-moderate episodes after vancomycin treatment fails. FMT is also recommended for moderate C. difficile infections that do not respond to standard therapy after more than 1 week or severe cases that do not respond after 48 h of standard therapy. The available data on FMT in children are sparse.3 The choice of FMT is pivotal, and even more critical, if the patient is a child. Adults exhibit a relatively stable gut microbiome, but the microbial composition in children varies significantly and evolves alongside their immune system and other physiological functions.6 Therefore, selecting an appropriate donor for children is a complex task. Also, the optimal route of administration remains elusive for children. Should oral capsules, nasogastric tubes or other methods be used? The lack of detailed guidelines poses challenges for paediatric practitioners. An interesting retrospective multi-centre study on the use of FMT for children, published in 2020, showed that success rates were higher in children who received FMT with a fresh donor stool, underwent FMT via colonoscopy, or had less previous episodes of C. difficile infection before the procedure.7 In a paper published in Acta Paediatrica, Lauwers et al.8 report the results of a systemic review on the use of FMT in adults and children. This well-written, comprehensive review guides us through the different aspects of FMT, such as the evidence on the effects on recurrent C. difficile infections, inflammatory bowel disease, irritable bowel syndrome, obesity and allergic colitis. It also covers other important issues, such as the route of administration, donor selection and the risk of adverse events. Although randomised controlled trials (RCTs) that have evaluated the efficacy of FMT for recurrent C. difficile have been lacking in children, the systematic review identified 538 reported cases in the literature. The average overall efficacy after one or more FMT was 85% in this systematic review, which was within the same range reported by RCTs on adults. The lack of well-designed, large RCTs on FMT treatment for children is problematic. There is potentially a high risk of publication bias from selective reporting of positive outcomes skewing the overall understanding of this intervention. Also, the lack of sham-treated control groups makes it challenging to differentiate between improvements due to FMT and those that would have occurred naturally over time. Another important issue in the paediatric population is the risk of adverse events. Severe side effects have been reported as a result of FMT treatment, but they seem to be very uncommon. However, they may occur more frequently in immunocompromised patients and patient with immune-mediated diseases where FMT could induce flares, such as inflammatory bowel disease.5 Every patient, and their parents in the case of paediatric patients, need to be informed about the potential risks before FMT is administered. The most common side effects are abdominal pain, diarrhoea, vomiting, low-grade fever, flatulence and nausea, as well as the complications from the endoscopy and/or drugs used to sedate the patient. It is notable that information about the long-term effects are lacking, since there have not been any follow-up studies on children. The review by Lauwers et al. also discusses the lack of effect on other conditions. ClinicalTrials.gov lists several RCTs on inflammatory bowel disease and irritable bowel syndrome that are currently being carried out and we await their results. Hopefully, they will change our knowledge in this area, but there may also be intrinsic reasons why we have not seen any convincing effects in patients with these conditions. FMT predominantly targets colonic microbiota when it is administered via a colonoscopy, while most of the interaction between the microbiome and the gut immune system occurs in the small intestine. Moreover, the idea of dysbiosis is overly simplistic. We are still struggling to define what a healthy gut microbiome is and the fact that the gut microbiome develops fast during the first years of life does not make it easier.6 We will probably not make any further discoveries about FMT if we do not individualise microbiome transplants based on individual responsiveness. That is why future regimens warrant precision-based medicine, including analyses of the recipient's genome, microbiome and proteome. This requires adaptive RCTs that include large integrative omics analyses. There is a parallel need to develop alternative methods to deliver FMTs that are more suitable for children and avoid the obvious risks associated with performing endoscopies that need anaesthesia. Oral capsules seem to be an attractive option, but may not be feasible for young children. Enemas are often less tolerated in children and have lower retention time. However, alternative techniques have been reported. For example, one paper has described colonic transendoscopic enteral tubing, which limits the amount of anaesthesia needed to insert multiple FMTs by colonoscopy. The probe is fixed with clips during the colonoscopy and can be used until the clips fall out.9 In conclusion, FMT appears to be effective against recurrent C. difficile in children, but there are still many issues to consider when conducting FMT in paediatric patients. These particularly include the uniformity of transplant protocols, the route of administration, donor selection, the frequency of treatment cycles and the long-term effects. We definitely need well-designed RCTs to assess the effect of FMT treatment on recurrent C. difficile and other conditions, such as inflammatory bowel disease, irritable bowel syndrome and neurological and neuropsychiatric disorders in children. Thomas Abrahamsson: Conceptualization; writing – original draft; writing – review and editing. None.

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Microbiome Fecal microbiota transplantation is a successful way of treating the distressing symptoms of irritable bowel disease or Clostridium difficile infection. The procedure is done by administering a concentrate of colonic bacteria from a healthy donor. Li et al. used metagenomic data to look at single-nucleotide variants after transplants in humans. Donor and recipient strains coexisted for at least 3 months. Some donor strains replaced related strains of the same species, but totally novel species from a donor were unlikely to thrive in a recipient. Rational design of personalized fecal transplant “cocktails” will therefore rely on resolution beyond the species level. Science , this issue p. [586][1] [1]: /lookup/doi/10.1126/science.aad8852

Repeated Courses of Orally Administered Fecal Microbiota Transplantation for the Treatment of Steroid Resistant and Steroid Dependent Intestinal Acute Graft Vs. Host Disease: A Pilot Study (NCT 03214289)

Fecal microbiota transplantation (FMT), also known as fecal bacteriotherapy or fecal infusion, consists of injection of a liquid filtrate of feces from a healthy donor into the gastrointestinal tract of a recipient individual. FMT has been proposed as a therapeutic approach for functional diseases of the gastrointestinal tract by reestablishment of a wide diversity of intestinal flora. Clostridium difficile infection (CDI) treatment guideline from American Gastroenterology Association (AGA) recommends that FMT can be used as the treatment protocols of relapse CDI. Numerous case reports, retrospective case series, and randomized controlled trials have shown the benefit of FMT in patients with functional bowel disorders, including inflammatory bowel disease, irritable bowel syndrome and constipation, etc. Evidence regarding the safety of FMT is relatively limited because the very rapid adoption of FMT as a therapeutic modality for CDI occurred before the performance of large, long prospective trials that are typically conducted to assess the safety of new interventions. Potential adverse events can be categorized as short-term and long-term, and short-term events can further be divided into those related to the method of FMT delivery (colonoscopy, sedation) and those related to the FMT itself. Due to the recent emergence of FMT, little data exist regarding long-term events and many safety concerns are speculative. Capsulized FMT therapy solves the clinical problems associated with the use of fresh FMT suspensions for long-term maintenance i.e. repeat transplantation and invasive procedures, which is of great significance to optimize the traditional FMT clinical strategy. Future work will focus on establishing best practices and more robust safety data than exist currently, as well as refining FMT beyond current "whole-stool" transplants to increase safety and tolerability. Encapsulated formulations, full-spectrum stool-based products, and defined microbial consortia are all in the immediate future. Although challenges exist, regulatory agencies have been willing to work with stakeholders and will continue to evolve and adapt policy as therapeutics based on human gut microbiota research emerge.

393 Non-GI Related Healthcare Utilization of Adolescents With Irritable Bowel Syndrome: The Effect of a Behavioral Intervention