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Introduction. At the present time there is increase the number of patients diagnosed with pseudomembranous colitis due to Clostridiodes difficile, respectively it significantly increases the frequency of hospitalizations, the length of hospital stay and the cost of treatment. Approved drug methods for correcting a pathological condition are not always able to lead to recovery after the first use, repeated and prolonged courses of therapy are often required, especially with recurrent Clostridiodes difficile. An alternative way of treatment is fecal microbiota transplantation from a donor. Nowadays, fecal microbiota transplantation is included in national clinical guidelines in several countries in Europe, the USA and Australia. In Russia this method has not been registered, however, there are some publications about its successful application in gastrointestinal diseases, oncohematology, and some autoimmune diseases. Aim. To show the result of successful treatment of severe pseudomembranous colitis after a single fecal microbiota transplantation.Material and methods. Outpatient treatment of an acute respiratory infection with a broad-spectrum antibacterial drug caused the development of severe pseudomembranous colitis in a young patient. Standard courses of metronidazole and vancomycin were unsuccessful. Transplantation of fecal microbiota from a donor was performed via ileocolonoscopy.Results. A single fecal microbiota transplantation contributed to the patient's complete recovery, short term rehabilitation and the absence of recurrence of Clostridiodes difficile within two years. Conclusions. Evidence-based medicine has shown the high efficiency of fecal microbiota transplantation. In Russia a legislative basis is needed for including fecal microbiota transplantation in clinical guidelines for the treatment of severe Clostridiodes difficile resistant to standard therapy. ; Введение. В настоящее время отмечен прирост числа пациентов, у которых диагностирован псевдомембранозный колит, вызванный Clostridiodes difficile, что значительно увеличивает частоту госпитализаций, срок пребывания пациентов в стационаре, затраты на их лечение. Известные медикаментозные способы коррекции патологического состояния не всегда способны привести к выздоровлению после первого курса лечения – зачастую требуются повторные и длительные курсы терапии, особенно при рецидиве псевдомембранозного колита. Альтернативным способом лечения является трансплантация фекальной микробиоты (ТФМ) от донора. В настоящее время ТФМ включена в национальные клинические руководства в ряде стран Европы, США, Китае и Австралии. В России данный метод не зарегистрирован, однако имеются отдельные публикации о его успешном применении при ряде заболеваний желудочнокишечного тракта, онкогематологических, аутоиммунных заболеваниях. Цель работы. Показать результат успешного лечения тяжёлого псевдомембранозного колита после процедуры трансплантации фекальной микробиоты от донора.Материал и методы. Амбулаторное лечение острой респираторной инфекции антибактериальным препаратом широкого спектра действия привело к развитию тяжёлого псевдомембранозного колита у пациентки молодого трудоспособного возраста. Стандартная медикаментозная терапия метронидазолом и ванкомицином была безуспешна. Во время илеоколоноскопии выполнена трансплантация фекальной микробиоты от донора.Результаты. Однократная процедура фекальной трансплантации способствовала полному выздоровлению пациентки, быстрой реабилитации, отсутствию рецидива псевдомембранозного колита в течение более 2 лет наблюдения.Заключение. С позиции доказательной медицины в настоящее время показана высокая эффективность метода трансплантации фекальной микробиоты, однако в России необходима законодательная база для введения данного метода лечения с его включением в клинические рекомендации для лечения тяжёлых форм клостридиальной инфекции, резистентной к стандартной терапии, и при рецидиве инфекции.

Growing evidence implicates the gut microbiome in cognition. Viruses, the most abundant life entities on the planet, are a commonly overlooked component of the gut virome, dominated by the Caudovirales and Microviridae bacteriophages. Here, we show in a discovery (n = 114) and a validation cohort (n = 942) that subjects with increased Caudovirales and Siphoviridae levels in the gut microbiome had better performance in executive processes and verbal memory. Conversely, increased Microviridae levels were linked to a greater impairment in executive abilities. Microbiota transplantation from human donors with increased specific Caudovirales (>90% from the Siphoviridae family) levels led to increased scores in the novel object recognition test in mice and up-regulated memory-promoting immediate early genes in the prefrontal cortex. Supplementation of the Drosophila diet with the 936 group of lactococcal Siphoviridae bacteriophages resulted in increased memory scores and upregulation of memory-involved brain genes. Thus, bacteriophages warrant consideration as novel actors in the microbiome-brain axis. ; This work was partially funded by the Instituto de Salud Carlos III (Madrid, Spain) through the project PI15/01934, PI18/01022, PI21/01361) to J.M.F.-R. and the project PI20/01090 (co-funded by the European Regional Development Fund . "A way to make Europe") to J.M.-P., the grants SAF2015-65878-R from the Ministry of Economy and Competitiveness , Prometeo/2018/A/133 from Generalitat Valenciana, Spain and also by the Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013- 602891 ), the Catalan Government (AGAUR, #SGR2017-669 , #2017 SGR- 734, ICREA Academia Award 2015 to R.M. and ICREA Academia Award 2022 to J.M.F.R.), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020 ), the European Regional Development Fund (project No. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT), and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). CIBERobn is also co-funded by the European Regional Development Fund. We also acknowledge the funding from the Spanish Ministry of Science, Innovation and Universities ( RTI2018-099200-B-I00 ), and the Generalitat of Catalonia (Agency for Management of University and Research grants ( 2017SGR696 ) and Department of Health (SLT002/16/00250)) to R.M M.A.-R. is funded by the Instituto de Salud Carlos III , Río Hortega ( CM19/00190 ). J.M.-P. is funded by the Miguel Servet Program from the Instituto de Salud Carlos III ( ISCIII CP18/00009 ), co-funded by the European Social Fund "Investing in your future." A.C.-N. is funded by the Instituto de Salud Carlos III , Sara Borrell. MMG was funded by the Spanish Ministry of Science, Innovation and Universities RTI2018-094248-B-I00.

Growing evidence implicates the gut microbiome in cognition. Viruses, the most abundant life entities on the planet, are a commonly overlooked component of the gut virome, dominated by the Caudovirales and Microviridae bacteriophages. Here, we show in a discovery (n = 114) and a validation cohort (n = 942) that subjects with increased Caudovirales and Siphoviridae levels in the gut microbiome had better performance in executive processes and verbal memory. Conversely, increased Microviridae levels were linked to a greater impairment in executive abilities. Microbiota transplantation from human donors with increased specific Caudovirales (>90% from the Siphoviridae family) levels led to increased scores in the novel object recognition test in mice and up-regulated memory-promoting immediate early genes in the prefrontal cortex. Supplementation of the Drosophila diet with the 936 group of lactococcal Siphoviridae bacteriophages resulted in increased memory scores and upregulation of memory-involved brain genes. Thus, bacteriophages warrant consideration as novel actors in the microbiome-brain axis. ; This work was partially funded by the Instituto de Salud Carlos III (Madrid, Spain) through the project PI15/01934, PI18/01022, PI21/01361) to J.M.F.-R. and the project PI20/01090 (co-funded by the European Regional Development Fund. "A way to make Europe") to J.M.-P., the grants SAF2015-65878-R from the Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain and also by the Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, #2017 SGR- 734, ICREA Academia Award 2015 to R.M. and ICREA Academia Award 2022 to J.M.F.R.), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the European Regional Development Fund (project No. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT), and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). CIBERobn is also co-funded by the European Regional Development Fund. We also acknowledge the funding from the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia (Agency for Management of University and Research grants (2017SGR696) and Department of Health (SLT002/16/00250)) to R.M M.A.-R. is funded by the Instituto de Salud Carlos III, Río Hortega (CM19/00190). J.M.-P. is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund "Investing in your future." A.C.-N. is funded by the Instituto de Salud Carlos III, Sara Borrell. MMG was funded by the Spanish Ministry of Science, Innovation and Universities RTI2018-094248-B-I00.

Worldwide, there is a rising demand for thoroughly screened, high-quality fecal microbiota transplantation (FMT) products that can be obtained at a reasonable cost. In the light of this evolving therapeutic area of the intestinal microbiota, both private and public stool banks have emerged. However, some of the larger difficulties when establishing stool banks are caused by the absence of or international disagreement on regulation and legislative formalities. In this context, the establishment of a stool bank within a nonprofit blood and tissue transplant service has several advantages. Especially, this setting can ensure that every step of the donation process, laboratory handling, and donor-traceability is in agreement with the current expert guidelines and meets the requirements of the European Union's regulative directives on human cells and tissues. Although safety and documentation are the top priority of the stool bank setup presented here, cost-effectiveness of the production is possible due to a high donor screening success rate and the knowhow, infrastructure, facilities, personnel, and laboratory- and quality-management systems that were already in place. Overall, our experience is that a centralized, nonprofit, blood and tissue transplant service is an ideal and safe facility to run a stool bank of high quality FMT products that are based on stool donations from volunteer, unpaid, healthy, blood donors.

Since Ilya Metchnikoff's studies, both medical science and clinical practice have accumulated a large amount of evidence that human intestinal microbiota possesses a unique characteristics for our existence. However, only recently, scientists have achieved the actual breakthrough in this field of human physiology, and we start to understand the precise mechanisms of the complex interplay of microbial activity with human homeostasis and discover numerous new functions of intestinal microbes. In this regard, a novel medical technology evolves since 1958, so called fecal microbiota transplantation (FMT), which is the administration of donor feces to the patients suffering from different kinds of diseases. Such infusion of donor feces restores the natural balance of gut commensal germs. FMT is most efficacious in severe or recurrent Clostridium difficile infection. FMT has been also reported to cure diarrhea and constipation caused by different conditions, such as multiple sclerosis, Crohn 's disease etc. In the U.S. and Canada as well as in other countries FMT is of uttermost interest of not merely clinical practitioners but lately also of regulatory authorities. The paper also addresses the possibility of application the Russian pharmaceutical legislation to FMT. ; Начиная с работ Ильи Мечникова, в медицинской науке и практике накоплено большое количество доказательств влияния состояния кишечной микробиоты на здоровье человека. Однако лишь в последние годы в исследованиях в этой области произошел качественный перелом: мы стали понимать механизмы влияния микробиоты на гомеостаз, а также выяснять все новые функции живущих в нас микроорганизмов. На этом фоне с 1958 г. развивается трансплантация фекальной микробиоты (ТФМ) от здоровых доноров пациентам с различными заболеваниями, которая восстанавливает нарушенный баланс кишечных микроорганизмов. Наибольшую эффективность данный метод проявляет при терапии тяжелых кишечных инфекций, вызываемых Clostridium difficile. Также ТФМ показала потенциальную эффективность при диарее и запоре различного генеза, рассеянном склерозе, болезни Крона и др. В США, Канаде и других странах ТФМ является предметом интереса не только врачей-клиницистов, но и с недавних пор - регуляторных, органов. В статье также рассматривается возможность применения российского законодательства в сфере обращения лекарственных средств к этому новому методу.

BACKGROUND: Fecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of feces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council. OBJECTIVE: Several European and international consensus statements concerning fecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document. METHODS: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about fecal microbiota transplantation. RESULTS: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening. CONCLUSION: The implementation of fecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor feces preparations for patients.

BACKGROUND: Fecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of feces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council. OBJECTIVE: Several European and international consensus statements concerning fecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document. METHODS: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about fecal microbiota transplantation. RESULTS: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening. CONCLUSION: The implementation of fecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor feces preparations for patients.

Inflammatory bowel disease; Faecal microbiota transplantation; Rat model of colitis ; Enfermedad inflamatoria intestinal; Trasplante de microbiota fecal; Modelo de colitis en ratas ; Malaltia inflamatòria intestinal; Trasplantament de microbiota fecal; Model de colitis en rates ; Background: Faecal microbiota transplantation (FMT) is a novel potential therapy for inflammatory bowel diseases, but it is poorly characterised. Methods: We evaluated the performance of the mouse and rat as a pre-clinical model for human microbiota engraftment. We then characterised the effect of a single human stool transfer (HST) on a humanised model of DSS-induced colitis. Colonic and faecal microbial communities were analysed using the 16S rRNA approach and clinical manifestations were assessed in a longitudinal setting. Findings: The microbial community of rats showed greater similarity to that of humans, while the microbiome of mice showed less similarity to that of humans. Moreover, rats captured more human microbial species than mice after a single HST. Using the rat model, we showed that HST compensated faecal dysbiosis by restoring alpha-diversity and by increasing the relative abundance of health-related microbial genera. To some extent, HST also modulated the microbial composition of colonic tissue. These faecal and colonic microbial communities alterations led to a relative restoration of colon length, and a significant decrease in both epithelium damage and disease severity. Remarkably, stopping inflammation by removing DSS before HST caused a faster and greater recovery of both microbiome and clinical manifestation features. Interpretation: Our results indicate that the rat outperforms the mouse as a model for human microbiota engraftment and show that the efficacy of HST can be enhanced when inflammation stimulation is withdrawn. Finally, our findings support a new therapeutic strategy based on the use FMT combined with anti inflammatory drugs. ; Study funded by the Instituto de Salud Carlos III/FEDER (PI17/00614), a government agency. The funder had no role in study design, data collection, data analysis, interpretation or writing of the report.

Brieuc Van Nieuwenhuyse1, Dimitri Van der Linden1,2, Olga Chatzis2, Cédric Lood3,4, Jeroen Wagemans3, Rob Lavigne4, Catherine de Magnée5, Étienne Sokal1,6, Hector Rodriguez-Villalobos7, Sarah Djebara8, Maya Merabishvili9, Patrick Soentjens8, Jean-Paul Pirnay9. 1Institute of Experimental and Clinical Research's Pediatric department, UCLouvain, Brussels, Belgium; 2Pediatric Infectious Diseases, General Pediatrics Department, Cliniques universitaires Saint-Luc, Brussels, Belgium; 3Department of Biosystems, Laboratory of Gene Technology, KULeuven, Leuven, Belgium; 4Department of Microbial and Molecular Systems, Centre of Microbial and Plant Genetics, KULeuven, Leuven, Belgium; 5Pediatric and Transplantation Surgery, Cliniques universitaires Saint-Luc, Brussels, Belgium; 6Pediatric Hepatology and Gastro-enterology, Cliniques universitaires Saint-Luc, Brussels, Belgium; 7Department of Microbiology, Cliniques universitaires Saint-Luc, Brussels, Belgium; 8Center for Infectious Diseases, Queen Astrid Military Hospital, Brussels, Belgium; 9Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, Belgium A 14-month old boy undergoes a first liver transplantation (LT) (Day 0), from an ABO-incompatible living donor. On D+20, we detect a fecal carriage of an extensively drug-resistant (XDR) Pseudomonas aeruginosa (Pa) strain. Besides intermediate susceptibility to aztreonam and colistin and susceptibility to gentamycin, the strain is resistant to all other antibiotics. On D+53, the child enters a severe septic state due to a bacteremia with the same Pa strain. New antibiogram suggests a resistance to colistin. Liver bilomas' drainage material is cultured and grows the same Pa strain. Admission to the pediatric intensive care unit and adjunction of intravenous (IV) aztreonam, gentamycin, and colistin led to no improvement on the microbiological or clinical levels during the next four days. By collaborating with Queen Astrid Military Hospital (Brussels, Belgium), we initiated phage therapy (PT) on D+57 in accordance to the Article 37 of the Declaration of Helsinki and with the patient's parents' consent. PT is the use of lytic bacteriophage viruses to achieve antibacterial effect. Phage cocktail BFC1 contains two anti-Pa phages (PNM and 14/1) and one anti-Staphylococcus aureus phage (ISP). BFC1 was administered in situ by instillations through biliary catheter during six days, and in IV for 86 days (72 days until 2nd LT, 14 days afterwards), the longest described duration for IV PT in a child. Previous antibiotic therapy was pursued all along. Intraoperative PT was performed during 2nd LT by bathing the peritoneal cavity in phage solution during the anhepatic phase. To further our understanding of the case, seven Pa isolates, both bloodborne and liver-borne, were sequenced. Serum samples obtained before, during, and after phage therapy were analyzed through double agar overlay method to search for phage immune neutralization (PIN). Phage-induced virulence tradeoffs (PIVT) assays were performed in a Galleria mellonella model. In vitro phage-antibiotic interactions were evaluated with OmniLog® system. PT initiation was followed by immediate (<24 h) eradication of Pa from blood cultures. Reappearance of Pa in blood cultures after four days of PT led to a doubling of the PT dose, which was followed by eradication of Pa from bloodstream until 2nd LT. The child has known no further infectious episode since then. Sequencing confirmed the emergence of bacterial phage resistance (BPR) in four isolates. Such BPR did not lead to therapeutic failure, possibly thanks to PIVT. PIN against phage ISP was detected, but not against any anti-Pa phage. OmniLog® assays suggested synergistic properties between phage PNM and three antibiotics administered concomitantly to the patient. In conclusion, prolonged IV phage therapy combined with antibiotics led to the durable eradication of an XDR Pa sepsis in an immunosuppressed 14-month old boy, eventually allowing for 2nd LT. This possibly relied on synergy between phages and antibiotics. This combined therapy was safe.