Fecal microbiota transplantation: current challenges and future landscapes.

SUMMARYGiven the importance of gut microbial homeostasis in maintaining health, there has been considerable interest in developing innovative therapeutic strategies for restoring gut microbiota. One such approach, fecal microbiota transplantation (FMT), is the main "whole gut microbiome replacement" strategy and has been integrated into clinical practice guidelines for treating recurrent Clostridioides difficile infection (rCDI). Furthermore, the potential application of FMT in other indications such as inflammatory bowel disease (IBD), metabolic syndrome, and solid tumor malignancies is an area of intense interest and active research. However, the complex and variable nature of FMT makes it challenging to address its precise functionality and to assess clinical efficacy and safety in different disease contexts. In this review, we outline clinical applications, efficacy, durability, and safety of FMT and provide a comprehensive assessment of its procedural and administration aspects. The clinical applications of FMT in children and cancer immunotherapy are also described. We focus on data from human studies in IBD in contrast with rCDI to delineate the putative mechanisms of this treatment in IBD as a model, including colonization resistance and functional restoration through bacterial engraftment, modulating effects of virome/phageome, gut metabolome and host interactions, and immunoregulatory actions of FMT. Furthermore, we comprehensively review omics technologies, metagenomic approaches, and bioinformatics pipelines to characterize complex microbial communities and discuss their limitations. FMT regulatory challenges, ethical considerations, and pharmacomicrobiomics are also highlighted to shed light on future development of tailored microbiome-based therapeutics.

Fine-tuning the gut ecosystem: the current landscape and outlook of artificial microbiome therapeutics.

The gut microbiome is acknowledged as a key determinant of human health, and technological progress in the past two decades has enabled the deciphering of its composition and functions and its role in human disorders. Therefore, manipulation of the gut microbiome has emerged as a promising therapeutic option for communicable and non-communicable disorders. Full exploitation of current therapeutic microbiome modulators (including probiotics, prebiotics, and faecal microbiota transplantation) is hindered by several factors, including poor precision, regulatory and safety issues, and the impossibility of providing reproducible and targeted treatments. Artificial microbiota therapeutics (which include a wide range of products, such as microbiota consortia, bacteriophages, bacterial metabolites, and engineered probiotics) have appeared as an evolution of current microbiota modulators, as they promise safe and reproducible effects, with variable levels of precision via different pathways. We describe the landscape of artificial microbiome therapeutics, from those already on the market to those still in the pipeline, and outline the major challenges for positioning these therapeutics in clinical practice.

Donor screening for fecal microbiota transplantation with a direct stool testing-based strategy: a prospective cohort study.

Fecal microbiota transplantation (FMT) is effective against recurrent Clostridioides difficile infection (rCDI), but its safety is jeopardized by the potential transmission of pathogens, so international guidelines recommend either a quarantine or a direct stool testing. Whereas reports of the quarantine-based approach are emerging, data on the direct testing-based approach are not available. Our aim is to report outcomes of a donor screening framework for FMT including direct stool testing. In this prospective cohort study, all donor candidates recruited at our FMT centre underwent a four-step screening process to be enrolled as actual donors. Each collected stool donation was then evaluated with a direct stool testing including a molecular assay for gut pathogens and a culture assay for multi-drug resistant organisms (MDRO). From January 2019 to June 2023, 72 of 227 candidates (32%) were considered eligible and provided 277 stool donations. Ninety-nine donations (36%) were discarded for positivity to intestinal pathogens, most commonly enteropathogenic Escherichia coli (n = 37) and Blastocystis hominis (n = 20). Overall, 337 stool aliquots were obtained from 165 approved donations. All suspensions were used for patients with rCDI, and no serious adverse events or clinically evident infections were observed at 12 weeks after procedures. In our study, screening of donor faeces including direct stool testing led to the discard of a considerable rate of stool donations but was also extremely safe. This approach may represent a reliable strategy to guarantee the safety of FMT programs, especially in countries with high prevalence of MDRO.

Probiotic mixture in patients after Helicobacter pylori eradication: a real-life experience.

BACKGROUND: Eradication for Helicobacter pylori usually induces digestive dysbiosis that, in turn, elicits symptoms. Consequently, probiotic supplementation may counterbalance the disturbed microbiota after this procedure. So, probiotics may restore microbiota homeostasis quickly relieve complaints. METHODS: The current study evaluated the efficacy and safety of Abivisor®, a food supplement containing Lacticaseibacillus rhamnosus LR06 (3 billion living cells), Lactiplantibacillus pentosus LPS01(100 million living cells), Lactiplantibacillus plantarum LP01 (1 billion living cells), and N-acetyl cysteine (60 mg). Patients were randomized into two groups (2:1). Group A took one stick/daily for 60 days after eradication. Group B was considered as control. Patients were evaluated at baseline (T0) and after 15 (T1), 30 (T2), and 60 (T3) days. The severity of digestive symptoms was measured by patients using a Visual Analog Scale. The percentage of patients with each symptom was also evaluated. RESULTS: Abivisor® has significantly and progressively diminished intestinal symptoms' presence and severity at T1, T2, and even more at T3. Accordingly, the percentage of symptomatic patients diminished more rapidly and significantly in group A than in B. All patients well tolerated the food supplement. CONCLUSIONS: The present study suggests that Abivisor® may be an effective and safe therapeutic option for managing patients undergoing H. pylori eradication.

Micro(nano)plastics and Their Potential Impact on Human Gut Health: A Narrative Review.

Microplastics and nanoplastics (MNPs) are becoming an increasingly severe global problem due to their widespread distribution and complex impact on living organisms. Apart from their environmental impact, the effects of MNPs on living organisms have also continued to attract attention. The harmful impact of MNPs has been extensively documented in marine invertebrates and larger marine vertebrates like fish. However, the research on the toxicity of these particles on mammals is still limited, and their possible effects on humans are poorly understood. Considering that MNPs are commonly found in food or food packaging, humans are primarily exposed to them through ingestion. It would be valuable to investigate the potential harmful effects of these particles on gut health. This review focuses on recent research exploring the toxicological impacts of micro- and nanoplastics on the gut, as observed in human cell lines and mammalian models. Available data from various studies indicate that the accumulation of MNPs in mammalian models and human cells may result in adverse consequences, in terms of epithelial toxicity, immune toxicity, and the disruption of the gut microbiota. The paper also discusses the current research limitations and prospects in this field, aiming to provide a scientific basis and reference for further studies on the toxic mechanisms of micro- and nanoplastics.

Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms.

The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to suboptimal treatment. This is due to the lack of appropriate molecular markers that can guide patients toward the best therapeutic options. Here, we assess and confirm subtype-specific markers for IPMN across two independent cohorts of patients using two Spatial Transcriptomics (ST) technologies. Specifically, we identify HOXB3 and ZNF117 as markers for Low-Grade Dysplasia, SPDEF and gastric neck cell markers in borderline cases, and NKX6-2 and gastric isthmus cell markers in High-Grade-Dysplasia Gastric IPMN, highlighting the role of TNFα and MYC activation in IPMN progression and the role of NKX6-2 in the specific Gastric IPMN progression. In conclusion, our work provides a step forward in understanding the gene expression landscapes of IPMN and the critical transcriptional networks related to PDAC progression.

Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis: Clinical Protocol and Evaluation of Microbiota Immunity Axis.

The fecal microbial transplantation (FMT) is a therapeutic transplant of fecal microbiota from healthy donors to patients. This practice is aimed at restoring eubiosis and rebalancing the enteric and systemic immune responses, and then eliminating pathogenic triggers of multiple disease, including neurodegenerative diseases. Alterations of gut microbiota (GM) affect the central nervous system (CNS) health, impacting neuro-immune interactions, synaptic plasticity, myelination, and skeletal muscle function. T-regulatory lymphocytes (Treg) are among the most important players in the pathogenesis of amyotrophic lateral sclerosis (ALS), altering the disease course. Along with circulating neuropeptides, other immune cells, and the gut-brain axis, the GM influences immunological tolerance and controls Treg's number and suppressive functions. A double-blind, controlled, multicenter study on FMT in ALS patients has been designed to evaluate if FMT can modulate neuroinflammation, by restoring Treg number, thus modifying disease activity and progression.

The Role of Diet and Nutritional Interventions for the Infant Gut Microbiome.

The infant gut microbiome plays a key role in the healthy development of the human organism and appears to be influenced by dietary practices through multiple pathways. First, maternal diet during pregnancy and infant nutrition significantly influence the infant gut microbiota. Moreover, breastfeeding fosters the proliferation of beneficial bacteria, while formula feeding increases microbial diversity. The timing of introducing solid foods also influences gut microbiota composition. In preterm infants the gut microbiota development is influenced by multiple factors, including the time since birth and the intake of breast milk, and interventions such as probiotics and prebiotics supplementation show promising results in reducing morbidity and mortality in this population. These findings underscore the need for future research to understand the long-term health impacts of these interventions and for further strategies to enrich the gut microbiome of formula-fed and preterm infants.

Fecal Microbiota Transplantation as Emerging Treatment in European Countries 2.0.

Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections and one of the leading causes of morbidity and mortality in hospitalized patients in the world. Although several antibiotics effectively treat CDI, some individuals may not respond to these drugs and may be cured by transplanting stool from healthy donors. FMT has demonstrated extraordinary cure rates for the cure of CDI recurrences.Moreover, FMT has also been investigated in other disorders associated with the alteration of gut microbiota, such as inflammatory bowel disease (IBD), where the alterations of the gut microbiota ecology have been theorized to play a causative role. Although FMT is currently not recommended to cure IBD patients in clinical practice, several studies have been recently carried out with the ultimate goal to search new therapeutic options to patients.This review summarizes data on the use of FMT for the treatment of both CDI and IBD, with a special attention to highlight studies conducted in European countries.

Henoch-schonlein purpura following exposure to SARS-CoV2 vaccine or infection: a systematic review and a case report.

BACKGROUND: Henoch-Schonlein purpura (HSP) is an IgA-mediated systemic small-vessel vasculitis (IgAV) that typically presents with a variable tetrad of symptoms. HSP if often preceded by respiratory tract infections, vaccinations, drugs or malignancies. During the recent COVID-19 pandemic multiples cases of HSP have been described after both infection and vaccination for SARS-CoV2. This study aims to perform a systematic review of literature and describe an additional complicated case of de-novo HSP appeared after the administration of the third dose of a mRNA-SARS-CoV2 vaccination. METHODS: Electronic bibliographic research was performed to identify all the original reports describing cases of de-novo HSP or IgAV appeared after respiratory infection or vaccine administration for SARS-CoV2. We included all case series or case reports of patients who respected our inclusion and exclusion criteria. RESULTS: Thirty-eight publications met our pre-defined inclusion criteria, for an overall number of 44 patients. All patients presented with palpable purpura variable associated with arthralgia, abdominal pain or renal involvement. Increased levels of inflammation markers, mild leukocytosis and elevated D-dimer were the most common laboratory findings. Up to 50% of patients presented proteinuria and/or hematuria. Almost all skin biopsies showed leukocytoclastic vasculitis, with IgA deposits at direct immunofluorescence in more than 50% of cases. CONCLUSIONS: Our results suggest that the immune response elicited by SARS-CoV2 vaccine or infection could play a role in the development of HSP. Current research suggests a possible role of IgA in immune hyperactivation, highlighted by early seroconversion to IgA found in some COVID-19 patients who develop IgA vasculitis.

Gut microbiota and immunotherapy of renal cell carcinoma.

The gut microbiome has recently been proposed as a key player in cancer development and progression. Several studies have reported that the composition of the gut microbiome plays a role in the response to immune checkpoint inhibitors (ICIs). The gut microbiome modulation has been investigated as a potential therapeutic strategy for cancer, mainly in patients undergoing therapy with ICIs. In particular, modulation through probiotics, FMT or other microbiome-related approaches have proven effective to improve the response to ICIs. In this review, we examine the role of the gut microbiome in enhancing clinical responses to ICIs in the treatment of renal cancer.

Serial Fecal Microbiota Infusions via Colonoscopy for Active Ulcerative Colitis: A Feasibility, Safety, and Translational Monocentric Italian Study.

The effectiveness of fecal microbiota transplantation (FMT) in ulcerative colitis (UC) remains unclear. This study aimed to investigate the feasibility and effectiveness of serial fecal infusions via colonoscopy in patients with active UC. Subjects with mild-to-moderate UC received three consecutive fecal infusions via colonoscopy. A control population with the same baseline features receiving Infliximab treatment was enrolled. Adverse events and clinical, endoscopic, and microbial outcomes were investigated. Nineteen patients with mildly-to-moderately active UC were enrolled. Clinical response was obtained in six patients at week 2, in eight at week 6, and in nine at week 12. Clinical response was maintained in eight patients at week 24. Endoscopic remission at week 12 was reached in six patients. In the control population, 13/19 patients achieved clinical response at week 6, and 10/19 patients maintained clinical response after 6 months. Microbiota richness was higher in responders compared with the non-responders. Peptostreptococcus, Lactobacillus, and Veillonella were higher in non-responders, while Parabacteroides, Bacteroides, Faecalibacterium, and Akkermansia were higher in responders at all timepoints. Serial FMT infusions appear to be feasible, safe, and effective in UC patients, with a potential role in inducing and maintaining clinical response. Specific bacteria predict the response to FMT.

Histamine-producing bacteria and their role in gastrointestinal disorders.

INTRODUCTION: Gut microbiota produces thousands of metabolites, which have a huge impact on the host health. Specific microbial strains are able to synthesize histamine, a molecule with a crucial role in many physiologic and pathologic mechanisms of the host. This function is mediated by the histidine decarboxylase enzyme (HDC) that converts the amino acid histidine to histamine. AREAS COVERED: This review summarizes the emerging data on histamine production by gut microbiota, and the effect of bacterial-derived histamine in different clinical contexts, including cancer, irritable bowel syndrome, and other gastrointestinal and extraintestinal pathologies. This review will also outline the impact of histamine on the immune system and the effect of probiotics that can secrete histamine. Search methodology: we searched the literature on PubMed up to February 2023. EXPERT OPINION: The potential of modulating gut microbiota to influence histamine production is a promising area of research, and although our knowledge of histamine-secreting bacteria is still limited, recent advances are exploring their diagnostic and therapeutical potential. Diet, probiotics, and pharmacological treatments directed to the modulation of histamine-secreting bacteria may in the future potentially be employed in the prevention and management of several gastrointestinal and extraintestinal disorders.

Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota.

Short-chain fatty acids (SCFAs) play a key role in health and disease, as they regulate gut homeostasis and their deficiency is involved in the pathogenesis of several disorders, including inflammatory bowel diseases, colorectal cancer, and cardiometabolic disorders. SCFAs are metabolites of specific bacterial taxa of the human gut microbiota, and their production is influenced by specific foods or food supplements, mainly prebiotics, by the direct fostering of these taxa. This Review provides an overview of SCFAs' roles and functions, and of SCFA-producing bacteria, from their microbiological characteristics and taxonomy to the biochemical process that lead to the release of SCFAs. Moreover, we will describe the potential therapeutic approaches to boost the levels of SCFAs in the human gut and treat different related diseases.

Fecal microbiota transplantation for recurrent Clostridioides difficile infection in frail and very old patients.

BACKGROUND: Older age is a well-known risk factor for recurrent and severe Clostridioides difficile infection (CDI). Fecal microbiota transplantation (FMT) is widely recognized as an effective and safe therapeutic option for the treatment of recurrent CDI (rCDI). However, the efficacy and safety of FMT for rCDI in very old patients are uncertain. This study evaluated the efficacy and safety of FMT in a group of very old subjects with rCDI, and the reliability of overall comorbidity and frailty assessment for identifying patients at higher risk of worse clinical outcomes. METHODS: This is a retrospective single-center study including patients ≥85 years undergoing FMT for rCDI between 2014 and 2022. Primary outcomes included efficacy of FMT, defined as cure of CDI at 8 week-follow-up, and safety evaluation. At baseline, comorbidity was measured with the Charlson Comorbidity Index (CCI). Frailty was measured with the Clinical Frailty Scale (CFS). RESULTS: Overall, 43 patients with a median age of 88 years underwent FMT by colonoscopy in the study period. The rate of first FMT success was 77%. Five of the 10 patients who failed the first FMT infusion were cured after repeat FMT, with an overall efficacy of 88%. In patients with successful treatment, the CFS was significantly lower compared to those who failed the FMT or underwent repeat FMT (p < 0.01 for both). Mild adverse events occurred in 11 patients (25%). One death, not related to FMT or rCDI, occurred within 7 days from the first procedure. CONCLUSIONS: FMT is effective and safe in very old patients. Frailty and high comorbidity do not limit use of FMT in these patients. Frailty assessment has potential to better identify patients at higher risk of worse outcomes or for repeat treatment with FMT.

The first international Rome consensus conference on gut microbiota and faecal microbiota transplantation in inflammatory bowel disease.

BACKGROUND: Several randomised clinical trials (RCTs) performing faecal microbiota transplantation (FMT) for the management of inflammatory bowel disease (IBD), particularly for ulcerative colitis, have recently been published, but with major variations in study design. These include differences in administered dose, route and frequency of delivery, type of placebo and evaluated endpoints. Although the overall outcomes appear to be promising, they are highly dependent on both donor and recipient factors. OBJECTIVE: To develop concensus-based statements and recommendations for the evaluation, management and potential treatment of IBD using FMT in order to move towards standardised practices. DESIGN: An international panel of experts convened several times to generate evidence-based guidelines by performing a deep evaluation of currently available and/or published data. Twenty-five experts in IBD, immunology and microbiology collaborated in different working groups to provide statements on the following key issues related to FMT in IBD: (A) pathogenesis and rationale, (B) donor selection and biobanking, (C) FMT practices and (D) consideration of future studies and perspectives. Statements were evaluated and voted on by all members using an electronic Delphi process, culminating in a plenary consensus conference and generation of proposed guidelines. RESULTS AND CONCLUSIONS: Our group has provided specific statements and recommendations, based on best available evidence, with the end goal of providing guidance and general criteria required to promote FMT as a recognised strategy for the treatment of IBD.

Key determinants of success in fecal microbiota transplantation: From microbiome to clinic.

Fecal microbiota transplantation (FMT) has achieved satisfactory results in preventing the recurrence of Clostridioides difficile infection, but these positive outcomes have only been partially replicated in other diseases. Several factors influence FMT success, including those related to donors and recipients (including diversity and specific composition of the gut microbiome, immune system, and host genetics) as well as to working protocols (fecal amount and number of infusions, route of delivery, and adjuvant treatments). Moreover, initial evidence suggests that the clinical success of FMT may be related to the degree of donor microbial engraftment. The application of cutting-edge technologies for microbiome assessment, along with changes in the current vision of fecal transplants, are expected to improve FMT protocols and outcomes. Here, we review the key determinants of FMT success and insights and strategies that will enable a close integration of lab-based and clinical approaches for increasing FMT success.

Future Modulation of Gut Microbiota: From Eubiotics to FMT, Engineered Bacteria, and Phage Therapy.

The human gut is inhabited by a multitude of bacteria, yeasts, and viruses. A dynamic balance among these microorganisms is associated with the well-being of the human being, and a large body of evidence supports a role of dysbiosis in the pathogenesis of several diseases. Given the importance of the gut microbiota in the preservation of human health, probiotics, prebiotics, synbiotics, and postbiotics have been classically used as strategies to modulate the gut microbiota and achieve beneficial effects for the host. Nonetheless, several molecules not typically included in these categories have demonstrated a role in restoring the equilibrium among the components of the gut microbiota. Among these, rifaximin, as well as other antimicrobial drugs, such as triclosan, or natural compounds (including evodiamine and polyphenols) have common pleiotropic characteristics. On one hand, they suppress the growth of dangerous bacteria while promoting beneficial bacteria in the gut microbiota. On the other hand, they contribute to the regulation of the immune response in the case of dysbiosis by directly influencing the immune system and epithelial cells or by inducing the gut bacteria to produce immune-modulatory compounds, such as short-chain fatty acids. Fecal microbiota transplantation (FMT) has also been investigated as a procedure to restore the equilibrium of the gut microbiota and has shown benefits in many diseases, including inflammatory bowel disease, chronic liver disorders, and extraintestinal autoimmune conditions. One of the most significant limits of the current techniques used to modulate the gut microbiota is the lack of tools that can precisely modulate specific members of complex microbial communities. Novel approaches, including the use of engineered probiotic bacteria or bacteriophage-based therapy, have recently appeared as promising strategies to provide targeted and tailored therapeutic modulation of the gut microbiota, but their role in clinical practice has yet to be clarified. The aim of this review is to discuss the most recently introduced innovations in the field of therapeutic microbiome modulation.