The gut microbiota may influence Parkinson’s disease’s (PD) pathophysiology. Faecal Microbiota Transplantation (FMT) may therefore improve symptoms. We reviewed five randomized controlled trials (RCT), three cohort studies, one case series, and two single case reports (total of 236 subjects). FMT methods varied (donor selection, FMT preparation method, pre-treatment, administration). Mild, self-limiting gastrointestinal symptoms were the most common adverse events (AEs). Constipation improved consistently after FMT. Motor and non-motor outcomes were heterogeneous, with improvements mainly reported in uncontrolled studies. One RCT demonstrated motor improvement at 8-12 weeks, another only after one year, while others showed no significant changes. In most RCTs, changes fell within or just beyond the minimal clinically important differences (MCID). Five studies reported taxonomic shifts, most consistently increased within the phylum Firmicutes. Large, well-designed RCTs with optimized FMT protocol for patient selection, FMT preparation and delivery, and donor selection are needed to determine whether FMT can affect PD symptoms or disease progression.

BACKGROUND:Fecal microbiota transplantation (FMT) is validated for recurrent Clostridioides difficile infections but is increasingly considered for compassionate indications: steroid-refractory graft-versus-host disease (GVHD), multidrug-resistant organism (MDRO) eradication, severe inflammatory or infectious colitis. Evidence remains limited outside clinical trials. METHODS:Retrospective multicenter analysis of requests submitted to the French National Commission for compassionate FMT between 2019 and 2022. Approved cases were evaluated for feasibility, safety, and clinical outcomes. RESULTS:Among 67 requests, 54 were approved and 40 FMT procedures were performed. The main indications were severe steroid-resistant GVHD (35%), MDRO carriage (28%), and inflammatory/infectious colitis (12%). Overall success was 37.5%. The response rate for GVHD was 53% and 31% for MDRO eradication. Adverse events were mostly mild. CONCLUSIONS:Compassionate FMT in France is feasible through a centralized process but shows variable efficacy depending on the indication. GVHD seems to be the most promising target, while MDRO eradication and colitis require further evaluation.

Because few studies have focused on recurrent Campylobacter bacteremia, we investigated two clinical cases of patients with common variable immunodeficiency and repeated Campylobacter bacteremia over a period of 6–10 years. We analyzed and compared genomes from isolates obtained from both patients during follow-up. For patient #1, 18 isolates of Campylobacter coli and 17 isolates of Campylobacter jejuni were obtained from 2014 to 2024. For patient #2, 10 isolates of C. coli were obtained from 2019 to 2024. Next-generation sequencing was used to identify species, characterize antimicrobial resistance, perform multilocus sequence typing, and analyze core-genome single-nucleotide polymorphisms, as well as to uncover potential sources of contamination. For patient #1, all 18 C. coli isolates obtained from 2022 to 2024 were from the same clonal complex and source of contamination (chicken) and exhibited high levels of genomic resemblance based on core-genome single-nucleotide polymorphism analysis. Each C. coli isolate probably originated from the same initial strain. However, two clusters of C. jejuni were identified: one consisting of isolates from 2014 and the other consisting of the remaining isolates from 2022 to 2024. A 16S rRNA mutation in position A1387G was present in four C. coli isolates from 2022 and 2023, and this was associated with gentamicin resistance. One C. coli isolate was also resistant to ertapenem and exhibited an amino acid duplication within the PorA protein sequence. For patient #2, each C. coli isolate was from the same clonal complex, which was of porcine origin. Similar to patient #1, three of the isolates from 2023 had an A1464G 16S rRNA mutation and were gentamicin resistant. Retrospective analyses of antimicrobial use for both patients highlighted an association between antimicrobial selection pressure and the emergence of resistance markers, suggesting in vivo selection.

The rise of antimicrobial resistance presents a challenge to public health, undermines the efficacy of antibiotics, and compromises the management of infectious diseases. Gut colonisation by multidrug-resistant organisms, such as multidrug-resistant Enterobacterales and vancomycin-resistant enterococci, is associated with increased morbidity and mortality rates, as well as health-care costs. Of late, the role of the gut microbiome in combating colonisation by multidrug-resistant organisms, which could precede invasive infection, has garnered interest. Innovative interventions, including faecal microbiota transplantation, probiotics, phage therapy, and bacterial consortia, represent potential preventive or therapeutic options to counteract colonisation by multidrug-resistant organisms. In this Personal View, we have synthesised the current findings on these interventions and elucidated their potential as solutions to the crisis of antimicrobial resistance.

BACKGROUND:Recurrent urinary tract infection (rUTI) is a common condition, affecting approximately one-third of women after an initial UTI. It significantly impacts health care costs and patients' quality of life. The relationship between the pathophysiology of UTI and the gut and vaginal microbiota is recognized as a contributing factor to rUTI in women. As antibiotic resistance among uropathogens continues to increase, there is a clear need to develop novel therapeutic interventions. Faecal microbiota transfer (FMT) is a potent nonantimicrobial strategy for modulating the gut microbiota; however, its clinical relevance in the context of rUTI is unclear. OBJECTIVES:This narrative review aimed to summarize the current evidence on the use of FMT for the treatment of rUTI, focusing on women, excluding those with mechanical dysfunctions such as urinary incontinence, neurogenic bladder, and bladder cancer, compared with other nonantimicrobial interventions. We also discussed the pathophysiology and epidemiology of rUTI to identify patients for whom microbiota-targeting therapies may be the most effective. CONTENT:Periurethral colonization and migration to the bladder of uropathogens that inhabit the gut and vagina have been linked to the aetiology of UTI in women, particularly in patients with multidrug-resistant organisms. FMT appears to be a promising approach for preventing the clinical development of rUTI, although prospective data remain limited. In contrast, other reported nonantimicrobial strategies targeting the gut and urogenital microbiota have shown variable significant clinical efficacy. Prospective randomized controlled clinical trials are then needed to further confirm a potential therapeutic benefit, optimize the FMT procedure, and better assess its cost-effectiveness.

Faecalibacterium has recently garnered attention for its potential health implications. To better understand its role, we developed and assessed real-time PCR assays for detecting and quantifying various Faecalibacterium species in human stool samples from both healthy individuals and Crohn's disease patients, either in flare or remission. The assays targeted the Microbial Anti-inflammatory Molecule (MAM) genes, which encode MAM proteins. These assays demonstrated 100% species-specificity using strains from six Faecalibacterium species: Faecalibacterium prausnitzii, Faecalibacterium taiwanense, Faecalibacterium duncaniae, Faecalibacterium longum, Faecalibacterium hattori, and Faecalibacterium CNCM4541. They also showed high sensitivity with detection limits of 10^5 bacteria per gram of sample. In healthy individuals, the different Faecalibacterium species varied in abundance. F. taiwanense, F. duncaniae, and F. longum were the most prevalent, around 10^10 bacteria/g of stool. In contrast, F. hattori and CNCM4541 were less abundant, with 10^7 bacteria/g. Despite its low abundance, F. hattori was present in all healthy subjects, while CNCM4541 was detected in only 50% of them. Notably, F. taiwanense, F. duncaniae, and F. longum were found in all healthy individuals. In Crohn's disease patients, both in flare and remission, a decrease in Faecalibacterium species was observed, with no recovery in remission. The most abundant species in Crohn's disease patients were F. prausnitzii and F. duncaniae, around 10^7 bacteria/g, while F. longum, F. hattori, and F. taiwanense were present at lower levels (10^6 bacteria/g), and CNCM4541 was no longer detected. Interestingly, F. prausnitzii showed a smaller decrease in abundance compared with other species. Moreover, F. prausnitzii was significantly more prevalent in patients in remission than in those in flare, suggesting that it may be more resistant to inflammation. These findings highlight the importance of accurately characterizing and quantifying Faecalibacterium species to better understand their role in health and disease.

Aging is a key contributor of morbidity and mortality during acute viral pneumonia. The potential role of age-associated dysbiosis on disease outcomes is still elusive. In the current study, we used high-resolution shotgun metagenomics and targeted metabolomics to characterize SARS-CoV-2-associated changes in the gut microbiota from young (2-month-old) and aged (22-month-old) hamsters, a valuable model of COVID-19. We show that age-related dysfunctions in the gut microbiota are linked to disease severity and long-term sequelae in older hamsters. Our data also reveal age-specific changes in the composition and metabolic activity of the gut microbiota during both the acute phase (day 7 post-infection, D7) and the recovery phase (D22) of infection. Aged hamsters exhibited the most notable shifts in gut microbiota composition and plasma metabolic profiles. Through an integrative analysis of metagenomics, metabolomics, and clinical data, we identified significant associations between bacterial taxa, metabolites and disease markers in the aged group. On D7 (high viral load and lung epithelial damage) and D22 (body weight loss and fibrosis), numerous amino acids, amino acid-related molecules, and indole derivatives were found to correlate with disease markers. In particular, a persistent decrease in phenylalanine, tryptophan, glutamic acid, and indoleacetic acid in aged animals positively correlated with poor recovery of body weight and/or lung fibrosis by D22. In younger hamsters, several bacterial taxa (Eubacterium, Oscillospiraceae, Lawsonibacter) and plasma metabolites (carnosine and cis-aconitic acid) were associated with mild disease outcomes. These findings support the need for age-specific microbiome-targeting strategies to more effectively manage acute viral pneumonia and long-term disease outcomes.

Norovirus (NoV) infections can lead to severe complications in immunocompromised patients ( 1 Flynn T.G. Olortegui M.P. Kosek M.N. Viral gastroenteritis. The Lancet. 2024 Mar; 403: 862-876https://doi.org/10.1016/S0140-6736(23)02037-8 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ). Nitazoxanide, ribavirin and intravenous (IV) or oral immunoglobulins (Ig) have shown limited efficacy ( 1 Flynn T.G. Olortegui M.P. Kosek M.N. Viral gastroenteritis. The Lancet. 2024 Mar; 403: 862-876https://doi.org/10.1016/S0140-6736(23)02037-8 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar , 2 Dang W. Xu L. Ma B. Chen S. Yin Y. Chang K.O. et al. Nitazoxanide Inhibits Human Norovirus Replication and Synergizes with Ribavirin by Activation of Cellular Antiviral Response. Antimicrob Agents Chemother. 2018 Nov; 62: e00707-e00718https://doi.org/10.1128/aac.00707-18 Crossref PubMed Scopus (0) Google Scholar ). The gut microbiota has been described as impacting NoV infectivity and might constitute a therapeutic target ( 3 Rodríguez-Díaz J. García-Mantrana I. Vila-Vicent S. Gozalbo-Rovira R. Buesa J. Monedero V. et al. Relevance of secretor status genotype and microbiota composition in susceptibility to rotavirus and norovirus infections in humans. Sci Rep. 2017 Mar 30; 745559https://doi.org/10.1038/srep45559 Crossref PubMed Scopus (63) Google Scholar ), which can be modulated by faecal microbiota transplantation (FMT) ( 4 Allegretti J.R. Mullish B.H. Kelly C. Fischer M. The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications. The Lancet. 2019 Aug; 394: 420-431https://doi.org/10.1016/S0140-6736(19)31266-8 Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar ).

Introduction La transplantation de microbiote fécal (TMF) est le traitement recommandé pour les infections à C. difficile (ICD) multi-récidivantes (≥2 récidives). Son efficacité a également été décrite pour les ICD sévère-compliquées ou dès un premier épisode d'ICD. Nous rapportons ici les résultats de l'utilisation de la TMF pour ICD en France dans le cadre de l'observatoire du Groupe Français de Transplantation Fécale (GFTF) et l'analyse des facteurs cliniques et pharmaceutiques associés à l'efficacité de la TMF dans l'ICD en vie réelle. Matériels et méthodes Etude portant sur l'analyse de toutes les TMF réalisées au sein du Groupe français de transplantation fécale pour ICD de 2018 à 2022. Les données cliniques (antécédents médicaux, traitements, efficacité, voie d'administration utilisée) et démographiques ont été recueillies rétrospectivement à partir des dossiers médicaux des receveurs, tandis que les caractéristiques techniques de préparation du transplant fécal (poids et mode de préparation des selles) ont été recueillies prospectivement au sein de chaque pharmacie préparatrice. Des analyses univariées (test de Fisher) et multivariées (régression logistique multiple) ont été réalisées pour identifier les facteurs associés au succès de la TMF défini par l'absence de récidive de l'ICD à 8 semaines. Résultats Sur la période d'étude, 658 TMF ont été réalisées en France dans 17 centres. L'efficacité globale de la TMF était de 79,0 % (520/658), avec 0,5 % d'effets indésirables sévères possiblement liés à la TMF (3/658). En analyse multivariée, l'insuffisance rénale chronique sévère (OR : 2,12, IC95%:1,12 - 3,93), l'ICD réfractaire non sévère (OR : 11,60, IC95%: 1,03 - 261,7), l'utilisation de glycérol dans les préparations congelées (OR : 2,26, IC95% 1,02 - 4, 98), et l'échec technique de la procédure (nettoyage insuffisant de l'intestin ou rétention insuffisante de la TMF; OR 5,05, IC95% : 1,35 - 21,58) étaient associés à la récidive de l'ICD dans les 8 semaines alors que la décongélation des fèces congelées à l'aide d'un bain-marie à 37°C était protectrice (OR : 0,25, IC95% : 0,10 - 0,64). Il n'y avait pas d'association significative entre l'efficacité de la TMF et la voie d'administration (voie gastro-duodénale: n=393 p=0,06; lavement: n=77, p=0,13; capsule: n=90, p=0,26; ou coloscopie: n=42, p=0.24), un pré-traitement par fidaxomicine en monothérapie (n=64; p=0,87) ou l'utilisation d'un poids de selles <30g (n=140 p=0,48). Conclusion L'expérience française montre que l'efficacité de la TMF pour les formes multi-récidivantes, sévère-compliquées ou avec <2 de récidives est confirmée en vie réelle alors que l'utilisation de la TMF pour ICD réfractaire non sévère est associée à un risque d'échec important devant probablement faire évoquer en premier lieu un diagnostic différentiel. La méthode de décongélation et les conditions de congélation sont des paramètres clés sous-estimés qui doivent être mieux standardisés pour optimiser l'efficacité de la TMF en particulier chez des patients insuffisants rénaux sévères à haut risque d'échec.Liens d'intérêts déclarés :N.B. a reçu des honoraires de Tillots Pharma et des bourses de voyage de Pfizer, a participé à réalisé une activité de conseil pour Ferring Pharmaceuticals avec paiement à son institution, est un PI d'un essai clinique soutenu par Exeliom Biosciences.

Colorectal cancer (CRC) is a worldwide public health issue specifically in patients with chronic diseases associated with a western lifestyle, such as metabolic diseases and inflammatory bowel diseases (IBD). Interestingly, both metabolic disorders and IBD are characterized by a chronic state of inflammation that contributes to the carcinogenesis with specific alteration of the gut microbiota composition and function. Evidence now shows that this altered gut microbiota contributes fueling a chronic pro-inflammatory state in a vicious circle that can favor CRC development. In this review article, we present the current knowledge concerning the involvement of the gut microbiota as a procarcinogenic factor shared by IBD and cardiometabolic diseases, and provide clues as to how it may be used to prevent or diagnose CRC.

A growing number of advanced therapies are available for inflammatory bowel disease (IBD), raising the question of their optimal therapeutic sequence. Few direct head-to-head trials exist, and their cost and complexity make unlikely to carry out prospective comparative evaluations of all the various possible therapeutic strategies. Using real-world data to simulate patient trajectories is a promising strategy to fill knowledge gap. In ulcerative colitis (UC), vedolizumab, a humanized monocolonal anti-α4β7, has shown a better efficacy compared to adalimumab in the phase IIIB VARSITY trial.1 However, few data are available to determine vedolizumab's position in the therapeutic sequence for Crohn's disease (CD). In this issue, Louis and collaborators developed a semi-Markov model to assess how the positioning of vedolizumab in the therapeutic sequence of CD patients can impact patients outcomes.2 Markov models are stochastic models that can simulate the evolution of a patient in different simplified states of health (e.g. "health", "sick", "dead"), by determining a given transition probability to switch between these different states for a given time period.3 Mainly used in health economic studies it can also be developed to address clinical questions.4 A common outcome used for Markov-model-based studies is quality-adjusted life-years (QALYs), that combines health-related quality of life and life duration and can be considered as an approximation of a criterion combining the effectiveness and safety of a treatment. In their model, Louis et al, have evaluated different treatment sequences including vedolizumab, corticosteroids, infliximab, adalimumab, and ustekinumab using real-world data of patients with moderate-severe CD. In an original setting, the authors also modeled in addition to QALYs the proportion of patients undergoing surgery at 10 years and patient-reported outcomes (PROs-based on stool frequency, abdominal pain and wellbeing score). According to this model, first-line vedolizumab was more effective based on PROs and outcomes at 10 years than first-line infliximab (QALYs 5.11 vs. 4.84; patients undergoing surgery: 28.9% vs. 31.9%) or than a first-line of either infliximab or adalimumab (aggregated data, QALYs 5.09 vs. 4.97; patients undergoing surgery 28.35% vs. 29.85%). Of note, adalimumab was associated with better results when used as a first-line treatment for both QALYs (5.09 vs. 5.07) and PROs. When comparing the different patient trajectories, vedolizumab as first-line treatment occupied the optimal position for all types of outcomes assessed. Markov models can model clinical problems and provide interesting insights when applied properly.5, 6 In IBD, it has been already used to assess the most cost-effective sequencing of biologics or the optimal position of vedolizumab in UC.7, 8 In CD, it has been also used to estimate the probability of treatment maintenance according to the therapeutic sequence when using adalimumab or infliximab.9 Several assumptions and simplifications are needed when using Markov models. As discussed in depth by the authors, the external validity of the results may be considered with caution. In particular, the model assumes that all patients are comparable at baseline despite the lack of clinical information to support it. Furthermore, combination therapy and the occurrence of serious infections have not been modeled. Finally, the reliability of a model highly depends on the incorporated data. Here, a substantial part of the data is based on studies prior to 2010, and transition probabilities, which are essential for the Markov model, were sometimes estimated from a set of just a few patients. However, probabilistic sensitivity analyses were carried out to assess the impact of the uncertain parameters used in the model, and confirmed that the optimal position for vedolizumab was first-line in 89% of probabilistic simulations when considering QALYs (1780 over 2000 iterations). Regardless of these limitations, this work provides interesting complementary information to the available data from clinical trials on the vedolizumab. In accordance with these results, post-hoc analysis of GEMINI trials has also shown that the use of vedolizumab in early disease course was associated with a decreased risk of surgery in CD patients with low/intermediate probability of treatment response.10 Thus, further evidence is needed to demonstrate the benefit of first-line vedolizumab use in CD, but modeling patient trajectories using real-world data, as performed by Louis and colleagues, is a relevant method for testing and identifying the best therapeutic sequence in IBD in addition to clinical trials. Nicolas Benech received lecture fees from Tillots Pharma and Mayoly Spindler, travel grants from Pfizer, participated on an advisory board for Ferring Pharmaceuticals with payment to his institution, is a PI of a clinical trial supported by Exeliom Biosciences. Julien Kirchgesner received lecture fees from Galapagos, Janssen and Lilly, and consulting fees from Roche, Pfizer, Janssen, Abbvie, Takeda, Lilly, Celltrion, Tillots, and Galapagos. The authors received no financial support for the research, authorship, and/or publication of this article.

Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila . IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1 KI -CD89 tg ) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins—a risk locus for IgA nephropathy—inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.

Diffuse gastric cancer (DGC) is a poorly differentiated adenocarcinoma of the stomach characterized by independent "signet-ring" cells that invade the gastric wall with mainly submucosal infiltration resulting in delayed diagnosis [1]. Mutations in the CDH1 gene, encoding E-cadherin, have been identified in families with multiple cases of gastric cancer, with a 50%–80% increased risk of DGC in carriers [2]. In cases with a proven constitutional CDH1 mutation, guidelines recommend prophylactic total gastrectomy between the ages of 20 and 30 years, or endoscopic surveillance if surgery is refused or postponed [3].

Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-β1 (TGFβ1) produced by intestinal epithelial cells. TGFβ signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.

Preparing fecal microbiota transplants immediately after donation is resource-intensive, and a proportion are destroyed following abnormal screening results. We retrospectively compared two processes, frozen fecal preparation (FFP) and fresh native frozen preparation (FNFP), for clinical efficacy in the treatment of recurrent Clostridioides difficile infection (rCDI). FFP and FNFP were similarly effective with clinical success rates of 76.7% and 86.7% (P = 0.32), respectively. FNFP is an efficient procedure that saves resources while maintaining clinical efficacy in rCDI.