Inflammatory Bowel Disease (IBD) is a spectrum of chronic inflammatory diseases of the intestine that includes subtypes of ulcerative colitis (UC) and Crohn's Disease (CD) and currently has no cure. While IBD results from a complex interplay between genetic, environmental, and immunological factors, sequencing advances over the last 10-15 years revealed signature changes in gut microbiota that contribute to the pathogenesis of IBD. These findings highlight IBD as a disease target for microbiome-based therapies, with the potential to treat the underlying microbial pathogenesis and provide adjuvant therapy to the emerging spectrum of advanced therapies for IBD. Building on the success of fecal microbiota transplantation (FMT) for Clostridioides difficile infection, therapies targeting gut microbiota have emerged as promising approaches for treating IBD; however, unique aspects of IBD pathogenesis highlight the need for more precision in the approach to microbiome therapeutics that leverage aspects of recipient and donor selection, diet and xenobiotics, and strain-specific interactions to enhance the efficacy and safety of IBD therapy. This review focuses on both pre-clinical and clinical studies that support the premise for microbial therapeutics for IBD and aims to provide a framework for the development of precision microbiome therapeutics to optimize clinical outcomes for patients with IBD.

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by deficits in social communication and restricted, repetitive, and stereotyped behaviors. In addition to neurobehavioral symptoms, children with ASD often have gastrointestinal symptoms (e.g. constipation, diarrhea, gas, abdominal pain, reflux). Several studies have proposed the role of gut microbiota and metabolic disorders in gastrointestinal symptoms and neurodevelopmental dysfunction in ASD patients; these results offer promising avenues for novel treatments of this disorder. Interventions targeting the gut microbiota - such as fecal microbiota transplant (FMT), microbiota transplant therapy (MTT), probiotics, prebiotics, synbiotics, antibiotics, antifungals, and diet - promise to improve gut health and can potentially improve neurological symptoms. The modulation of the gut microbiota using MTT in ASD has shown beneficial and long-term effects on GI symptoms and core symptoms of autism. Also, the modulation of the gut microbiota to resemble that of typically developing individuals seems to be the most promising intervention. As most of the studies carried out with MTT are open-label studies, more extensive double-blinded randomized control trials are needed to confirm the efficacy of MTT as a therapeutic option for ASD. This review examines the current clinical research evidence for the use of interventions that target the microbiome - such as antibiotics, antifungals, probiotics/prebiotics, synbiotics, and MTT - and their effectiveness in changing the gut microbiota and improving gastrointestinal and neurobehavioral symptoms in ASD.

Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD) is increasing in prevalence worldwide and has become the greatest potential risk for cirrhosis and hepatocellular liver cancer. Currently, the role of gut microbiota in the development of MASLD has become a research hotspot. The development of MASLD can affect the homeostasis of gut microbiota, and significant changes in the composition or abundance of gut microbiota and its metabolite abnormalities can influence disease progression. The regulation of gut microbiota is an important strategy and novel target for the treatment of MASLD with good prospects. In this paper, we summarize the role of gut microbiota and its metabolites in the pathogenesis of MASLD, and describe the potential preventive and therapeutic efficacy of gut microbiota as a noninvasive marker to regulate the pathogenesis of MASLD based on the "gut-hepatic axis", which will provide new therapeutic ideas for the clinic.

To study the impact of differing specific pathogen-free gut microbiomes (GMs) on a murine model of inflammatory bowel disease, selected GMs were transferred using embryo transfer (ET), cross-fostering (CF), and co-housing (CH). Prior work showed that the GM transfer method and the microbial composition of donor and recipient GMs can influence microbial colonization and disease phenotypes in dextran sodium sulfate-induced colitis. When a low richness GM was transferred to a recipient with a high richness GM via CH, the donor GM failed to successfully colonize, and a more severe disease phenotype resulted when compared to ET or CF, where colonization was successful. By comparing CH and gastric gavage for fecal material transfer, we isolated the microbial component of this effect and determined that differences in disease severity and survival were associated with microbial factors rather than the transfer method itself. Mice receiving a low richness GM via CH and gastric gavage exhibited greater disease severity and higher expression of pro-inflammatory immune mediators compared to those receiving a high richness GM. This study provides valuable insights into the role of GM composition and colonization in disease modulation.

Fecal microbiota transplantation (FMT) is a procedure involving the transfer of intestinal microbiota from a healthy donor to a patient to restore a functional intestinal microbiome. First described in modern science in 1958, the use of FMT has been practiced for decades, but only during the past dozen years have clinical frameworks and legal regulations from competent authorities been developed. Future development of microbiota-derived medical therapies will be shaped by the regulatory frameworks of various jurisdictions. This review examines the historical development and status of FMT regulations in the United States and Europe, with particular attention to their respective approaches to ensuring the safety and quality of the therapeutic product and patient access.

The development of fecal microbiota transplantation and defined live biotherapeutic products for the treatment of human disease has been an empirically driven process yielding a notable success of approved drugs for the treatment of recurrent Clostridioides difficile infection. Assessing the potential of this therapeutic modality in other indications with mixed clinical results would benefit from consistent quantitative frameworks to characterize drug potency and composition and to assess the impact of dose and composition on the frequency and duration of strain engraftment. Monitoring these drug properties and engraftment outcomes would help identify minimally sufficient sets of microbial strains to treat disease and provide insights into the intersection between microbial function and host physiology. Broad and correct usage of strain detection methods is essential to this advancement. This article describes strain detection approaches, where they are best applied, what data they require, and clinical trial designs that are best suited to their application.

Immune checkpoint blockade therapies have markedly advanced cancer treatment by invigorating antitumor immunity and extending patient survival. However, therapeutic resistance and immune-related toxicities remain major concerns. Emerging evidence indicates that microbial dysbiosis diminishes therapeutic response rates, while a diverse gut ecology and key beneficial taxa correlate with improved treatment outcomes. Therefore, there is a growing understanding that manipulating the gut microbiota could boost therapy efficacy. This review examines burgeoning methods that target the gut microbiome to optimize therapy and innovative diagnostic tools to detect dysbiosis, and highlights challenges that remain to be addressed in the field.

This review and commentary outline the strong rationale for normalizing the abnormal microbiota of patients with ulcerative colitis, Crohn's disease, and pouchitis and focus on strategies to improve current variable outcomes of fecal microbial transplant (FMT) in ulcerative colitis. Applying lessons from successful FMT therapy of recurrent Clostridioides difficile and insights from basic scientific understanding of host/microbial interactions provide strategies to enhance clinical outcomes in IBD. We outline promising approaches to develop novel-defined consortia of live biotherapeutic products and combination treatments to improve current results and to optimize and personalize treatment approaches in individual patients and disease subsets.

Clostridioides difficile infection (CDI) and recurrent CDI (rCDI) are significant causes of morbidity and mortality. The microbiome plays a significant role in the body's defense against CDI and rCDI. Antibiotics can cause significant injury to the microbiome which leads to an increased risk of CDI and rCDI. Ongoing perturbations of the microbiome perpetuate this risk. Antibiotic treatments for CDI can kill C difficile but also can impact the microbiome. Microbiome therapeutics are effective in restoring the function of the gut microbiota and re-establishing colonization resistance. The field of microbiome therapeutics is evolving with newer, more refined, modalities in development.

With the increasing indications for fecal microbiota transplantation for the treatment of diseases, there is a growing demand for the preparation of frozen or lyophilized fecal microbiota products that are viable and can stably colonize the recipient. The addition of protective agents plays an important role in the preparation. However, there has been no systematic evaluation of the protective agents used in fecal microbiota sample transplantation preparation for transplantation.

We were used the donor bacterial flora containing 10 different formulations of protective agents were frozen, lyophilized, and stored. Plate counting, CCK8 assay, flow cytometry after LIVE/DEAD staining, and fluorescence intensity were used to assess viable bacteria in vitro. In addition, the donor bacterial flora samples containing different formulations protective agents were transplanted into antibiotic-treated SPF mice, with 3 mice in each group and a total of 5 groups. Fecal samples were collected for metagenomic sequencing to observe the colonization of the bacterial flora in the recipient mice.

The preliminary screening results showed that the survival rate of bacteria in the 5% trehalose (T) groups, and 5% sucrose, 5% inulin, and 1% cysteine hydrochloride (SI) groups was slightly higher than that in the other groups. SI groups tended to be more protective against anaerobes than T groups. The donor gut microbiota containing the SI groups protective agent exhibited the best colonization of the recipient mice. The protective effects of different formulations of protective agents on the colonized probiotic strains and the metabolic function of the bacterial flora in recipient mice were found to be species specific.

SI groups can not only better protect the activity of anaerobic bacteria in the intestine, but also effectively promote the effective colonization of donor intestinal bacteria in the recipient mice, and the effect of frozen storage method is less, and can be used at the same time as frozen and freeze-dried preparation. It can be used as a reference for the selection of protective agents in the preparation of fecal microbiota transplantation samples.

Parkinson's disease is the second most common neurodegenerative disorder and fastest growing neurological condition worldwide, yet its etiology and progression remain poorly understood. This disorder is characterized pathologically by the prion-like spread of misfolded neuronal alpha-synuclein proteins in specific brain regions leading to Lewy body formation, neurodegeneration, and progressive neurological impairment. It is unclear what triggers Parkinson's and where α-synuclein protein aggregation begins, although proposed induction sites include the olfactory bulb and dorsal motor nucleus of the vagus nerve. Within the last 20 years, there has been increasing evidence that Parkinson's could be triggered by early microbiome changes and α-synuclein accumulation in the gastrointestinal system. Gut microbiota dysbiosis that alters gastrointestinal motility, permeability, and inflammation could enable prion-like spread of α-synuclein from the gut-to-brain via the enteric nervous system. Individuals with isolated rapid eye movement sleep behavior disorder have a high likelihood of developing Parkinson's and might represent a prodromal 'gut-first' subtype of the condition. The gut-first model of Parkinson's offers novel gut-based therapeutic avenues, such as anti-, pre-, and pro-biotic preparations and fecal microbiota transplants. Crucially, gut-based interventions offer an avenue to treat Parkinson's at early prodromal stages with the aim of mitigating evolution to clinically recognizable Parkinson's disease characterized by motor impairment.

Clostridioides difficile infection (CDI) is a significant global health threat, often resulting from antibiotic-induced disruption of the gut microbiota, which leads to severe gastrointestinal issues. Current treatments, such as vancomycin, are effective but can cause subsequent relapses, further microbiota disruption, and high treatment costs. Probiotics offer a promising microbiota-based therapeutic strategy. Following an in vitro screening for novel lactic acid bacterial (LAB) strains with strong anti-C. difficile ability and good tolerance to digestive challenges, Lactiplantibacillus plantarum GMNL-661 emerged as a potential solution to combat CDI. In a CDI mice model, the appropriate dose of GMNL-661 effectively alleviated CDI, which caused weight loss, gut inflammation, and mucin depletion. GMNL-661 alleviated CDI symptoms through increased gut barrier genes and downregulated IL-1 and IL-18. 16s rDNA analysis of mice stool from CDI and CDI supplemented with GMNL-661 showed distinct microbiota ecology. GMNL-661 dramatically affected the microbiome of CDI, increasing Lactobacillus spp. and Clostridium cluster XVIII while reducing Clostridium and Enterococcus species. Genome analysis of GMNL-661 revealed minimal safety concerns in antibiotic resistance and virulence genes, confirming that it is suitable for inclusion in the food chain. Antimicrobial peptide (AMP) prediction on GMNL-661 and 299v genome suggested a strong potential candidate for anti-CD antimicrobial peptides. These findings highlighted L. plantarum GMNL-661 as an effective and highly safe therapeutic agent against CDI in clinical.

The human body is habitat to a wide spectrum of microbial populations known as microbiota, which play an important role in overall health. The considerable research has mostly focused on the gut microbiota due to its potential to impact numerous physiological functions and its correlation with a variety of disorders, such as cardiovascular diseases (CVDs). Imbalances in the gut microbiota, known as dysbiosis, have been linked to the development and progression of CVDs through various processes, including the generation of metabolites like trimethylamine-N-oxide and short-chain fatty acids. Studies have also looked at the idea of using therapeutic interventions, like changing your diet, taking probiotics or prebiotics, or even fecal microbiota transplantation (FMT), to change the gut microbiota's make-up and how it works in order to prevent or treat CVDs. Exploring the cause-and-effect connection between the gut microbiota and CVDs offers a hopeful path for creating innovative microbiome-centered strategies to prevent and cure CVDs. This review presents an in-depth review of the correlation between the gut microbiota and CVDs, as well as potential therapeutic approaches for manipulating the gut microbiota to enhance cardiovascular health.

The importance of the intestinal microbita in a multitude of physiological processes is well-evidenced. These include metabolism of nutrients and xenobiotics, biosynthesis of vitamin K and vitamin B12, immunomodulation, maintenance of the gut mucosal barrier integrity and protection against some pathogens. Interindividual differences in the intestinal microbiota composition have impacts on health. The bioavailability and activity of some pharmaceuticals are heavily influenced by interindividual variability in metabolism, which has a genetic basis. This variability, primarily occurring in the liver but also in the intestine, has been studied extensively. Despite the advancement of this field - pharmacogenetics - its integration into clinical practice remains limited for reasons discussed herein. This highlights the even greater challenge of applying emerging knowledge on variability in the gut microbiota to drug therapy. However, ignoring these opportunities would be a mistake. While clinical applications of microbiota-guided drug therapy are currently absent and the ideas in this article are largely theoretical, research is uncovering that in cases where a substantial portion of a drug or its metabolites reaches the colon, or where drugs are formulated for colonic delivery, the gut microbiota can significantly affect drug metabolism and activity. Greater focus should be placed on research into how interindividual variability in the intestinal microbiome can modify pharmaceutical bioavailability and activity. This article is deliberately speculative and exploratory but proposes that, though there are still no clinical examples of microbiome-guided drug therapy, these interactions could afford opportunities for improvements in personalised medicine and also for drug design.

Everyday actions such as eating, tooth brushing or applying cosmetics inherently modulate our microbiome. Advances in sequencing technologies now facilitate detailed microbial profiling, driving intentional microbiome-targeted product development. Inspired by an academic-industry workshop held in January 2024, this review explores the oral, skin and gut microbiomes, focussing on the potential long-term implications of perturbations. Key challenges in microbiome safety assessment include confounding factors (ecological variability, host influences and external conditions like geography and diet) and biases from experimental measurements and bioinformatics analyses. The taxonomic composition of the microbiome has been associated with both health and disease, and perturbations like regular disruption of the dental biofilm are essential for preventing caries and inflammatory gum disease. However, further research is required to understand the potential long-term impacts of microbiome disturbances, particularly in vulnerable populations including infants. We propose that emerging technologies, such as omics technologies to characterize microbiome functions rather than taxa, leveraging artificial intelligence to interpret clinical study data and in vitro models to characterize and measure host-microbiome interaction endpoints, could all enhance the risk assessments. The workshop emphasized the importance of detailed documentation, transparency and openness in computational models to reduce uncertainties. Harmonisation of methods could help bridge regulatory gaps and streamline safety assessments but should remain flexible enough to allow innovation and technological advancements. Continued scientific collaboration and public engagement are critical for long-term microbiome monitoring, which is essential to advancing safety assessments of microbiome perturbations.

Chronic enteropathies (CE) are common in cats, and alterations of the intestinal microbiota might be involved in the pathogenesis.

To evaluate the efficacy of a single enema fecal microbiota transplantation (FMT) in improving intestinal dysbiosis and clinical scores in cats with CE.

Twenty-eight cats with either chronic inflammatory enteropathy (CIE; n = 19) or small cell gastrointestinal lymphoma (SCGL; n = 9) were prospectively enrolled.

Eleven cats were randomly selected to receive a single enema FMT (FMT-group), and 17 cats were used as controls. Clinical activity was determined using the Feline Chronic Enteropathy Activity Index (FCEAI), and intestinal dysbiosis was determined using the feline dysbiosis index (DI) on the day of FMT (T0) and 30 days after FMT (T1).

At T0, 14/28 cats had an abnormal DI > 0. No significant difference was found in the DI from T0 to T1 in the FMT group (mean[SD]: 0.01[2.5] vs. 0.7[2.1]; p = 0.47). No significant difference was found in the DI between the FMT group and the control group at T1 (mean[SD]: -0.7[2.1] vs. 0.8[1.8]; p = 0.92). FCEAI significantly decreased at T1 compared to T0 in the FMT group (median[IQR] 10.0[7.7-11.3] vs. 4.5[4-5]; p = 0.002). No significant difference was found in the FCEAI between the FMT group and the control group at T1 (median[IQR] 4.5[4-5] vs. 4[3-5.75]; p = 0.64).

In this study, single enema FMT did not lead to a significant improvement in DI or FCEAI in cats with CE compared to controls.

This review provides an updated overview of the gut microbiota's involvement in spondyloarthritis (SpA) from a clinical perspective. It explores mechanisms by which the gut microbiota may influence SpA pathogenesis and considers the therapeutic implications of targeting the microbiome in SpA treatment.

The pathogenesis of SpA is multifactorial, involving genetic predisposition, external factors and dysregulation of the immune system. Recent studies have identified alterations in the gut microbiome of patients with SpA, including changes in microbial diversity and specific taxa linked to disease activity. HLA-B27 status seems to influence gut microbiota composition, potentially impacting disease progression. In HLA-B27 transgenic rats, the association between gut microbiota and SpA development has been confirmed, supporting findings from human studies. A compromised gut barrier, influenced by proteins like zonulin, may allow microbial antigens to translocate, triggering immune responses associated with SpA.

These findings highlight the potential for microbiota-modulating therapies, such as probiotics, prebiotics, diet and exercise, in managing SpA. However, methodological variability in human studies exposes the need for more rigorous research to better understand these associations. This may offer the opportunity to refine treatment strategies, offering a personalized approach to managing the disease.

Invading new territory is a central aspect of the microbial lifestyle. However, invading microbes rarely find novel territories uninhabited; resident microbes can interact with the newcomers and, in many cases, impede their invasion - an effect known as 'biotic resistance'. Accordingly, invasions are shaped by the interplay between dispersal and resistance. However, these two factors are difficult to disentangle or manipulate in natural systems, making their interplay challenging to understand. To address this challenge, we track microbial invasions in the lab over space and time - first in a model system of two interacting microbes, then in a multi-strain system involving a pathogen invading resident communities. In the presence of biotic resistance, we observe three qualitatively different invasion regimes: 'consistent', 'pulsed', and 'pinned', where, in the third regime, strong biotic resistance stalls the invasion entirely despite ongoing invader dispersal. These rich invasion dynamics could be qualitatively predicted with a simple, parameter-free framework that ignores individual species interactions, even for rather complex communities. Moreover, we show that this simple framework could accurately predict simulated invasions from different mechanistic models, indicating its broad applicability. Our work offers an understanding of how biotic resistance impacts invasions and introduces a predictive tool to identify invasion-resistant communities.

Clostridioides difficile infection (CDI) has emerged as a prevalent and recurrent antibiotic-associated infection. Fecal microbiota transplantation (FMT) is the most effective treatment for recurrent CDI (rCDI). Despite high success rates, FMT is ineffective in 5%-20% of cases. Factors associated with failure have not been clearly defined.

In this study, we seek to identify factors predictive of FMT failure.

Retrospective cohort study.

A retrospective chart review was conducted on adult patients who were screened at the Complicated C. difficile Clinic at the University of Virginia Health System and received FMT for rCDI between 2013 and 2022. The primary outcome was failure of FMT, defined as either rCDI or all-cause death within 1 year.

In total, 240 patients underwent FMT: 70.4% were female, the median age was 68, and the median episode of CDI was 4. A total of 24.6% experienced failure within 1 year (18.3% had rCDI and 7.1% died). Age 70 or older (odds ratio (OR) = 2.66 (1.29-5.67)), ⩾4 episodes of CDI (OR = 3.13 (1.47-7.09)), and diabetes mellitus (OR = 2.82 (1.25-6.50)) were associated with failure on multivariate analysis.

Our study shows that FMT remains an effective treatment for rCDI. We highlight several factors associated with FMT failure, such as older age, ⩾4 episodes of CDI, and diabetes mellitus, and the need for additional research to clearly define causality.

The human gastrointestinal tract harbors a vast array of microorganisms, which play essential roles in maintaining metabolic balance and immune function. While bacteria dominate the gut microbiome, fungi represent a much smaller, often overlooked fraction. Despite their relatively low abundance, fungi may significantly influence both health and disease. Advances in next-generation sequencing, metagenomics, metatranscriptomics, metaproteomics, metabolomics, and computational biology have provided novel opportunities to study the gut mycobiome, shedding light on its composition, functional genes, and metabolite interactions. Emerging evidence links fungal dysbiosis to various diseases, including inflammatory bowel disease, colorectal cancer, metabolic disorders, and neurological conditions. The gut mycobiome also presents a promising avenue for precision medicine, particularly in biomarker discovery, disease diagnostics, and targeted therapeutics. Nonetheless, significant challenges remain in effectively integrating gut mycobiome knowledge into clinical practice. This review examines gut fungal microbiota, highlighting analytical methods, associations with human diseases, and its potential role in precision medicine. It also discusses pathways for clinical translation, particularly in diagnosis and treatment, while addressing key barriers to implementation.

Faecal microbiota transplantation is proposed as an alternative therapy to treat alcohol use disorder and has completed a Phase 1 clinical trial, with a Phase 2 clinical trial underway. Alcohol, a modifiable risk factor for noncommunicable diseases, resulted in approximately 3 million global deaths (5 %) in 2016 according to the World Health Organization.

A narrative synthesis examines the effects of alcohol and faecal microbiota transplantation on gut microbiota and how gut microbiota impacts the gut-brain axis, leading to certain behavioural symptoms of alcohol use disorder. These behavioural symptoms are alcohol craving and relapse in humans; and preference for alcohol, anxiety and depression in rodents.

Electronic databases PubMed, Embase, and Scopus were searched in January 2024 using the terms: faecal microbiota trans* AND alcohol AND microbio*. Ten studies out of 964 met the inclusion criteria of published primary studies with faecal microbiota transplantation as an intervention to study the gut-brain axis in alcohol use disorder.

The gut microbiota is altered in alcohol use disorder, which can be modified with faecal microbiota transplantation. Behavioural symptoms such as alcohol craving and relapse are associated with inflammation due to a loss of intestinal barrier function. Beneficial microbiota produce short-chain fatty acids that maintain intestinal barrier function and reduce inflammation. Studies also reported anxiety and depression-like behaviours, in addition to a preference for alcohol in alcohol-naïve rodents after faecal microbiota transplantation from patients with alcohol use disorder.

Faecal microbiota transplantation may moderate the behavioural symptoms of alcohol use disorder by altering gut microbiota, affecting intestinal permeability and inflammation, however, specific gut microbiota composition and long-term treatment outcomes require further clinical studies.

The landscape of clinical microbiome research has dramatically evolved over the past decade. By leveraging in vivo and in vitro experimentation, multiomic approaches and computational biology, we have uncovered mechanisms of action and microbial metrics of association and identified effective ways to modify the microbiome in many diseases and treatment modalities. This Review explores recent advances in the clinical application of microbiome research over the past 5 years, while acknowledging existing barriers and highlighting opportunities. We focus on the translation of microbiome research into clinical practice, spearheaded by Food and Drug Administration (FDA)-approved microbiome therapies for recurrent Clostridioides difficile infections and the emerging fields of microbiome-based diagnostics and therapeutics. We highlight key examples of studies demonstrating how microbiome mechanisms, metrics and modifiers can advance clinical practice. We also discuss forward-looking perspectives on key challenges and opportunities toward integrating microbiome data into routine clinical practice, precision medicine and personalized healthcare and nutrition.

The objectives of this study are to investigate the presence of Clostridioides difficile in faeces of patients with recurrent C. difficile infection (rCDI) before and after faecal microbiota transplantation (FMT) and to identify risk factors for faecal C. difficile and C. difficile infection (CDI) recurrence.

n = 83 faecal sample triads (pre-FMT [∼1 day], post-FMT [∼3 weeks], and a corresponding FMT donor sample), and n = 22 long-term (∼1-3 years) follow-up faecal samples were collected from FMT-treated patients. The presence of C. difficile in faeces was assessed by enrichment broth culture and PCR (tcdB gene) and associated with patient characteristics, FMT outcome, duration of pre-FMT vancomycin, FMT donor, post-FMT antibiotic use, and faecal microbiota composition (shotgun metagenomics).

The FMT cure rate for rCDI was 92.8% (77/83), with six early CDI recurrences (<2 months post-FMT). Toxigenic C. difficile was cultured in 27.7% (23/83) of all patients post-FMT, 23.4% (18/77) of patients cured 2 months post-FMT, and 13.6% (3/22) at long-term follow-up. Early CDI recurrence (n = 6) was associated with positive C. difficile culture post-FMT (21.7% [5/23] vs. 1.7% [1/60], p 0.01), post-FMT antibiotics (30.0% [3/10] vs. 4.6% [3/65], p 0.03), and a short course of pre-FMT vancomycin (median 6.0 days, IQR [5-12] vs. 18 days, IQR [10.8-29], p < 0.05). Additionally, positive C. difficile culture directly pre-FMT was associated with a short course of pre-FMT vancomycin (median 9 days IQR [5-18] vs. 17 days, IQR [10-29.2], p 0.04). Gut microbiota analyses did not reveal signatures associated with C. difficile culture result, despite statistically non-significant trends in relative abundances of the Enterobacteriaceae family, and Dorea, Roseburia, and Clostridiales species.

Although eradication of C. difficile is not required for clinical cure of rCDI by FMT, it is associated with reduced prevalence of early CDI recurrence, as are the full completion of pre-FMT vancomycin (at least 10 days) and avoiding post-FMT antibiotics.

We aimed to describe the characteristics of Clostridioides difficile infection (CDI) in cancer patients, analysing risk factors for 90-day recurrence and attributable mortality.

Retrospective analysis on all CDI episodes from 2020 to 2022 in three Australian hospitals and one Spanish hospital. Logistic regression analyses were performed.

A total of 547 CDI episodes in cancer patients were documented. Treatment predominantly involved vancomycin (81.5%), followed by metronidazole (15.0%) and fidaxomicin (9.1%). Combined antibiotics were used in 61 (11.2%) episodes. The 90-day recurrence rate was 15.6%. Independent risk factors for CDI recurrence were female sex (OR 2.26, 95% CI 1.13-4.52), age >75 years (OR 2.69, 95% CI 1.30-5.59), dialysis (OR 5.15, 95% CI 1.45-18.27), vomiting at presentation (OR 0.06, 95% CI 0.01-0.55), colonic wall thickening in the CT abdomen (OR 2.42, 95% CI 1.06-5.49) and vancomycin therapy (OR 4.60, 95% CI 1.34-15.84). Overall, 90-day mortality was 22.3%, but attributable mortality was 4.9%. Risk factors for mortality attributed to CDI were age >65 years (OR 15.91, 95% CI 2.64-95.80), previous cerebrovascular disease (OR 20.27, 95% CI 3.12-131.84), antibiotic therapy within the last 30 days (OR 0.17, 95% CI 0.05-0.54), high-output diarrhoea (OR 6.68, 95% CI 1.68-26.56), high CRP-levels (OR 11.60, 95% CI 1.90-70.81) and need for treatment change (OR 6.65, 95% CI 2.20-20.08).

CDI recurrence rates among cancer patients remain significant. Nonetheless, fidaxomicin and other preventive strategies are seldom used. We identified several factors that could inform the implementation of these strategies in cancer patients.

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders primarily comprising two main conditions: ulcerative colitis and Crohn's disease. The gut microbiota's role in driving inflammation in IBD has garnered significant attention, yet the precise mechanisms through which the microbiota influences IBD pathogenesis remain largely unclear. Given the limited therapeutic options for IBD, alternative microbiota-targeted therapies-including prebiotics, probiotics, postbiotics, and symbiotics-have been proposed. While these approaches have shown promising results, microbiota modulation is still mainly considered an adjunct therapy to conventional treatments, with a demonstrated impact on patients' quality of life. Fecal microbiota transplantation (FMT), already approved for treating Clostridioides difficile infection, represents the first in a series of innovative microbiota-based therapies under investigation. Microbial biotherapeutics are emerging as personalized and cutting-edge tools for IBD management, encompassing next-generation probiotics, bacterial consortia, bacteriophages, engineered probiotics, direct metabolic pathway modulation, and nanotherapeutics. This review explores microbial modulation as a therapeutic strategy for IBDs, highlighting current approaches and examining promising tools under development to better understand their potential clinical applications in managing intestinal inflammatory disorders.

Faecal microbiota transplantation (FMT) has shown promise as a treatment for recurrent or refractory Clostridioides difficile infections. This study aimed to evaluate the decolonization effects of FMT on vancomycin-resistant Enterococcus (VRE).

This feasibility trial prospectively recruited patients with more than three recurrent VRE infections. FMT was performed by infusing faecal microbiota solutions from healthy, unrelated donors into the participants' guts via colonoscopy. Faecal microbiota profiles before and after FMT were analysed.

Three of the six patients (50%) experienced VRE decolonization after FMT, lasting over 6 months. Baseline analysis revealed that patients who achieved decolonization had greater microbial diversity compared to those with persistent VRE colonization. Throughout the study, there were no adverse events observed in the patients after FMT. Elevated alpha diversity persisted in responders, while non-responders showed no significant changes. In responders, the abundance of genera within the phylum Firmicutes (Bacillota), including Anaerostipes, Blautia, Faecalibacterium, and Ruminococcus, and the genus Collinsella within the phylum Actinobacteriota increased steadily through 180 days post-FMT.

FMT may leverage bacterial strain competition to facilitate decolonization of drug-resistant organisms, with successful VRE decolonization potentially linked to increased abundance of phyla Firmicutes and Actinobacteriota over 6 months.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition wherein excessive fat accumulates in the liver, leading to inflammation and potential liver damage. In this narrative review, we evaluate the tissue microbiota, how they arise and their constituent microbes, and the role of the intestinal and hepatic microbiota in MASLD. The history of bacteriophages (phages) and their occurrence in the microbiota, their part in the potential causation of MASLD, and conversely, "phage therapy" for antibiotic resistance, obesity, and MASLD, are all described. The microbiota metabolism of bile acids and dietary tryptophan and histidine is defined, together with the impacts of their individual metabolites on MASLD pathogenesis. Both periodontitis and intestinal microbiota dysbiosis may cause MASLD, and how individual microorganisms and their metabolites are involved in these processes is discussed. Novel treatment opportunities for MASLD involving the microbiota exist and include fecal microbiota transplantation, probiotics, prebiotics, synbiotics, tryptophan dietary supplements, intermittent fasting, and phages or their holins and endolysins. Although FDA is yet to approve phage therapy in clinical use, there are multiple FDA-approved clinical trials, and this may represent a new horizon for the future treatment of MASLD.

SUMMARYThe human microbiome, including bacteria, fungi, archaea, and viruses, is intimately linked to both health and disease. The relationship between bacteria and disease has received much attention and intensive investigation, while that of the fungal microbiome, also known as mycobiome, has lagged far behind bacteria. There is growing evidence showing mycobiome dysbiosis in cancer patients, and certain cancer-specific fungi may contribute to cancer progression by interacting with both host and bacteria. It was also demonstrated that the role of fungi-derived products in cancer should also not be underestimated. Therefore, investigating how fungal pathogenesis contributes to the onset and spread of cancer would yield crucial information for cancer diagnosis, prevention, and anti-cancer therapy.

The intervention of microbiota modulation in the treatment of infection complications after allogeneic hematopoietic stem cell transplantation in pediatric patients with hematological malignancies has shown potential benefits. Through the use of probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT), these interventions modulate the gut microbiota and enhance immune function to prevent and treat infections. They have been shown to reduce the incidence of diarrhea and intestinal infections, mitigate the issue of antibiotic resistance, and promote the recovery of gut microbiota. Future research is needed to further assess the safety and efficacy of these interventions and to establish standardized treatment protocols.

The gut-brain axis, i.e. the bidirectional communication system between the gut and the brain, has become of central importance in Parkinson disease (PD) research over the past 20 years.

We aimed to describe the milestones of the gut-brain axis research in PD and the development of theories proposing the involvement of the gastrointestinal tract in PD pathogenesis.

We searched PubMed using the terms 'gut-brain axis' AND 'Parkinson disease', and selected relevant articles to provide the foundation for reconstructing an historical overview of the gut-brain axis research in PD.

Mounting evidence from preclinical, clinical and post-mortem studies suggests that a subgroup of PD patients present with a range of prodromal symptoms (e.g., autonomic dysfunction, rapid eye movement sleep behaviour disorder) which reflect initial accumulation and later spread of pathological α-synuclein rostrally from the gastrointestinal tract ("body-first" PD). Through neural connections along the gut-brain axis, pathological α-synuclein may spread to the brain, producing clinically manifest disease. Recently, two mechanisms involving the gut-brain axis have attracted increasing attention for their role in PD pathogenesis and progression, namely the perturbation of the composition of the microorganisms living in the gut (the gut microbiome), and the dysfunction of enteroendocrine cells.

Treatments targeting the gut-brain axis, especially the gut microbiome and the enteroendocrine cells pathway, could potentially slow disease progression or even prevent disease onset. Among these, pre/probiotics, faecal microbiota transplantation, and glucagon-like peptide-1 receptor agonists, have entered advanced stages of clinical trials in humans and shown potential symptomatic and disease-modifying effects.

The stability and metabolic functionality of donor microbiota are critical determinants of fecal microbiota transplantation (FMT) efficacy in inflammatory bowel disease (IBD). While probiotics show potential to enhance microbiota resilience, their role in optimizing donor microbiota for FMT remains underexplored.

This study investigated whether pretreatment of donor microbiota with L. plantarum GR-4 could improve FMT outcomes in a DSS-induced colitis model by modulating microbial stability, metabolic activity, and host-microbiome interactions.

Donor mice received L. plantarum GR-4 for 3 weeks to generate modified FMT (MFMT). DSS-colitis mice were treated with MFMT, conventional FMT, or 5-aminosalicylic acid (5-ASA). Multi-omics analyses and functional assays (stress resistance, engraftment efficiency) were used to evaluate therapeutic mechanisms.

GR-4 pretreatment conferred three key advantages to donor microbiota: Ecological stabilization: 1. GR-4-driven acidification (pH 3.97 vs. 4.59 for LGG, p < 0.0001) enriched butyrogenic Butyricicoccus (73 % butyrate increase, p < 0.05) and improved stress resistance to bile acids/gastric conditions (1.25 × survival vs. FMT). 2. Metabolic reprogramming: GR-4 metabolized 25.3 % of tryptophan (vs. 10.3 % for LGG) to generate immunomodulatory indoles (ILA, IAA), activating aryl hydrocarbon receptor (AHR) signaling and upregulating anti-inflammatory IL-10/IL-22. 3. Bile acid remodeling: MFMT restored sulfolithocholic acid and β-MCA levels, outperforming FMT in resolving DSS-induced dysregulation. MFMT achieved an 83 % remission rate (vs. 50 % for FMT), enhanced gut barrier integrity, and reversed colitis-associated metabolic dysregulation (e.g., elevated spermidine, 7-sulfocholic acid). Probiotic preconditioning improved donor engraftment by 1.25 × and enriched success-associated taxa (Sporobacter, Butyricimonas), while suppressing pathogens (Clostridium papyrosolvens).

L. plantarum GR-4 optimizes donor microbiota via pH-driven niche engineering, immunometabolic reprogramming, and bile acid modulation, addressing key limitations of conventional FMT. The multi-targeted efficacy of MFMT, evidenced by superior remission rates and metabolic restoration, establishes this approach as a translatable strategy for IBD therapy. This study establishes probiotic-enhanced FMT as a paradigm for precision microbiome interventions.

Perturbations in the intestinal microbiome are strongly linked to the pathogenesis of inflammatory bowel disease (IBD). Bacteria, fungi and viruses all make up part of a complex multi-kingdom community colonizing the gastrointestinal tract, often referred to as the gut microbiome. They can exert various effects on the host that can contribute to an inflammatory state. Advances in screening, multiomics and experimental approaches have revealed insights into host-microbiota interactions in IBD and have identified numerous mechanisms through which the microbiota and its metabolites can exert a major influence on the gastrointestinal tract. Looking into the future, the microbiome and microbiota-associated processes will be likely to provide unparalleled opportunities for novel diagnostic, therapeutic and diet-inspired solutions for the management of IBD through harnessing rationally designed microbial communities, powerful bacterial and fungal metabolites, individually or in combination, to foster intestinal health. In this Review, we examine the current understanding of the cross-kingdom gut microbiome in IBD, focusing on bacterial and fungal components and metabolites. We examine therapeutic and diagnostic opportunities, the microbial metabolism, immunity, neuroimmunology and microbiome-inspired interventions to link mechanisms of disease and identify novel research and therapeutic opportunities for IBD.

In recent years, nosocomial infections caused by Clostridium difficile (C. difficile) have risen, becoming a leading cause of hospital-acquired diarrhea. The global prevalence of C. difficile infection (CDI) varies across regions and populations. The diagnosis relies primarily on laboratory testing, including toxin, glutamate dehydrogenase, and nucleic acid amplification tests. Treatment strategies for CDI include antimicrobial therapy (e.g., metronidazole, vancomycin, and fidamycin), fecal transplantation, and immunotherapy (e.g., belotozumab), depending on the patient's specificity and severity. This paper reviews recent research on CDI's epidemiological characteristics, risk factors, diagnosis, treatment, and prevention, aiming to support hospitals and public health initiatives in implementing effective detection, prevention, and treatment strategies.

Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality within the Australian population. Treatment recommendations for CDI pose challenges at both community and hospital-based levels due to the recurrent, refractory and potentially severe nature of the disease. Since the last published Australasian guidelines in 2016, new therapeutic options are available, prompting a necessary update to management recommendations. On behalf of the Australasian Society of Infectious Diseases, we present the updated guidelines for the management of CDI in adults and children exploring the changes to treatment recommendations - including the replacement of oral metronidazole with vancomycin for initial CDI and the emerging role for fidaxomicin and faecal-microbiota transplant.

Recurrent Clostridioides difficile infection (CDI) is primarily driven by antibiotic-induced disruption of the indigenous intestinal microbiota. Restoration of microbiota through fecal microbiota transplantation (FMT) is effective in preventing subsequent CDI, although this effect is attenuated with additional antibiotic exposure. The aim of this study was to identify the risk factors for recurrent antibiotic administration after FMT.

This is a prospective cohort of patients who were administered FMT for recurrent CDI from 1 July 2019 through 23 November 2023 across 6 institutions in the United States. Providers collected de-identified data at the time of FMT administration and in the months post-FMT administration.

The analysis included 448 patients. Risk factors for non-CDI antibiotic administration within 2 months of FMT included immunocompromised status (odds ratio [OR], 2.2 [95% confidence interval {CI}, 1.1-4.4]; P = .02), >3 non-CDI antibiotic courses pre-FMT (OR, 3.1 [95% CI, 1.4-6.8]; P = .006), and prior hospitalization for CDI (OR, 2.0 [95% CI, 1.1-3.8]; P = .02). The most common indications for non-CDI antibiotic administration post-FMT were urinary tract infections, respiratory infections, and procedure prophylaxis.

Non-CDI antibiotic exposure significantly increases the risk of CDI recurrence post-FMT. Risk factors for non-CDI antibiotic administration within 2 months of FMT include immunocompromised status, multiple prior non-CDI antibiotics, and prior hospitalization for CDI. These individuals may benefit from additional or modified recurrent CDI prevention strategies.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.

Type 2 diabetes mellitus (T2DM) is considered as one of the most pressing public health challenges worldwide. Studies have shown significant differences in the gut microbiota between healthy individuals and T2DM patients, suggesting that gut microorganisms may play a key role in the onset and progression of T2DM. This review systematically summarizes the relationship between gut microbiota and T2DM, and explores the mechanisms through which gut microorganisms may alleviate T2DM. Additionally, it evaluates the potential of probiotics, fecal microbiota transplantation (FMT)/virome transplantation (FVT), and natural products in modulating gut microbiota to treat T2DM. Although existing studies have suggested that these interventions may delay or even halt the progression of T2DM, most research remained limited to animal models and observational clinical studies, with a lack of high-quality clinical data. This has led to an imbalance between theoretical research and clinical application. Although some studies have explored the regulatory role of the gut virome on the gut microbiota, research in this area remains in its early stages. Based on these current studies, future research should be focused on large-scale, long-term clinical studies and further investigation on the potential role of the gut virome in T2DM. In conclusion, this review aims to summarize the current evidence and explore the applications of gut microbiota in T2DM treatment, as well as providing recommendations for further investigation in this field.

Clostridioides difficile (C. difficile) remains the leading cause of healthcare-associated diarrhoea, posing treatment challenges because of antibiotic resistance and high relapse rates. Faecal microbiota transplantation is a novel treatment strategy to prevent relapses of C. difficile infection (CDI), however, the exact components conferring colonization resistance are unknown, hampering its translation to a medicinal product. The development of novel products independent of antibiotics, which increase colonization resistance or induce protective immune mechanisms is urgently needed.

To establish a framework for a Controlled Human Infection Model (CHIM) of C. difficile, in which healthy volunteers are exposed to toxigenic C. difficile spores, offering the possibility to test novel approaches and identify microbiota and immunological targets. Whereas experimental exposure to non-toxigenic C. difficile has been done before, a toxigenic C. difficile CHIM faces ethical, scientific, logistical, and biosafety challenges.

Specific challenges in developing a C. difficile CHIM were discussed by a group of international experts during a workshop organized by Inno4Vac, an Innovative Health Initiative-funded consortium.

The experts agreed that the main challenges are: developing a clinically relevant CHIM that induces mild to moderate CDI symptoms but not severe CDI, determining the optimal C. difficile inoculum dose, and understanding the timing and duration of antibiotic pretreatment in inducing susceptibility to CDI in healthy volunteers.

Should these challenges be tackled, a C. difficile CHIM will not only provide a way forward for the testing of novel products but also offer a framework for a better understanding of the pathophysiology, pathogenesis, and immunology of C. difficile colonization and infection.