Search Results (80)

Major depressive disorder (MDD) affects approximately 280 million people worldwide, yet conventional pharmacotherapy achieves remission in only 30–50% of patients, intensifying the search for novel biological substrates. This systematic review, conducted according to PRISMA 2020 guidelines across six electronic databases (2014–March 2025), synthesised 89 studies examining gut microbiota composition in adults with MDD compared to healthy controls. MDD was consistently associated with reduced alpha diversity and a recurrent dysbiotic pattern, herein proposed as a depressive dysbiosis signature, characterised by depletion of butyrate-producing genera (Faecalibacterium, Roseburia, Eubacterium, Coprococcus) and enrichment of pro-inflammatory taxa (Alistipes, Eggerthella, Streptococcus). While this pattern was observed across multiple cohorts, significant inter-study heterogeneity precludes its definition as a universal microbial signature for MDD. Beta diversity analyses demonstrated robust compositional separation between cohorts. Plausible mechanistic pathways included compromised short-chain fatty acid production, increased intestinal permeability, low-grade systemic inflammation, tryptophan shunting toward the kynurenine pathway, and hypothalamic–pituitary–adrenal axis dysregulation. Preclinical faecal microbiota transplantation provided translational evidence consistent with a causal interpretation, while randomised probiotic trials demonstrated significant reductions in depressive symptom severity compared with placebo. Probiotic effects are strain-specific according to ISAPP consensus; generalisation across strains is not warranted. Gut microbiota dysbiosis represents a biologically plausible mediator of depression pathophysiology, with a recurrent dysbiotic pattern, characterised by depletion of butyrate-producing taxa and enrichment of pro-inflammatory genera, showing emerging diagnostic and therapeutic potential. Full article

Highlighting its pivotal role in modern pharmacology, the gut microbiome is emerging as a key determinant of drug efficacy, toxicity, and bioavailability. This review proposes the Gut Microbiome Dependency Continuum, a four-layer framework describing progressively deeper levels of microbiome involvement in drug discovery and therapeutic function. The first layer, intact functional microbiome-dependent therapeutics and includes interventions such as faecal microbiota transplantation and defined microbial consortia. The second layer, microbiome-modulated approved drugs include widely used therapeutics whose pharmacokinetics or pharmacodynamics are strongly influenced by microbial metabolism. Examples include metformin, irinotecan, levodopa, and digoxin, where gut microbial interactions influence efficacy, toxicity, and inter-individual variability in treatment outcomes. The third layer, microbiota-transformable natural products, encompasses dietary and plant-derived compounds such as polyphenols, ginsenosides, alkaloids, fibres, isoflavones, lignans, and glucosinolates. Their biological activity depends on microbial biotransformation into bioactive metabolites. The fourth layer, engineered microbiome therapeutics, includes synthetic biology approaches such as programmable microbial systems, engineered probiotics, CRISPR-based microbiome editing, and microbiome-responsive drug delivery systems. It also includes synthetic microbial consortia, enabling targeted sensing, therapeutic delivery, and ecological reprogramming of gut microbial communities. Altogether, these layers define a continuum in which the gut microbiome evolves from a passive modulator to an essential metabolic organ and ultimately a programmable therapeutic platform. The article provides an integrated framework for microbiome-informed drug discovery. It also supports the development of precision, ecology-aware, and engineered microbial therapeutics. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the sixth most diagnosed cancer worldwide and a leading cause of cancer-related mortality. The majority of cases arise in the setting of chronic liver disease, where immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of systemic therapy for advanced disease. However, durable clinical benefit remains limited to a minority of patients, and reproducible biomarkers of ICI response are lacking. The gut–liver axis—encompassing bidirectional exchange of microbial products, metabolites, bile acids, and immune signals—has emerged as a biologically plausible determinant of both hepatocarcinogenesis and immunotherapy response. This narrative review synthesises current evidence on the role of the gut–liver axis in HCC and ICI response and proposes a unifying conceptual framework to resolve discrepancies in the existing literature. Methods: A narrative review was conducted through systematic searches of PubMed/MEDLINE, Embase, and Web of Science. Studies were selected based on relevance to the biological mechanisms, clinical associations, and experimental models underpinning gut–liver–immune interactions in HCC, with particular emphasis on studies providing mechanistic insight, addressing immunotherapy outcomes, or highlighting temporal and context-dependent effects. Results: Observational studies consistently associate higher microbial diversity and enrichment of homeostasis-promoting taxa—including Akkermansia, Bifidobacterium, and short-chain fatty acid-producing Ruminococcaceae—with ICI responsiveness in HCC. Functional microbial outputs, particularly short-chain fatty acids and secondary bile acids, exert mechanistically grounded effects on hepatic immune tone and T cell activity that are biologically proximate to ICI effector pathways. Therapeutic modulation of the gut–liver axis through probiotics, dietary interventions, faecal microbiota transplantation, and antibiotic exposure demonstrates context-dependent effects on immune activation and ICI outcomes, with timing and disease severity emerging as critical determinants. The limited reproducibility of microbiome-immunotherapy associations across cohorts is attributable primarily to the dynamic and treatment-sensitive nature of the gut–liver axis rather than a fundamental lack of mechanistic coupling. Conclusions: The gut–liver axis in HCC is best understood as a dynamic, treatment-sensitive system rather than a static baseline trait. This reframing shifts emphasis from single-timepoint taxonomic signatures toward functional and longitudinal readouts and provides a coherent rationale for the heterogeneity observed across existing studies. Longitudinal clinical studies incorporating mechanistic endpoints and functional biomarker assessment are needed to translate this framework into clinically actionable strategies for patient stratification and microbiota-targeted intervention in HCC immunotherapy. Full article

Increasing evidence suggests pancreatic cancer develops within a host–microbe ecosystem in which microbial communities across anatomical niches interact with tumour biology, immune regulation, metabolism, and therapeutic response. This review examines pancreatic cancer through the lens of humans as holobionts, integrating evidence from the oral, gut, biliary, and intratumoural microbiomes. Epidemiological and sequencing studies demonstrate consistent microbial alterations across these niches in pancreatic cancer, including oral dysbiosis associated with periodontal pathogens, gut microbial shifts toward pro-inflammatory taxa, disease-specific biliary microbial signatures, and the presence of distinct intratumoural microbial communities. Mechanistic studies indicate that intestinal barrier disruption, microbial translocation, immune and metabolite signalling can influence tumour immune architecture, macrophage polarisation, T-cell infiltration, oncogenic signalling pathways, and chemotherapeutic metabolism, particularly inactivation by tumour-associated bacteria. Microbiome-driven shifts in immunometabolism can reprogramme immune-cell metabolic pathways, impairing effective T-cell activation, promoting tumour-supportive macrophage phenotypes. Emerging therapeutic strategies aim to modulate the microbiome–tumour axis, including dietary interventions, probiotics and immunonutrition, faecal microbiota transplantation, engineered microbial therapies, and microbiome-informed antibiotic strategies. While pre-clinical findings are compelling and early-phase clinical studies suggest feasibility, most evidence remains associative and heterogeneous across cohorts and methodologies. Understanding pancreatic cancer as a multi-site ecological system may help explain inter-patient variability in disease progression and treatment response. This could usher in a new era for therapeutic manipulation where future progress will depend on longitudinal, multi-omic, and interventional studies to determine whether microbiome-targeted strategies can produce clinically meaningful improvements in pancreatic cancer outcomes. Full article

Differences in the gut microbiota are directly reflected in lung–gut axis crosstalk, which may increase susceptibility to pulmonary infections, such as those caused by the bacterium Pseudomonas aeruginosa. Deficiency of the cytokine IL-10 leads to gut inflammation, and this pro-inflammatory environment is partly due to changes in the gut microbiota. To better understand the effects of IL-10 deficiency on the gut microbiota, the intestinal microbial composition of IL-10 KO mice was assessed, and an increase in the phyla Bacteroidetes and Proteobacteria and a decrease in the phylum Firmicutes were observed in the faeces compared with the wild-type group (WT). Additionally, IL-10 KO mice had a higher pro-inflammatory immunostimulatory caecal content. Furthermore, it was found that heterologous faecal microbiota transplantation (FMT) between groups reversed this gut imbalance. IL-10 KO mice showed greater susceptibility to acute pulmonary infection by P. aeruginosa, with a higher recovery of viable bacteria in the lung and spleen, greater tissue damage and increased expression of genes encoding pro-inflammatory cytokines in the lungs. This greater susceptibility was reversed after FMT. Taken together, these results demonstrate the role of endogenous IL-10 in the gut microbiota constitution and its importance in the pulmonary immune response against P. aeruginosa infection. Full article

Background: The antibiotic ibezapolstat and the live biotherapeutic product live-JSLM are promising future approaches for treating Clostridioides difficile infection. Ibezapostat is a highly specific antibiotic for Clostridioides difficile, with minimal impact on the intestinal flora. Live-JSLM is designed to restore healthy intestinal microbiota, thus preventing recurrence of Clostridioides difficile infection. In this narrative review, we reviewed available data on ibezapostat and live-JSLM, considering that they are prototypes of two distinct, unique mechanisms of action against Clostridioides difficile. Methods: Data sources: PubMed and SCOPUS databases were searched from 1 January 2012 to 15 November 2025. Original articles reporting data on ibezapolstat and live-JSLM were included. Results: 31 studies were included. When compared to conventional anti-Clostridioides difficile antibiotics, ibezapolstat had a similar level of effectiveness and minimal impact on the gut microbiota. The available data confirm live-JSLM safety and efficacy in restoring the gut microbiota following the conclusion of the standard anti-Clostridioides difficile antibiotic regimen. Conclusions: The results on ibezapolstat efficacy are promising, but require confirmation in larger patient populations through double-blind, randomised phase III trials. In the near future, an integrated approach may enhance the management of Clostridioides difficile infection: starting with highly specific antibiotics, i.e., ibezapolstat, followed by microbiome-based therapies such as live-JSLM. Full article

Background and Aims: Severe alcohol-associated hepatitis (SAH) can trigger unstable decompensations in cirrhosis patients. They experience high rates of emergency department visits and hospitalization. We evaluated real-world clinical outcomes following palliative-faecal microbiota transplantation (pFMT) compared to best supportive care (BSC) in this critically ill population. Patients and Methods: From July 2021 to April 2024, 28 patients on pFMT were compared with 37 on BSC. Patients on pFMT received nasoduodenal healthy donor stool infusion daily for 5-days. Patients were followed up for portal hypertension-related events, infections, hospitalizations, extrahepatic organ failure and 6- and 12-months survival. 16S rRNA sequencing on stool samples collected at baseline and on follow up were analysed for changes in relative abundance (RA) of bacterial communities. Results: Patients were matched for age, type of decompensation and liver disease severity at enrolment. Twelve-month survival was 64.3% in pFMT versus 51.4% in BSC groups. pFMT dramatically reduced hospital readmissions (mean 0.76 ± 0.76 vs. 2.29 ± 1.27, p < 0.001). Unstable decompensations beyond 3 months occurred in 14.3% of pFMT versus 64.9% of BSC (p < 0.001). Organ failures were lesser with pFMT: acute kidney injury 7.7% versus 93.8% (p < 0.001), hepatic encephalopathy 7.1% versus 68.2% (p < 0.001). Infection burden was significantly lower (53.6% vs. 83.8%, p = 0.008), particularly infections requiring admission (17.4% vs. 66.7%, p < 0.001) with pFMT. Microbiome analysis revealed progressive expansion of Gram-negative genera in BSC, and beneficial Actinobacteria in pFMT-treated patients at 3, 6, and 12 months. Conclusions: Palliative FMT represents a unique disease-modifying intervention in end-stage alcohol-related cirrhosis, preventing organ failure progression, reducing healthcare utilization, and improving survival trajectories. Full article

Background: Obesity is a multifactorial, chronic disease characterised by excessive fat accumulation, low-grade inflammation, and metabolic dysfunction. Emerging evidence suggests that the gut microbiome–mitochondria axis may play a significant role in the pathophysiology of obesity, particularly in regulating energy metabolism, inflammatory responses, and mitochondrial function. However, most mechanistic insights into this axis derive from preclinical animal studies, while human evidence remains limited and largely associative. Mitochondrial dysfunction disrupts cellular energy balance, increases reactive oxygen species production, and may exacerbate gut dysbiosis, further contributing to metabolic disturbances. In addition, factors such as micronutrient deficiencies also play a relevant role in obesity development and progression. Objectives: This review aims to examine the bidirectional interactions between the gut microbiome and mitochondrial systems in obesity, with a focus on the underlying molecular mechanisms and their potential as therapeutic targets. Methods: Evidence from experimental models and clinical studies was analysed to evaluate how modulation of the microbiome–mitochondria axis through probiotics, prebiotics, dietary strategies, and faecal microbiota transplantation influences mitochondrial function, inflammation, and metabolic regulation. Results: Preclinical studies indicate that the gut microbiome modulates mitochondrial activity through the production of bioactive metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan-derived compounds, which influence mitochondrial efficiency, lipid metabolism, and glucose regulation. Dysbiosis reduces these beneficial metabolites, impairing mitochondrial signalling and promoting adiposity and insulin resistance. Interventions targeting this axis have shown potential in restoring metabolic balance, improving mitochondrial function, and mitigating obesity-related complications such as hyperlipidaemia and glucose intolerance. Conclusions: Targeting the microbiome–mitochondria axis represents a promising therapeutic strategy for obesity, with the evidence based largely on preclinical findings. However, further well-designed human studies are required to clarify causality, optimise interventions, assess long-term safety and efficacy, and establish standardised clinical protocols for implementation. Full article

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder; to date, there is no long-term effective treatment. Recently, a relationship has been discovered between the human intestinal microbiome and the pathogenesis of ALS, on which basis faecal microbiota transplantation (FMT) has been proposed as a potential treatment for ALS. In this review, we compare three existing case studies examining the effect of FMT on the course of ALS, highlighting differences in methodology and results. In two of the studies, a halt in the progression of ALS symptoms was observed following FMT, accompanied by improvement in patient health. However, in the third and largest study, no significant effect of FMT was observed. The possible explanation for this discrepancy may be the intentional depletion of intestinal microorganisms using antibiotics prior to FMT in the third study. Future studies and/or completion of the ongoing clinical studies will help clarify the therapeutic effectiveness of FMT in ALS patients. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer and cancer-related death worldwide. Beyond the well-known factors influencing the risk of HCC, experimental data from animal models and observational human studies support a significant role of the gut microbiota (GM) in HCC initiation and progression. Dysbiosis and increased intestinal permeability synergistically disrupt the ‘gut–liver axis,’ exposing the liver to bacterial metabolites and microbial-associated molecular patterns, thereby contributing to hepatocarcinogenesis. While these findings have expanded our understanding of HCC pathogenesis, a critical translational gap persists as most data derive from preclinical settings, with limited validation in large-scale clinical studies. Methods: This narrative review aimed to contextualise the current evidence on the GM-HCC axis and its clinical translatability. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science up to July 2025 using Medical Subject Headings and related keywords, including HCC, GM, dysbiosis, intestinal permeability, gut–liver axis, microbial metabolites, inflammation/immune modulation, and microbiota-targeted interventions (probiotics, antibiotics, and faecal microbiota transplantation). Reference lists of relevant articles were also screened to identify additional studies. Results: Preclinical models consistently indicate that dysbiosis and impaired gut barrier function can promote hepatic inflammation, immune dysregulation, and pro-tumorigenic signalling through microbe-derived products and metabolite perturbations, supporting a contributory role of the GM in hepatocarcinogenesis. In humans, HCC and advanced chronic liver disease are associated with altered microbial composition and function, increased markers of intestinal permeability, and changes in bile acid and other metabolite profiles; however, reported signatures are heterogeneous across cohorts and analytical platforms. Conclusions: The GM is a biologically plausible and experimentally supported contributor to HCC initiation and progression, with potential for biomarker development and therapeutic targeting. However, clinical translation is limited by predominantly preclinical/associative evidence, interindividual variability, and non-standardised microbiome methods. Large longitudinal studies and adequately powered randomised trials are needed to establish causality, validate biomarkers, and determine whether GM modulation improves HCC prevention, detection, stratification, or outcomes. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread hepatic condition characterised by hepatic lipid accumulation and inflammation. Emerging research highlights the contribution of the intestinal microbiota and its metabolic byproducts to the pathogenesis of MASLD through the gut–liver axis. Apolipoprotein A-I (apoA-I), the principal structural component of high-density lipoprotein (HDL), is linked to various metabolic disorders; however, its function in MASLD has not yet been clearly elucidated. This study sought to examine whether apoA-I protects against MASLD, with a focus on the possible role of the gut microbiota and propionic acid (PPA). The contribution of the gut microbiota was evaluated using faecal microbiota transplantation (FMT) and antibiotic cocktail (ABX)-mediated depletion. Microbial composition was assessed via 16S rRNA sequencing, and concentrations of short-chain fatty acids (SCFAs) were quantified. The effects of PPA on MASLD were examined using in vivo and in vitro models. The results showed that apoA-I overexpression alleviated MASLD in a gut microbiota-dependent manner, restored microbial homeostasis, and elevated PPA levels. PPA supplementation improved MASLD phenotypes. Mechanistically, PPA treatment was associated with the activation of the GPR43–Ca²⁺–CAMKII–ATGL pathway, suggesting that PPA plays a role in stimulating hepatic lipolysis and enhancing mitochondrial β-oxidation. These findings reveal a novel pathway through which apoA-I ameliorates MASLD by modulating the gut microbiota and increasing PPA levels, which activate a hepatic lipolysis cascade. The apoA-I–microbiota–PPA axis represents a promising therapeutic target for MASLD intervention. Full article

Recurrent Clostridioides difficile infection (rCDI) remains a major therapeutic challenge. Although faecal microbiota transplantation (FMT) is highly effective and thought to restore microbial composition and metabolic function, the mechanisms underlying its success are not fully understood. In particular, the contribution of non-bacterial components such as soluble metabolites remains unclear. Therefore, further investigation is needed to identify the mechanistic drivers of FMT efficacy and clarify how non-bacterial factors contribute to therapeutic outcomes. Here, we applied untargeted three-dimensional Orbitrap secondary ion mass spectrometry (3D OrbiSIMS) to profile faecal metabolic reprogramming in rCDI patients pre- and post-FMT, alongside C. difficile cultures exposed to sterile faecal filtrates. FMT induced extensive metabolic shifts, restoring glyoxylate/dicarboxylate and glycerophosphoinositol pathways and normalising disrupted bile acid and amino acid profiles. Faecal filtrate exposure caused strain-specific metabolic disruption in C. difficile, depleting proline, fumarate and succinate while enriching tryptophan. While multiple metabolite classes were profiled, the most significant functional changes were observed in lipids. Lipidomics identified >3.8-fold enrichment of phosphatidylinositol (PI) species, which localised to bacterial membranes and conferred cytoprotection against C. difficile toxins and other epithelial insults. Spatial metabolomics imaging revealed, for the first time, metabolite compartmentalisation within C. difficile, with proline and succinate broadly distributed across the cell surface and fumarate confined to distinct microdomains, highlighting functional heterogeneity in pathogen metabolism. Collectively, these findings demonstrate that soluble metabolites within faecal filtrates mediate pathogen suppression and epithelial barrier protection, establishing metabolite-driven mechanisms underlying FMT efficacy and identifying PI lipids as candidate post-biotic therapeutics for rCDI. Full article

Preterm birth remains a significant global health challenge and is strongly associated with heightened risks of long-term neurodevelopmental impairments, including cognitive delays, behavioural disorders, and emotional dysregulation. In recent years, accumulating evidence has underscored the critical role of the gut microbiota in early brain development through the gut–brain axis. In preterm infants, microbial colonisation is frequently delayed or disrupted due to caesarean delivery, perinatal antibiotic exposure, formula feeding, and prolonged stays in neonatal intensive care units (NICUs), all of which contribute to gut dysbiosis during critical periods of neurodevelopment. This review synthesises current knowledge on the sources, temporal patterns, and determinants of gut microbiota colonisation in preterm infants. This review focuses on the gut bacteriome and uses faecal-sample bacteriome sequencing as its primary method of characterisation. We detail five mechanistic pathways that link microbial disturbances to adverse neurodevelopmental outcomes: immune activation and white matter injury, short-chain fatty acids (SCFAs)-mediated neuroprotection, tryptophan–serotonin metabolic signalling, hypothalamic–pituitary–adrenal (HPA) axis modulation, and the integrity of intestinal and blood–brain barriers (BBB). We also critically examine emerging microbiota-targeted interventions—including probiotics, prebiotics, human milk oligosaccharides (HMOs), antibiotic stewardship strategies, skin-to-skin contact (SSC), and faecal microbiota transplantation (FMT)—focusing on their mechanisms of action, translational potential, and associated ethical concerns. Finally, we identify key research gaps, including the scarcity of longitudinal studies, limited functional modelling, and the absence of standardised protocols across clinical settings. A comprehensive understanding of microbial–neurodevelopmental interactions may provide a foundation for the development of targeted, timing-sensitive, and ethically sound interventions aimed at improving neurodevelopmental outcomes in this vulnerable population. Full article

Faecal microbiota transplantation (FMT) is an emerging therapy for gastrointestinal and neurological disorders, acting via the microbiota–gut–brain axis. Altering gut microbial composition may influence cognitive function, but this has not been tested in cognitively healthy adults. This randomised, double-blinded, placebo-controlled pilot trial investigates whether FMT is feasible and improves cognition in adults with irritable bowel syndrome (IBS). Participants receive a single dose of FMT or placebo via rectal retention enema. Cognitive performance is the primary outcome, assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Secondary outcomes include IBS symptom severity and mood. Tertiary outcomes include microbiome composition and plasma biomarkers related to inflammation, short-chain fatty acids, and tryptophan metabolism. Outcomes are assessed at baseline and at one, three, six, and twelve months following treatment. We hypothesise that FMT will lead to greater improvements in cognitive performance than placebo, with benefits extending beyond practice effects, emerging at one month and persisting in the long term. The findings will contribute to evaluating the safety and efficacy of FMT and enhance our understanding of gut–brain interactions. Full article

Background/Objective: Dysbiosis is implicated in the pathogenesis of ulcerative colitis. Hydrogen has been reported to promote intestinal microbiota diversity and suppress ulcerative colitis progression in mice models. In this study, we investigated changes in the intestinal microbiota, therapeutic effects, and safety of hydrogen inhalation in patients with ulcerative colitis. Methods: In this randomised, double-blind, placebo-controlled trial, 10 active patients with ulcerative colitis (aged ≥20 years; Lichtiger’s clinical activity index, 3–10; and Mayo endoscopic subscores ≥1) participated, and they were assigned to either a hydrogen or air inhalation group (hydrogen and placebo groups, respectively). All patients inhaled gas for 4 h every day for 8 weeks. Subsequently, we performed clinical indices and microbiota analyses using the metagenomic sequencing of stool samples before and after inhalation. Results: There was significant difference in the sum of the Mayo endoscopic subscores before and after inhalation in the clinical assessment indices. The hydrogen group showed higher α-diversity (p = 0.19), and the variation in β-diversity was markedly different, compared to the placebo group, in intestinal microbiota analysis (p = 0.02). Functional gene analysis revealed 115 significant genetic changes in the hydrogen group following treatment. No inhalation-related adverse events were observed. Conclusions: Hydrogen inhalation appeared to improve intestinal microbiota diversity; however, no clear therapeutic effect on ulcerative colitis was observed. Further studies are needed, and hydrogen inhalation may possibly lead to a logical solution combined with microbiome therapy, such as faecal microbiota transplantation, with fewer adverse events. Full article