Substance use disorders (SUDs) involve a complex series of central and peripheral pathologies, leading to impairments in cognitive, behavioral, and physiological processes. Emerging evidence indicates a more significant role for the microbiome-gut-brain axis (MGBA) in SUDs than previously recognized. The MGBA is interconnected with various body systems by producing numerous metabolites, most importantly short-chain fatty acids (SCFAs), cytokines, and neurotransmitters. These mediators influence the human body's epigenome and transcriptome. While numerous epigenetic alterations in different brain regions have been reported in SUD models, the intricate relationship between SUDs and the MGBA suggests that the gut microbiome may partially contribute to the underlying mechanisms of SUDs. Promising results have been observed with gut microbiome-directed interventions in patients with SUDs, including prebiotics, probiotics, antibiotics, and fecal microbiota transplantation. Nonetheless, the long-term epigenetic effects of these interventions remain unexplored. Moreover, various confounding factors and study limitations have hindered the identification of molecular mechanisms and clinical applications of gut microbiome interventions in SUDs. In the present review, we will (i) provide a comprehensive discussion on how the gut microbiome influences SUDs, with an emphasis on epigenetic alterations; (ii) discuss the current evidence on the bidirectional relationship of gut microbiome and SUDs, highlighting potential targets for intervention; and (iii) review recent advances in gut microbiome-directed therapies, along with their limitations and future directions.

Bidirectional communications between the gut and the brain play an important role in the regulation of food intake, pain perception, mood, and cognitive function. The involved communication pathways are modulated by signals generated by the gut microbiome. Alterations in these communications have been implicated in several chronic brain and gut disorders, including food addiction, mood disorders, neurodevelopmental and neurodegenerative disorders, and functional and inflammatory bowel disorders. The gut microbiome holds great promise for the development of novel therapies normalizing altered brain-gut interactions.

The gut microbiota and its metabolites profoundly influence cardiac function, emerging as critical players in the pathophysiology of Sepsis-Induced Cardiomyopathy (SIC). Conversely, therapeutic interventions for SIC and the resultant cardiac alterations can reciprocally modulate gut microbial composition and function. To systematically elucidate this complex bidirectional relationship during SIC, this review delineates two key aspects: the 'forward gut-heart axis', defined as influences originating from the gut microbiota and its metabolites directed towards the cardiovascular system, and the 'reverse gut-heart axis', encompassing the reciprocal effects of cardiovascular drugs and cardiac factors on the gut microbiota. Furthermore, we explore potential therapeutic strategies for SIC centered on the targeted modulation of this intricate gut-heart interplay.

Background: Type 2 diabetes mellitus (T2DM) represents a major global health burden, with prevalence rates escalating due to rapid urbanization, economic growth, and the obesity epidemic. Despite intensive research, the underlying molecular mechanisms remain incompletely understood, with emerging evidence suggesting multifactorial origins involving genetic, epigenetic, lifestyle, and environmental factors. Methods: This review synthesizes current epidemiological data on T2DM prevalence, risk factors, and demographic patterns from 1990 to 2017, and discusses projected trends through 2030. We examine the role of intestinal barrier dysfunction and gut microbiota dysbiosis in T2DM pathogenesis, highlighting key mechanistic insights. Furthermore, we analyze recent findings on the role of butyrate, a major short-chain fatty acid, in preserving gut integrity and its potential therapeutic effects on metabolic health. Results: Global T2DM prevalence has risen markedly across all age groups, with particularly high rates in Western Europe and Pacific Island nations. Disruption of the intestinal barrier ("leaky gut") and gut microbiota alterations contribute significantly to systemic inflammation and insulin resistance, which are pivotal features in T2DM development. Butyrate plays a central role in maintaining epithelial barrier function, modulating immune responses, and regulating glucose metabolism. Preclinical studies have demonstrated that sodium butyrate supplementation improves gut integrity, reduces systemic endotoxemia, and ameliorates metabolic parameters. Emerging clinical evidence suggests benefits of sodium butyrate, particularly when combined with prebiotic fibers, in improving glycemic control and reducing inflammatory markers in T2DM patients. Conclusions: Gut barrier integrity and microbiota composition are critical factors in T2DM pathogenesis. Sodium butyrate shows promise as a complementary therapeutic agent in T2DM management, although further large-scale, long-term clinical trials are required to confirm its efficacy and safety. Targeting gut health may represent a novel strategy for the prevention and treatment of T2DM.

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.

The human gut microbiome's role in colorectal cancer (CRC) pathogenesis has gained increasing recognition. This study aimed to delineate the microbiome characteristics that distinguish CRC patients from healthy individuals, while also evaluating the influence of aging, through a comprehensive metagenomic approach. The study analyzed a cohort of 80 CRC patients and 80 matched healthy controls, dividing participants into a normal and a CRC group, further categorized by age into young, middle-aged, and old-aged subgroups. Extensive metagenomic sequencing of fecal samples allowed for the exploration of both the structural and functional profiles of the microbiome, with findings validated in an independent cohort to ensure robustness. Our results highlight notable differences in microbiome composition between CRC patients and healthy individuals, which exhibit age-dependent variations. Specifically, a higher prevalence of pathogenic bacteria, such as Bacteroides vulgatus, known to drive inflammation and carcinogenesis, was observed in CRC patients, alongside a reduction in beneficial microbes, including Lactobacillus. Functionally, the CRC-associated microbiome showed an increase in pathways related to DNA repair, cell cycle regulation, and metabolic activities, such as the Citrate cycle and Galactose metabolism, underscoring distinct microbial alterations in CRC patients that could influence disease onset and progression. These insights lay a foundation for future research into microbiome-based diagnostics and treatments for CRC.

This study underscores the critical role of the gut microbiome in colorectal cancer (CRC) pathogenesis, particularly in the context of aging. By identifying age-specific microbial biomarkers and functional pathways associated with CRC, our findings provide novel insights into how microbiome composition and metabolic activities influence disease progression. These discoveries pave the way for developing personalized microbiome-based diagnostic tools and therapeutic strategies, potentially improving CRC prevention and treatment outcomes across different age groups. Understanding these microbial dynamics could also inform interventions targeting gut microbiota to mitigate CRC risk and progression.

A 24 h artificial colon fermentation was performed to assess the effects of a prebiotic MIX and synthetic consortium (S7) on gut microbiota composition and microbial metabolite production in clinically stratified older adults (healthy and frail). Treatments included supplementation of the donor microbiota with a synthetic microbial consortium (S7), a prebiotic mix (MIX), and a combination of MIX and S7 (MIX+S7). The S7 treatment decreased the alpha diversity of long-stay-dwelling donor (LS, "frail") microbiota and increased the relative abundance of S7 taxa at 16 h. MIX alone caused the enrichment of reportedly beneficial genera such as Coprobacillus and Eubacterium in community-dwelling donor (CM, "healthy") microbiota and Citrobacter and Faecalibacterium in LS microbiota. The MIX+S7 treatment sustained higher overall S7 species richness and consortium taxon abundance at 24 h. Both MIX and MIX+S7 treatments enhanced short-chain acid production compared to control. These findings highlight the differential responses of microbiota from distinct elderly health strata to prebiotic and microbial consortia supplementation.

Growing evidence suggests that microbes located within the gastrointestinal tract and other anatomical locations influence the development and progression of diseases such as cancer.

Clinical and preclinical evidence suggests that microbes in the gastrointestinal tract and other anatomical locations, such as the respiratory tract, may affect carcinogenesis, development of metastases, cancer treatment response, and cancer treatment-related adverse effects. Within tumors of patients with cancer, microbes may affect response to treatment, and therapies that reduce or eliminate these microbes may improve outcomes in patients with cancer. Modulating gastrointestinal tract (gut) microbes through fecal microbiota transplant and other strategies such as dietary intervention (eg, high-fiber diet intervention) has improved outcomes in small studies of patients treated with cancer immunotherapy. In contrast, disruption of the gut microbiota by receipt of broad-spectrum antibiotics prior to treatment with cancer immunotherapy has been associated with poorer overall survival and higher rates of adverse effects in patients treated with immune checkpoint blockade for solid tumors and also with chimeric antigen receptor T-cell therapy for hematologic malignancies.

Microbes in the gut and other locations in the body may influence the development and progression of cancer and may affect the response to adverse effects from cancer therapy. Future therapies targeting microbes in the gut and other locations in the body could potentially improve outcomes in patients with cancer.

As the main active ingredient of the first FDA-approved phytochemical drug, epigallocatechin gallate (EGCG) can effectively alleviate glucolipid metabolic disorders. However, existing studies mainly focuses on the treatment of EGCG in disease models, with limited focus on its preventive effect on diseases in healthy models.

This study investigated how EGCG prevents and alleviates T2DM through gut microbiota and multi-organ interactions in Wistar healthy rats and GK T2DM rats.

The GK T2DM rat strain was established through repeated selective breeding of Wistar rats with glucose intolerance. Whether and how EGCG prevents and alleviates T2DM were evaluated, including glucose production and absorption efficiency, glucose transport, glucose metabolism, glucose excretion, T2DM-related tissue damage, gut microbiota, and liver transcriptome.

The health benefits of EGCG are primarily reliant on the involvement of the gut microbiota. Our study showed that although the specific microbial communities involved differ, the bidirectional interaction between EGCG and gut microbiota is widespread in healthy rats and T2DM rats. EGCG intervention elevated the relative abundance of specific microbial communities, which in turn promoted the metabolic processing of EGCG in the gut, producing numerous EGCG metabolites that may contribute to preventing and alleviating T2DM. In healthy rats, EGCG intervention selectively enhanced insulin secretion and serum insulin levels to prevent T2DM. In T2DM rats, EGCG intervention selectively lowered blood glucose levels, improved insulin resistance, delayed glucose production and absorption, and promoted urinary glucose excretion to alleviate T2DM. In both healthy and T2DM rats, EGCG intervention universally reduced gut microbiota-derived lipopolysaccharides, maintained systemic oxidative stress homeostasis, alleviated liver and kidney damage, increased muscle glycogen content, and promoted beige thermogenesis in white fat, thus demonstrating potential for preventing and alleviating T2DM.

As a natural active ingredient, EGCG could prevent and alleviate T2DM through gut microbiota and multi-organ interactions.

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.

In recent years, advancements in metagenomics, metabolomics, and single-cell sequencing have enhanced our understanding of the intricate relationships between gut microbiota and their hosts. Gut microbiota colonize humans from birth, with their initial composition significantly influenced by the mode of delivery and feeding method. During the transition from infancy to early childhood, exposure to a diverse diet and the maturation of the immune system lead to the gradual stabilization of gut microbiota's composition and distribution. Numerous studies have demonstrated that gut microbiota can influence a wide range of physiological functions and pathological processes by interacting with various tissues and organs through the gut-organ axis. Different intestinal segments exhibit unique physical and chemical conditions, which leads to the formation of vertical gradients along the intestinal tract: aerobes and facultative aerobes mainly live in the small intestine and anaerobic bacteria mainly live in the large intestine, and horizontal gradients: mucosa-associated microbiota and lumen-associated microbiota. In this review, we systematically summarize the distribution characteristics of gut microbiota across six intestinal segments: duodenum, jejunum, ileum, cecum, colon, and rectum. We also draw a conclusion that gut microbiota distributed in different intestinal segments affect the progression of different diseases. We hope to elucidate the role of microbiota at specific anatomic sites within the gut in precisely regulating the processes of particular diseases, thereby providing a solid foundation for developing novel diagnostic and therapeutic strategies for related diseases.

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.

Almonds, a nutrient-dense food rich in dietary fiber, polyphenols, and unsaturated fatty acids, exhibit significant potential as a functional food with prebiotic effects. Prebiotics selectively stimulate the growth and activity of beneficial gut microbiota, leading to improved gut and systemic health. This review synthesizes evidence from in vitro studies, clinical trials, and systematic reviews to elucidate the prebiotic effects of almond consumption. Almonds enhance gut microbiota diversity and composition, particularly increasing beneficial bacteria such as Bifidobacterium and Roseburia, while promoting the production of short-chain fatty acids (SCFAs), such as butyrate, which are critical for gut barrier integrity and inflammation modulation. The presence of polyphenols, such as proanthocyanidins, contributes to their antioxidative and antimicrobial properties, further supporting microbiome health. Despite variability in study outcomes, likely due to differences in population health status, study design, and almond preparation methods, the cumulative findings underscore almonds' role as a potential prebiotic food with the potential to improve cardiovascular health. Continued research focusing on individualized responses and standardized methodologies is essential to fully harness the health benefits of almond consumption.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease closely associated with dysbiosis of the gut microbiome, encompassing not only bacterial communities but also fungal populations. Despite the growing recognition of the gut microbiome's role in UC pathogenesis, the contribution of intestinal fungi has only recently garnered significant attention. In this review, we comprehensively examine the characteristics of intestinal fungi in both healthy individuals and UC patients, elucidating their role in disease pathogenesis and their interactions with bacterial communities. Additionally, we explore the impact of intestinal fungi on disease severity and therapeutic responses in UC. Furthermore, we evaluate the therapeutic potential of antifungal agents, probiotics, and fecal microbiota transplantation (FMT) in UC management, emphasizing the critical role of fungi in these treatment modalities. Future research should prioritize elucidating the multifunctional roles of fungi in UC pathogenesis and their implications for treatment strategies. Moreover, the identification of fungal biomarkers associated with FMT efficacy could pave the way for precision medicine approaches in FMT, offering novel insights into personalized therapeutic interventions for UC.

A robust index of gut microbiome taxa encompassing their association with host health and microbiome resilience would be valuable for development and optimization of microbiome-based therapeutics. Here we present a single ranked order for 201 taxa, the Health-Associated Core Keystone (HACK) index, derived using their association strengths with prevalence/community association in non-diseased subjects, longitudinal stability, and host health. The index was derived based on 127 discovery cohorts and 14 validation datasets (cumulatively encompassing 45,424 gut microbiomes, subject age >18 years, representing 42 countries, 28 disease categories, and 10,021 longitudinal samples). We show that this index is reproducible regardless of microbiome profiling strategies and cohort lifestyle. Specific consortia of high HACK index taxa respond positively to Mediterranean diet interventions and reflect immune checkpoint inhibitor responsiveness and associated with specific functional profiles at the genome level. The availability of HACK indices provides a rational basis for comparing microbiomes and facilitating selection and design of microbiome-based therapeutics.

The gut microbiome comprises a vast community of microbes inhabiting the human alimentary canal, playing a crucial role in various physiological functions. These microbes generally live in harmony with the host; however, when dysbiosis occurs, it can contribute to the pathogenesis of diseases, including osteoporosis. Osteoporosis, a systemic skeletal disease characterized by reduced bone mass and increased fracture risk, has attracted significant research attention concerning the role of gut microbes in its development. Advances in molecular biology have highlighted the influence of gut microbiota on osteoporosis through mechanisms involving immunoregulation, modulation of the gut-brain axis, and regulation of the intestinal barrier and nutrient absorption. These microbes can enhance bone mass by inhibiting osteoclast differentiation, inducing apoptosis, reducing bone resorption, and promoting osteoblast proliferation and maturation. Despite these promising findings, the therapeutic effectiveness of targeting gut microbes in osteoporosis requires further investigation. Notably, gut microbiota has been increasingly studied for their potential in early diagnosis, intervention, and as an adjunct therapy for osteoporosis, suggesting a growing utility in improving bone health. Further research is essential to fully elucidate the therapeutic potential and clinical application of gut microbiome modulation in the management of osteoporosis.

A recent study by A. Bhosle, M. I. Jackson, A. M. Walsh, E. A. Franzosa, et al. (mSystems 10:e00452-24, 2024, https://doi.org/10.1128/msystems.00452-24) enhances our understanding of dietary fiber's impact on the gut microbiome and metabolome in companion animals, uncovering individual variations in microbial and metabolic responses. By examining short-chain fatty acid (SCFA) profiles in response to fiber, the authors reveal potential therapeutic benefits of tailored dietary interventions, such as enhanced gut and immune health. These findings resonate with human microbiome research, where dietary fiber has shown health benefits through microbial diversity and SCFA production. The study emphasizes the potential for breed-specific responses to fiber, given the variation in microbiome composition and physiology across breeds. Such insights align with emerging concepts of personalized nutrition, offering an opportunity to develop precision dietary strategies that address specific health needs in both veterinary and human contexts. This foundational research positions dietary fiber as a valuable tool in preventive health, providing a roadmap for future studies to refine individualized approaches for gut microbiome modulation.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting reproductive-age women, characterized primarily by hyperandrogenism, ovulatory dysfunction, and metabolic abnormalities. In recent years, the gut microbiota has garnered widespread attention for its potential role as a key regulator of host metabolism in the pathogenesis of PCOS. Studies have shown that PCOS patients exhibit dysbiosis in their gut microbiota, characterized by reduced microbial diversity, an imbalance in the ratio of Firmicutes to Bacteroidetes, changes in the abundance of specific taxa, and abnormal levels of metabolic products. These alterations may exacerbate metabolic dysfunction in PCOS through multiple mechanisms, including influencing host energy metabolism, disrupting lipid and bile acid metabolism, and inducing chronic inflammation. Addressing gut dysbiosis through the modulation of patients' microbiomes-such the use of, prebiotics, fecal microbiota transplantation, and optimizing diet lifestyle-may offer strategies for improving metabolic abnormalities and alleviating clinical symptoms in PCOS. Additionally, the gut microbiome promises as a potential marker, aiding in the precise diagnosis and personalization of PCOS. Although our current understanding of how the gut microbiota influences PCOS is still limited, research is needed to explore the causal relationships and mechanisms involved, providing a more reliable theoretical basis for clinical. This review aims summarize the research progress on the relationship between gut microbiota and PCOS, and to suggest future directions to promote the development of prevention and treatment strategies for PCOS.

The healthy gut microbiome is important in maintaining health and preventing various chronic and metabolic diseases through interactions with the host via different gut-organ axes, such as the gut-brain, gut-liver, gut-immune, and gut-lung axes. The human gut microbiome is relatively stable, yet can be influenced by numerous factors, such as diet, infections, chronic diseases, and medications which may disrupt its composition and function. Therefore, microbial resilience is suggested as one of the key characteristics of a healthy gut microbiome in humans. However, our understanding of its definition and indicators remains unclear due to insufficient experimental data. Here, we review the impact of key drivers including intrinsic and extrinsic factors such as diet and antibiotics on the human gut microbiome. Additionally, we discuss the concept of a resilient gut microbiome and highlight potential biomarkers including diversity indices and some bacterial taxa as recovery-associated bacteria, resistance genes, antimicrobial peptides, and functional flexibility. These biomarkers can facilitate the identification and prediction of healthy and resilient microbiomes, particularly in precision medicine, through diagnostic tools or machine learning approaches especially after antimicrobial medications that may cause stable dysbiosis. Furthermore, we review current nutrition intervention strategies to maximize microbial resilience, the challenges in investigating microbiome resilience, and future directions in this field of research.

Cholecystectomy (CCE) can affect the enterohepatic circulation of bile acids and result in gut microbiome changes. This systematic review aimed to clarify the effect of CCE on gut microbiome composition and its clinical impact.

A systematic search was conducted in PubMed, Web of Science, and Scopus, combining keywords such as "cholecystectomy" or "post-cholecystectomy" with "gut microbiome," "stool microbiome," or "gut dysbiosis." Data were extracted and synthesized using narrative review. Study quality was assessed using the Newcastle-Ottawa scale.

A total of 1373 articles were screened and 14 studies were selected. Significant but inconsistent microbiome changes were reported. Changes were observed in alpha and beta diversity. At phylum level, an increase in Bacteroides and Ascomycota, decrease in Firmicutes, Actinomycetes, and Basidiomycota, and both increase and decrease in Fusobacteria were reported. At genus level, an increase in Prevotella and a decrease in Faecalibacterium were reported. In post-CCE diarrhea, decreased beta diversity, a decreased F/B ratio, an increase in Prevotella, an increase in Phocaeicola vulgatus, and a decrease in Prevotella copri were noted. For post-CCE syndrome, a higher abundance of Proteobacteria and decreased Firmicutes/Bacteroides (F/B) ratio were reported. A decreased relative abundance of Bifidobacterium longum subsp. longum from controls to CCE without colonic neoplasia to CCE with colonic neoplasia, and an increased abundance of Candida glabrata from controls, to CCE without colonic neoplasia and CCE with colonic neoplasia, were reported.

Patients who underwent CCE had significant gut dysbiosis. However, current studies could not clarify the detailed gut microbial structural and functional changes associated with CCE.

Human microbiomes are essential to health throughout the lifespan and are increasingly recognized and studied for their roles in metabolic, immunological and neurological processes. Although the full complexity of these microbial communities is not fully understood, their clinical and industrial exploitation is well advanced and expanding, needing greater oversight guided by a consensus from the research community. One of the most controversial issues in microbiome research is the definition of a 'healthy' human microbiome. This concept is complicated by the microbial variability over different spatial and temporal scales along with the challenge of applying a unified definition to the spectrum of healthy microbiome configurations. In this Perspective, we examine the progress made and the key gaps that remain to be addressed to fully harness the benefits of the human microbiome. We propose a road map to expand our knowledge of the microbiome-health relationship, incorporating epidemiological approaches informed by the unique ecological characteristics of these communities.

Microbial communities inhabiting various body sites play critical roles in the initiation, progression, and treatment of cancer. The gut microbiota, a highly diverse microbial ecosystem, interacts with immune cells to modulate inflammation and immune surveillance, influencing cancer risk and therapeutic outcomes. Local tissue microbiota may impact the transition from premalignant states to malignancy. Characterization of the intratumoral microbiota increasingly reveals distinct microbiomes that may influence tumor growth, immune responses, and treatment efficacy. Various bacteria species have been reported to modulate cancer therapies through mechanisms such as altering drug metabolism and shaping the tumor microenvironment (TME). For instance, gut or intratumoral bacterial enzymatic activity can convert prodrugs into active forms, enhancing therapeutic effects or, conversely, inactivating small-molecule chemotherapeutics. Specific bacterial species have also been linked to improved responses to immunotherapy, underscoring the microbiome's role in treatment outcomes. Furthermore, unique microbial signatures in cancer patients, compared with healthy individuals, demonstrate the diagnostic potential of microbiota. Beyond the gut, tumor-associated and local microbiomes also affect therapy by influencing inflammation, tumor progression, and drug resistance. This review explores the multifaceted relationships between microbiomes and cancer, focusing on their roles in modulating the TME, immune activation, and treatment efficacy. The diagnostic and therapeutic potential of bacterial members of microbiota represents a promising avenue for advancing precision oncology and improving patient outcomes. By leveraging microbial biomarkers and interventions, new strategies can be developed to optimize cancer diagnosis and treatment.

The benefits of regular physical activity (PA) on disease prevention and treatment outcomes have been recognized for centuries. However, only recently has interorgan communication triggered by the release of "myokines" from contracting skeletal muscles emerged as a putative mechanism by which exercise confers protection against numerous disease states. Cross-talk between active skeletal muscles and the gut microbiota reveal how regular PA boosts host immunity, facilitates a more diverse gut microbiome and functional metabolome, and plays a positive role in energy homeostasis and metabolic regulation. In contrast, and despite the large interindividual variation in the human gut microbiome, reduced microbial diversity has been implicated in several diseases of the gastrointestinal (GI) tract, systemic immune diseases, and cancers. Although prolonged, intense, weight-bearing exercise conducted in extreme conditions can increase intestinal permeability, compromising gut-barrier function and resulting in both upper and lower GI symptoms, these are transient and benign. Accordingly, the gut microbiome has become an attractive target for modulating many of the positive effects of regular PA on GI health and disease, although the precise dose of exercise required to induce favourable changes in the microbiome and enhance host immunity is currently unknown. Future efforts should concentrate on gaining a deeper understanding of the factors involved in exercise-gut interactions through the generation of functional 'omics readouts (ie, metatranscriptomics, metaproteomics, and metabolomics) that have the potential to identify functional traits of the microbiome that are linked to host health and disease states, and validating these interactions in experimental and preclinical systems. A greater understanding of how PA interacts with the GI tract and the microbiome may enable targeted therapeutic strategies to be developed for individuals and populations at risk for a variety of GI diseases.

Human gut microbiome composition and function is influenced by environmental and lifestyle factors, including exercise and fitness. We studied the composition and functionality of the faecal microbiome of recreational (non-elite) runners (n = 62) with serial shotgun metagenomics, at 4 time points over a 7-week period. Gut microbiome composition and function was stable over time. Grouping of samples on the basis of their fitness level (fair, good, excellent, and superior) or habitual training (low (4-6 h/week), medium (7-9 h/week), high (10-12 h/week), and extreme (13 + hours/week)) revealed no significant microbiome-related differences. Overall, the species Faecalibacterium prausnitzii, Blautia wexlerae, and Prevotella copri were the most abundant members of the gut microbiome. Analysis of co-abundance groups (CAGs) revealed no significant relationship between CAGs and fitness levels or training subgroups. Functional pathways were similar across all samples and timepoints with no clustering based on associated metadata. The most abundant genes identified within samples corresponded to pathways for nucleoside and nucleotide biosynthesis, amino acid biosynthesis, and cell wall biosynthesis. Collectively, these results describe the microbiome of active recreational runners and note temporal stability amongst participants.

Gut single-celled eukaryotes (GSCEs) are found in billions of people worldwide, but we still know little about their functions and relationships in human gut ecology. Lately, retrospective analysis of bacterial data obtained by next-generation sequencing (NGS) methods has been used to identify links between GSCEs, gut bacteria, host metabolism, and host phenotypical traits, suggesting possible direct or indirect associations to favorable gut microbiome features and other health parameters. Here, we highlight some of the pitfalls related to the research strategy typically used so far and propose action points that could pave the way for a more accurate understanding of GSCEs in human health and disease.

Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that profoundly impacts cognitive function and the nervous system. Emerging evidence highlights the pivotal roles of iron homeostasis dysregulation and microbial inflammatory factors in the oral and gut microbiome as potential contributors to the pathogenesis of AD. Iron homeostasis disruption can result in excessive intracellular iron accumulation, promoting the generation of reactive oxygen species (ROS) and oxidative damage. Additionally, inflammatory agents produced by pathogenic bacteria may enter the body via two primary pathways: directly through the gut or indirectly via the oral cavity, entering the bloodstream and reaching the brain. This infiltration disrupts cellular homeostasis, induces neuroinflammation, and exacerbates AD-related pathology. Addressing these mechanisms through personalized treatment strategies that target the underlying causes of AD could play a critical role in preventing its onset and progression.

Previous observational studies suggest a potential link between gut microbiota, metabolites, and diabetic nephropathy. However, the exact causal relationship among these factors remains unclear.

We conducted a two-sample bidirectional Mendelian randomization study using summary statistics from the IEU OpenGWAS Project database to investigate gut microbiota, metabolites, and diabetic nephropathy. A range of methods, including inverse variance weighting, MR-Egger, weighted median, and simple median, were applied to examine causal associations. Sensitivity analyses were performed to assess the robustness of the results. Additionally, reverse Mendelian randomization analysis was conducted, treating significant gut microbiota as the outcome, to evaluate effects and perform sensitivity testing. This comprehensive approach provided an in-depth assessment of the interactions among gut microbiota, metabolites, and diabetic nephropathy.

The Inverse Variance Weighted estimates revealed that the abundance of Lachnospiraceae, Parasutterella, and Eubacterium exhibited negative causal effects on diabetic nephropathy, while Coprococcus, Sutterella, Faecalibacterium prausnitzii, and Bacteroides vulgatus showed protective causal effects against the condition. However, reverse Mendelian randomization analysis did not identify any significant associations between diabetic nephropathy and the identified gut microbiota. Furthermore, the estimates indicated that Cholesterol, Pyridoxate, Hexanoylcarnitine, X-12007, Octanoylcarnitine, 10-nonadecenoate (19:1n9), X-12734, and the average number of double bonds in a fatty acid chain had negative causal effects on diabetic nephropathy. In contrast, Methionine, Glycodeoxycholate, X-06351, 1-stearoylglycerol (1-monostearin), 5-dodecenoate (12:1n7), X-13859, 2-hydroxyglutarate, Glycoproteins, Phospholipids in IDL, and the concentration of small HDL particles demonstrated protective causal effects. Notably, sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy, ensuring the robustness of the findings.

Modulating gut microbiota diversity and composition offers a promising strategy for improving the incidence and prognosis of diabetic nephropathy. This highlights the need for future clinical trials focusing on microbiome-based interventions, potentially utilizing microbiome-dependent metabolites. Such approaches could transform the treatment and management of diabetic nephropathy and its associated risk factors, paving the way for more effective therapeutic strategies to combat this debilitating condition.

Advancing microbiome-gut-brain axis science requires systematic, rational and translational approaches to bridge the critical knowledge gaps currently preventing full exploitation of the gut microbiome as a tractable therapeutic target for gastrointestinal, mental and brain health. Current research is still marked by many open questions that undermine widespread application to humans. For example, the lack of mechanistic understanding of probiotic effects means it remains unclear why even apparently closely related strains exhibit different effects in vivo. For the therapeutic application of live microbial psychobiotics, consensus on their application as adjunct treatments to conventional neuromodulators, use in unmedicated populations or in at-risk cohorts with sub-clinical symptomatology is warranted. This missing information on both sides of the therapeutic equation when treating central nervous system (CNS) conditions makes psychobiotic research challenging, especially when compared to other pharmaceutical or functional food approaches. Expediting the transition from positive preclinical data to proven benefits in humans includes interpreting the promises and pitfalls of animal behavioural assays, as well as navigating mechanism-informed decision making to select the right microbe(s) for the job. In this review, we consider how these decisions can be supported in light of information accrued from a range of clinical studies across healthy, at-risk and pathological study populations, where specific strains have been evaluated in the context of gastrointestinal physiology, brain function and behaviour. Examples of successful, partial and unsuccessful translation from bench to bedside are considered. We also discuss the developments in in silico analyses that have enhanced our understanding of the gut microbiome and that have moved research towards pinpointing the host-microbe interactions most important for optimal gut-brain axis function. Combining this information with knowledge from functional assays across in vitro and ex vivo domains and incorporating model organisms can prime the discovery pipelines with the most promising and rationally selected psychobiotic candidates.

The human microbiome is a sensor and modulator of physiology and homeostasis. Remarkable tractability underpins the promise of therapeutic manipulation of the microbiome. However, the definition of a normal or healthy microbiome has been elusive. This is in part due to the underrepresentation of minority groups and major global regions in microbiome studies to date. We review studies of the microbiome in different populations and highlight a commonality among health-associated microbiome signatures along with major drivers of variation. We also provide an overview of microbiome-associated therapeutic interventions for some widespread, widely studied diseases. We discuss sources of bias and the challenges associated with defining population-specific microbiome reference bases. We propose a roadmap for defining normal microbiome references that can be used for population-customized microbiome therapeutics and diagnostics.

An altered gut microbiome is a feature of many multifactorial diseases, and microbiome effects on host metabolism, immune function, and possibly neurological function are implicated. Increased biological age is accompanied by a change in the gut microbiome. However, age-related health loss does not occur uniformly across all subjects but rather depends on differential loss of gut commensals and gain of pathobionts. In this article, we summarize the known and possible effects of the gut microbiome on the hallmarks of aging and describe the most plausible mechanisms. Understanding and targeting these factors could lead to prolonging health span by rationally maintaining the gut microbiome.

Irritable bowel syndrome is a common functional gastrointestinal disorder characterized by recurrent abdominal discomfort, bloating, cramping, flatulence, and changes in bowel movements. The pathophysiology of IBS involves a complex interaction between motor, sensory, microbiological, immunological, and psychological factors. Diversity, stability, and metabolic activity of the gut microbiota are frequently altered in IBS, thus leading to a situation of gut dysbiosis. Therefore, the use of probiotics and probiotic-derived metabolites may be helpful in balancing the gut microbiota and alleviating irritable bowel syndrome symptoms. This review aimed to report and consolidate recent progress in understanding the role of gut dysbiosis in the pathophysiology of IBS, as well as the current studies that have focused on the use of probiotics and their metabolites, providing a foundation for their potential beneficial effects as a complementary and alternative therapeutic strategy for this condition due to the current absence of effective and safe treatments.

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival.

Obesity is a multifactorial condition influenced by genetic, environmental, and microbiome-related factors. The gut microbiome plays a vital role in maintaining intestinal health, increasing mucus creation, helping the intestinal epithelium mend, and regulating short-chain fatty acid (SCFA) production. These tasks are vital for managing metabolism and maintaining energy balance. Dysbiosis-an imbalance in the microbiome-leads to increased appetite and the rise of metabolic disorders, both fuel obesity and its issues. Furthermore, childhood obesity connects with unique shifts in gut microbiota makeup. For instance, there is a surge in pro-inflammatory bacteria compared to children who are not obese. Considering the intricate nature and variety of the gut microbiota, additional investigations are necessary to clarify its exact involvement in the beginnings and advancement of obesity and related metabolic dilemmas. Currently, therapeutic methods like probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), dietary interventions like Mediterranean and ketogenic diets, and physical activity show potential in adjusting the gut microbiome to fight obesity and aid weight loss. Furthermore, the review underscores the integration of microbial metabolites with pharmacological agents such as orlistat and semaglutide in restoring microbial homeostasis. However, more clinical tests are essential to refine the doses, frequency, and lasting effectiveness of these treatments. This narrative overview compiles the existing knowledge on the multifaceted role of gut microbiota in obesity and much more, showcasing possible treatment strategies for addressing these health challenges.

The exponential growth of high-throughput sequencing (HTS) data on the microbial communities presents researchers with an unparalleled opportunity to delve deeper into the association of microorganisms with host phenotype. However, this growth also poses a challenge, as microbial data are complex, sparse, discrete, and prone to zero inflation. Herein, by utilizing 10 distinct counting models for analyzing simulated data, we proposed an innovative Bayesian zero-inflated negative binomial (ZINB) regression model that is capable of identifying differentially abundant taxa associated with distinctive host phenotypes and quantifying the effects of covariates on these taxa. Our proposed model exhibits excellent accuracy compared with conventional Hurdle and INLA models, especially in scenarios characterized by inflation and overdispersion. Moreover, we confirm that dispersion parameters significantly affect the accuracy of model results, with defects gradually alleviating as the number of analyzed samples increases. Subsequently applying our model to amplicon data in real multi-ethnic children cohort, we found that only a subset of taxa were identified as having zero inflation in real data, suggesting that the prevailing understanding and processing of microbial count data in most previous microbiome studies were overly dogmatic. In practice, our pipeline of integrating bacterial differential abundance in microbiome data and relevant covariates is effective and feasible. Taken together, our method is expected to be extended to the microbiota studies of various multi-cohort populations.

The microbiome is closely associated with physical indicators of the body, such as height, weight, age and BMI, which can be used as measures of human health. Accurately identifying which taxa in the microbiome are closely related to indicators of physical development is valuable as microbial markers of regional child growth trajectory. Zero-inflated negative binomial (ZINB) model, a type of Bayesian generalized linear model, can be effectively modeled in complex biological systems. We present an innovative ZINB regression model that is capable of identifying differentially abundant taxa associated with distinctive host phenotypes and quantifying the effects of covariates on these taxa, and demonstrate that its accuracy is superior to traditional Hurdle and INLA models. Our pipeline of integrating bacterial differential abundance in microbiome data and relevant covariates is effective and feasible.

Existing microbiota databases are biased toward adult samples, hampering accurate profiling of the infant gut microbiome. Here, we generated a metagenome-assembled genome inventory for children (MAGIC) from a large collection of bulk and viral-like particle-enriched metagenomes from 0 to 7 years of age, encompassing 3,299 prokaryotic and 139,624 viral species-level genomes, 8.5% and 63.9% of which are unique to MAGIC. MAGIC improves early-life microbiome profiling, with the greatest improvement in read mapping observed in Africans. We then identified 54 candidate keystone species, including several Bifidobacterium spp. and four phages, forming guilds that fluctuated in abundance with time. Their abundances were reduced in preterm infants and were associated with childhood allergies. By analyzing the B. longum pangenome, we found evidence of phage-mediated evolution and quorum sensing-related ecological adaptation. Together, the MAGIC database recovers genomes that enable characterization of the dynamics of early-life microbiomes, identification of candidate keystone species, and strain-level study of target species.

The term prebiotic has been used for almost 3 decades and has undergone numerous updates over the years. The scientific literature reveals that despite continuous efforts to establish a globally unified definition to guide jurisdictional regulations and product innovations, ambiguity continues to surround the terms prebiotic and prebiotic effect, leading to products that lack in full regulatory adherence being marketed worldwide. Thus, to reflect the current state of scientific research and knowledge and for the continuous advancement of the category, an update to the current prebiotic definition is warranted. This update includes removing the term selectivity, considering additional locations of action besides the gut, highlighting prebiotic performance benefits such as cognitive and athletic, and providing a clear standalone definition for prebiotic effect. The Global Prebiotic Association (GPA) is a leading information and industry hub committed to raising awareness about prebiotics, their emerging and well-established health benefits, and prebiotic product integrity and efficacy. In this position paper, GPA builds on previous prebiotic definitions to propose the following expanded definition for prebiotic: "a compound or ingredient that is utilized by the microbiota producing a health or performance benefit." In addition to prebiotic, GPA also defines prebiotic effect as "a health or performance benefit that arises from alteration of the composition and/or activity of the microbiota, as a direct or indirect result of the utilization of a specific and well-defined compound or ingredient by microorganisms." With these 2 definitions, GPA aims to paint a clearer picture for the term prebiotic, and by incorporating an industry point of view, these updated definitions may be used alongside current scientific and regulatory perspectives to move the category forward.

To provide some glimpses on the possibility of shaping the human gut microbiome (GM) through probiotic exchange with natural ecosystems, here we explored the impact of 15 days of daily interaction with horses on the GM of 10 urban-living Italian children. Specifically, the children were in close contact with the horses in an "educational farm", where they spent almost 10 h/day interacting with the animals. The children's GM was assessed before and after the horse interaction using metabarcoding sequencing and shotgun metagenomics, along with the horses' skin, oral and fecal microbiomes. Targeted metabolomic analysis for GM-produced beneficial metabolites (i.e., short-chain fatty acids) in the children's feces was also performed. Interaction with horses facilitated the acquisition of health-related traits in the children's GM, such as increased diversity, enhanced butyrate production and an increase in several health-promoting species considered to be next-generation probiotics. Among these, the butyrate producers Facecalibacterium prausnitzii and F. duncaniae and a species belonging to the order Christensenellales. Interaction with horses was also associated with increased proportions of Eggerthella lenta, Gordonibacter pamelae and G. urolithinfaciens, GM components known to play a role in the bioconversion of dietary plant polyphenols into beneficial metabolites. Notably, no increase in potentially harmful traits, including toxin genes, was observed. Overall, our pilot study provides some insights on the existence of possible health-promoting exchanges between children and horses microbiomes. It lays the groundwork for an implemented and more systematic enrollment effort to explore the full complexity of human GM rewilding through exchange with natural ecosystems, aligning with the One Health approach.

Over the past two decades, as the importance of gut microbiota to human health has become widely known, attempts have been made to treat diseases by correcting dysbiosis of gut microbiota through fecal microbiota transplantation (FMT). Apart from current knowledge of gut microbiota, FMT to treat disease has a long history, from the treatment of food poisoning in the fourth century to the treatment of Clostridioides difficile infections in the twentieth century. In 2013, FMT was recognized as a standard treatment for recurrent C. difficile because it consistently showed high efficacy. Though recurrent C. difficile is the only disease internationally recognized for FMT efficacy, FMT has been tested for other diseases and shown some promising preliminary results. Different FMT methods have been developed using various formulations and administration routes. Despite advances in FMT, some issues remain to be resolved, such as donor screening, manufacturing protocols, and unknown components in the fecal microbiota. In this review, we discuss the mechanisms, clinical indications, methods, and challenges of current FMT. We also discuss the development of alternative therapies to overcome the challenges of FMT.

The human gut microbiome is a dynamic and intricate ecosystem, composed of trillions of microorganisms that play a pivotal role in maintaining overall health and well-being. However, the gut microbiome is constantly exposed to various environmental factors, including the bile produced by the liver, which can significantly impact its composition and function. Bile acids, secreted by the liver and stored in the gallbladder, modulate the gut microbiome, influencing its composition and function. This altered microbiome profile can, in turn, impact the tumor microenvironment (TME), promoting an immunosuppressive environment that favors tumor growth and metastasis. Furthermore, changes in the gut microbiome can also influence the production of bile acids and other metabolites that directly affect cancer cells and their behavior. Moreover, bile acids have been shown to shape the microbiome and increase antibiotic resistance, underscoring the need for targeted interventions. This review provides a comprehensive overview of the intricate relationships between bile, the gut microbiome, and the TME, highlighting the mechanisms by which this interplay drives cancer progression and resistance to therapy. Understanding these complex interactions is crucial for developing novel therapeutic strategies that target the gut-bile-TME axis and improve patient outcomes.