Antimicrobial resistance (AMR) and the evolution of multiple drug-resistant (MDR) bacteria is of grave public health concern. To combat the pandemic of AMR, it is necessary to focus on novel alternatives for drug development. Within the host, the interaction of the pathogen with the microbiome plays a pivotal role in determining the outcome of pathogenesis. Therefore, microbiome-pathogen interaction is one of the potential targets to be explored for novel antimicrobials.

This review focuses on how the gut microbiome has evolved as a significant component of the resistome as a source of antibiotic resistance genes (ARGs). Antibiotics alter the composition of the native microbiota of the host by favouring resistant bacteria that can manifest as opportunistic infections. Furthermore, gut dysbiosis has also been linked to low-dosage antibiotic ingestion or subtherapeutic antibiotic treatment (STAT) from food and the environment.

Colonization by MDR bacteria is potentially acquired and maintained in the gut microbiota. Therefore, it is pivotal to understand microbial diversity and its role in adapting pathogens to AMR. Implementing several strategies to prevent or treat dysbiosis is necessary, including faecal microbiota transplantation, probiotics and prebiotics, phage therapy, drug delivery models, and antimicrobial stewardship regulation.

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

Probiotics and prebiotics serve as vital tools in managing gut microecology and enhancing immune responses. However, the effectiveness of non-encapsulated probiotics often diminishes during processing, storage, and transport to the gastrointestinal tract, especially at elevated temperatures. To address this challenge, a novel loading strategy for Lactobacillus reuteri DPC16 (L. reuteri) is proposed in this work, using pressure-sensitive high-methoxy pectin (HMP)/fructooligosaccharides (FOS) hydrogel. The HMP/FOS hydrogel melted at 600 MPa to form a sol. The resulting sol was mixed with L. reuteri immediately at ambient conditions, which underwent a sol-to-gel transition subsequently to form a composite hydrogel with a continuous porous structure. The resulting HMP/FOS@L. reuteri hydrogel achieved a loading concentration of viable bacteria at 109 CFU/mL. In vitro assessments reveal that the hydrogel demonstrates good biocompatibility and targeted release of probiotics within the intestine. Furthermore, the hydrogel substantially boosted the short-chain fatty acids levels and increased the amounts of acetic and isovaleric acids, respectively. This work underscores the unique advantages of employing a pressure-sensitive HMP/FOS hydrogel for loading and targeted delivery of probiotics and prebiotics to improve intestinal health.

Ageing disrupts how our bodies process nutrients, leading to deregulation of nutrient-sensing and increased inflammation. Dietary interventions can promote healthy ageing, which demonstrates the importance of both metabolism and the gastrointestinal tract for our health. Bitter taste receptors (TAS2R) present in the intestine are key members of metabolic regulation. TAS2R are involved in controlling enterohormonal secretion, detect phenolic compounds in our diet, and potentially have a great impact on the ageing process. Here, we aimed to analyze the potential role of intestinal TAS2R on the ageing process and establish potential impact of these receptors on the biomarkers. Healthy subjects were divided into two age cohorts: young (38.9±6) and aged (63.6±6). TAS2R expression was analyzed in the colon. Analyses of metabolomics and of phenolic markers were performed in plasma. Best discriminatory parameters were obtained using three machine-learning methods. Finally, Spearman's rank correlation was performed. The best separators of the age cohorts were docosahexaenoic acid and multiple lipoprotein fractions. Two TAS2R were also identified: TAS2R5 and TAS2R38. TAS2R5 correlated with multiple lipoprotein-derived fractions, inflammatory marker IL-6 and polyunsaturated fatty acids. TAS2R38 was much more selective, correlating with a few parameters, including membrane lipid sphingomyelin, ketone body acetone, and omega acids. Both TAS2R5 and TAS2R38 correlated with β-hydroxybutyrate. The parameters that correlated with TAS2R have known effects on the ageing process. This suggests that TAS2R5 and TAS2R38 are the bitter receptors most likely to play a role in the development and progress of ageing.

Biological ageing is a time-dependent process that has implications for health and disease. Cellular senescence is a key driver in ageing and age-related diseases. Senotherapeutic agents have been shown to slow biological ageing by eliminating senescent mammalian cells. Given the increasing awareness of the gut microbiome in regulating human health, this study aimed to investigate the effects of senotherapeutic agents as pharmacological interventions on the human gut microbiota. In this study, the bidirectional effects of four senotherapeutic agents, quercetin, fisetin, dasatinib, and sirolimus, with the gut microbiota sourced from healthy human donors were investigated. The results revealed that quercetin was completely biotransformed by the gut microbiota within six hours, while dasatinib was the most stable of the four compounds. Additionally, metagenomic analysis confirmed that all four compounds increased the abundance of bacterial species associated with healthy ageing (e.g., Bacteroides fragilis, Bifidobacterium longum, and Veillonella parvula), and decreased the abundance of pathogenic bacteria primarily associated with age-related diseases (e.g., Enterococcus faecalis and Streptococcus spp.). The findings from this study provide a comprehensive understanding of the pharmacobiomics of senotherapeutic interventions, highlighting the potential of microbiome-targeted senolytics in promoting healthy ageing.

The gut microbiota has emerged as a critical determinant of immune checkpoint inhibitor (ICI) efficacy, resistance, and toxicity. Retrospective and prospective studies profiling the taxonomic composition of intestinal microbes of patients treated with ICI have revealed specific gut microbial signatures associated with response. By contrast, dysbiosis, which can be caused by chronic inflammatory processes (such as cancer) or comedications, is a risk factor of resistance to ICI. Recent large-scale meta-analyses have confirmed that antibiotic (ATB) use before or during ICI therapy alters the microbiota repertoire and significantly shortens overall survival, even after adjusting for prognostic factors. These results underscore the importance of implementing ATB stewardship recommendations in routine oncology practice. Microbiota-centered interventions are now being explored to treat gut dysbiosis and optimize ICI responses. Early-phase clinical trials evaluating fecal microbiota transplantation (FMT) from ICI responders or healthy donors have shown that this approach is safe and provided preliminary data on potential efficacy to overcome both primary and secondary resistance to ICI in melanoma, non-small cell lung cancer, and renal cell carcinoma. More targeted interventions including live bacterial products including Clostridium butyricum and Akkermansia massiliensis represent novel microbiome-based adjunct therapies. Likewise, dietary interventions, such as high-fiber diets, have shown promise in enhancing ICI activity. In this ASCO Educational Book, we summarize the current state-of-the-evidence of the clinical relevance of the intestinal microbiota in cancer immunotherapy and provide a practical guide for ATB stewardship.

The gut microbiota plays a pivotal role in human life and undergoes dynamic changes throughout the human lifespan, from infancy to old age. During our life, the gut microbiota influences health and disease across life stages. This review summarizes the discussions and presentations from the symposium "Gut microbiota development from infancy to old age" held in collaboration with the Journal of Internal Medicine. In early infancy, microbial colonization is shaped by factors such as mode of delivery, antibiotic exposure, and milk-feeding practices, laying the foundation for subsequent increased microbial diversity and maturation. Throughout childhood and adolescence, microbial maturation continues, influencing immune development and metabolic health. In adulthood, the gut microbiota reaches a relatively stable state, influenced by genetics, diet, and lifestyle. Notably, disruptions in gut microbiota composition have been implicated in various inflammatory diseases-including inflammatory bowel disease, Type 1 diabetes, and allergies. Furthermore, emerging evidence suggests a connection between gut dysbiosis and neurodegenerative disorders such as Alzheimer's disease. Understanding the role of the gut microbiota in disease pathogenesis across life stages provides insights into potential therapeutic interventions. Probiotics, prebiotics, and dietary modifications, as well as fecal microbiota transplantation, are being explored as promising strategies to promote a healthy gut microbiota and mitigate disease risks. This review focuses on the gut microbiota's role in infancy, adulthood, and aging, addressing its development, stability, and alterations linked to health and disease across these critical life stages. It outlines future research directions aimed at optimizing the gut microbiota composition to improve health.

Gut microbial communities are likely remodeled in tandem with accumulated physiological decline during aging, yet there is limited understanding of gut microbiome variation in advanced age. Here, we performed a metagenomics-based enterotype analysis in a geographically homogeneous cohort of 367 enrolled Chinese individuals between the ages of 60 and 94 years, with the goal of characterizing the gut microbiome of elderly individuals and identifying factors linked to enterotype variations. In addition to two adult-like enterotypes dominated by Bacteroides (ET-Bacteroides) and Prevotella (ET-Prevotella), we identified a novel enterotype dominated by Escherichia (ET-Escherichia), whose prevalence increased in advanced age. Our data demonstrated that age explained more of the variance in the gut microbiome than previously identified factors such as type 2 diabetes mellitus (T2DM) or diet. We characterized the distinct taxonomic and functional profiles of ET-Escherichia, and found the strongest cohesion and highest robustness of the microbial co-occurrence network in this enterotype, as well as the lowest species diversity. In addition, we carried out a series of correlation analyses and co-abundance network analyses, which showed that several factors were likely linked to the overabundance of Escherichia members, including advanced age, vegetable intake, and fruit intake. Overall, our data revealed an enterotype variation characterized by Escherichia enrichment in the elderly population. Considering the different age distribution of each enterotype, these findings provide new insights into the changes that occur in the gut microbiome with age and highlight the importance of microbiome-based stratification of elderly individuals.

Aging is a complex biological process associated with nearly all diseases. Alternative splicing is increasingly recognized as an important contributor to aging and a key research pathway for extending human lifespan. In this review, we highlight the findings of alternative splicing in the hallmarks of aging including key processes such as genomic instability, telomere length, protein stability, autophagy processes, etc., as well as antagonistic hallmarks of aging such as various metabolic signals, energy metabolism, clearance of senescent cells, stem cell self-renewal, cell communication and inflammatory process, etc. We also discuss the roles of alternative splicing in age-related diseases, including neurodegenerative diseases, cardiovascular diseases, skeletal muscle-related diseases, metabolic disorders, cancer, sensory degeneration, and chronic inflammation, etc. These studies suggest that new anti-aging therapies could be developed by regulating key splicing proteins or specific splicing events.

Aging processes underlie common chronic cardiometabolic diseases such as heart failure and diabetes. Cross-organ/tissue interactions can accelerate aging through cellular senescence, tissue wasting, accelerated atherosclerosis, increased vascular stiffness, and reduction in blood flow, leading to organ remodeling and premature failure. This interorgan/tissue crosstalk can accelerate aging-related dysfunction through inflammation, senescence-associated secretome, and metabolic and mitochondrial changes resulting in increased oxidative stress, microvascular dysfunction, cellular reprogramming, and tissue fibrosis. This may also underscore the rising incidence and co-occurrence of multiorgan dysfunction in cardiometabolic aging in the population. Examples include interactions between the heart and the lungs, kidneys, liver, muscles, and brain, among others. However, this phenomenon can also present new translational opportunities for identifying diagnostic biomarkers to define early risks of multiorgan dysfunction, gain mechanistic insights, and help to design precision-directed therapeutic interventions. Indeed, this opens new opportunities for therapeutic development in targeting multiple organs simultaneously to disrupt the crosstalk-driven process of mutual disease acceleration. New therapeutic targets could provide synergistic benefits across multiple organ systems in the same at-risk patient. Ultimately, these approaches may together slow the aging process itself throughout the body. In the future, with patient-centered multisystem coordinated approaches, we can initiate a new paradigm of multiorgan early risk prediction and tailored intervention. With emerging tools including artificial intelligence-assisted risk profiling and novel preventive strategies (eg, RNA-based therapeutics), we may be able to mitigate multiorgan cardiometabolic dysfunction much earlier and, perhaps, even slow the aging process itself.

Heart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N-oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes.

Pathophysiological mechanisms of unhealthy aging, particularly the transition from robustness to frailty, remain poorly understood. Despite extensive microbiome research on taxonomy, the behavior of early prefrail gut bacteria in their natural community-host mucosal tissue context remains unexplored. Using fecal samples from the INSPIRE-T aging human cohort, we characterized gut microbiota phenotype during prefrailty stages using a polymicrobial biofilm model. Results revealed that prefrail-derived biofilms exhibited distinct taxonomic and physical alterations, enhanced dispersal, and increased epithelial virulence compared to robust counterparts. Multiparametric analyses linked biofilm characteristics to clinical traits, suggesting their potential as aging status indicators. Polyphenol-rich grape pomace extract partially reversed prefrail biofilm alterations and reduced proinflammatory prefrail biofilm responses in vitro. Microbiota from prefrail-aged mice induced colon damage in antibiotic-treated recipients, establishing a prefrail microbiome-inflammation causality. Overall, the findings identified novel prefrail microbiome characteristics, established causal inflammatory links, and supported microbiota-targeted geroprotective interventions for the prefrail populations.

This study investigated the intestinal protective effects of a probiotic mixture (PM) composed of Limosilactobacillus fermentum HF07 and Lactococcus lactis HF08 on d-gal/DSS-induced aging colitis in mice. The PM alleviated age-related colitis symptoms including weight loss, increased disease activity index scores, colonic shortening, and tissue damage. PM supplementation reshaped the gut microbiota by restoring the relative abundances of Lactobacillus, Dubosiella, Odoribacter, and Clostridia_UCG-014, thereby enhancing levels of bile acids (BAs) such as alpha-muricholic acid, isolithocholic acid, and ursodeoxycholic acid. Moreover, transcriptomic analysis revealed that PM administration activated the cAMP pathway through the gut microbiota-secondary BAs axis. Western blot analysis further demonstrated that the effects of anti-inflammatory and intestinal barrier repair induced by PM were associated with downregulation of key proteins in the NLRP3 and RhoA/ROCK pathways, both of which are downstream of the cAMP pathway. Additionally, the role of gut metabolites in mediating these effects via G protein-coupled receptor 5 (TGR5) activation was confirmed through in vitro experiments using Caco-2 cells. These findings provided a comprehensive understanding of how probiotics target intestinal metabolites and leverage the gut microbiota-BAs axis to mitigate age-related gastrointestinal diseases.

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.

Thermal treatments used in ultra-processed foods (UPFs) lead to advanced glycation end products (AGEs). UPFs and serum AGEs are associated with cardiometabolic disease. We explore differential cooking methods as a mechanistic link between UPFs and detrimental health outcomes through a randomized cross-over cooking method trial in healthy subjects using identical ingredients and a deep profiling analysis. We show that low-AGE-generating cooking methods such as boiling and steaming decrease serum AGEs, improve lipid profiles, and increase serum protein 4E-BP1. In contrast, high-AGE-generating cooking methods such as grilling and baking increase fecal butyrate. In sum, this suggests that low-AGE-generating cooking methods should be considered in cardiovascular risk prevention. Since current dietary guidelines focus on ingredients, but not cooking methods, our results suggest that culinary techniques should be considered as an important factor in cardiometabolic preventive strategies and future dietary trial design. This study was registered at ClinicalTrials.gov (NCT06547190).

As ageing is linked to the development of neurodegenerative diseases (NDs), such as Alzheimer's Disease and Parkinson's Disease, it is important to disentangle the independent effect of age-related changes from those due to disease processes. To do so, changes to central nervous system (CNS) cells as a function of advanced age need better characterisation. Microglia are of particular interest due to their proposed links with the development and progression of NDs through control of the CNS immune response. Therefore, understanding the extent to which microglial dysfunction is related to phyisological ageing, rather than a disease process, is critical. As microglia age, they are believed to take on a pro-inflammatory phenotype with a distinct dystrophic morphology. Nevertheless, while established hallmarks of ageing have been investigated across a range of other cell types, such as macrophages, a detailed consideration of functional changes that occur in aged microglia remains elusive. Here, we describe the dynamic phenotypes of microglia and evaluate the current state of understanding of microglial ageing, focusing on the recently updated twelve hallmarks of ageing. Understanding how these hallmarks present in microglia represents a step towards better characterisation of microglial ageing, which is essential in the development of more representative models of NDs.

Multiple sclerosis (MS) is the most common demyelinating disease caused by a multifaceted interplay of genetic predispositions and environmental factors. Most patients initially experience the relapsing-remitting form of the disease (RRMS), which is characterized by episodes of neurological deficits followed by periods of symptom resolution. However, over time, many individuals with RRMS advance to a progressive form of the disease, known as secondary progressive MS (SPMS), marked by a gradual worsening of symptoms without periods of remission. The mechanisms underlying this transition remain largely unclear, and current disease-modifying therapies (DMTs) are partially effective in treating SPMS. Age is widely acknowledged as a risk factor for the transition from RRMS to SPMS. One factor associated with aging that may influence the progression of MS is gut dysbiosis. This review discusses how aging and age-related gut dysbiosis affect the progression of MS.

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.

Aging manifests a decline of immune function, induces microbiome dysbiosis, drives organ inflammation, and impedes the resolution of inflammation. However, the mechanisms underlying age-related intestinal inflammation remain poorly described. Here, we find that the resolution of T cell-initiated intestinal inflammation is impaired with aging. This impairment is mediated by disrupting the immune-microbiota interplay, controlled by intestinal eicosanoid metabolism. Pharmacologically inhibiting eicosanoid biosynthesis, blocking the prostaglandin E receptor subtype 4 (EP4), or genetically ablating EP4 diminishes age-related impairment of intestinal inflammation resolution. Mechanistically, mononuclear phagocyte-intrinsic eicosanoid-EP4 signaling impedes the resolution of intestinal inflammation through fostering gut microbial dysbiosis and, more importantly, interrupting segmented filamentous bacterial adhesion to the intestinal epithelium. Colonization with EP4-ablated mouse microbiota or segmented filamentous bacteria improves the resolution of intestinal inflammation. These findings reveal that eicosanoid-dependent immune-microbiota interactions impair inflammation resolution in the aged intestine, highlighting potential intervention strategies for improving age-related gut health.

The gut microbiota is a complex and dynamic community of microorganisms that reside in the gastrointestinal tract, playing a critical role in the host. It produces many metabolites, such as bile acids, which play an important role in the metabolism of the host. One area of particular interest is its involvement in the development and treatment of cancer. Carcinogens, which are substances known to promote cancer formation and development, are present in various sources in our daily lives, including cigarettes, barbecues, and moldy foods. The types, amounts, and metabolism of carcinogens have been closely linked to cancer risk, underscoring the importance of understanding their interplay with the gut microbiota. Numerous studies have demonstrated significant differences in the composition and function of the gut microbiota in individuals with cancer compared to healthy individuals. The gut microbiota and its metabolites have been shown to influence the metabolism of various carcinogens, thereby affecting cancer progression. While much attention has been paid to the relationship between the gut microbiota and cancer risk, the potential interplay between the gut microbiota and carcinogens has received less focus. This review aims to emphasize the importance of exploring the interplay between the gut microbiota with its metabolites and carcinogens in cancer development and therapy. By uncovering the mechanisms of the interplay, new approaches for cancer prevention and treatment can be developed.

Fertility is a dynamic, multifactorial process governed by hormonal, immune, metabolic, and environmental factors. Recent evidence highlights the gut microbiota as a key systemic regulator of reproductive health, with notable impacts on endometrial function, implantation, pregnancy maintenance, and the timing of birth. This review examines the gut-endometrial axis, focusing on how gut microbial communities influence reproductive biology through molecular signaling pathways. We discuss the modulatory roles of microbial-derived metabolites-including short-chain fatty acids, bile acids, and tryptophan catabolites-in shaping immune tolerance, estrogen metabolism, and epithelial integrity at the uterine interface. Emphasis is placed on shared mechanisms such as β-glucuronidase-mediated estrogen recycling, Toll-like receptor (TLR)-driven inflammation, Th17/Treg cell imbalance, and microbial translocation, which collectively implicate dysbiosis in the etiology of gynecological disorders including endometriosis, polycystic ovary syndrome (PCOS), recurrent implantation failure (RIF), preeclampsia (PE), and preterm birth (PTB). Although most current evidence remains correlational, emerging insights from metagenomic and metabolomic profiling, along with microbiota-depletion models and Mendelian randomization studies, underscore the biological significance of gut-reproductive crosstalk. By integrating concepts from microbiology, immunology, and reproductive molecular biology, this review offers a systems-level perspective on host-microbiota interactions in female fertility.

A number of investigations have shown that gut microbiome influences humans' ability to communicate with others, and impairments in social interactions are linked to alterations in gut microbiome composition and diversity, via epigenetic mechanisms. This article reviews the links among gut microbiome, social behavior, and epigenetic shifts relevant to gut microbiome-derived metabolites. First, we discuss how different social determinants of health, such as socioeconomic status, diet, environmental chemicals, migration, ecological conditions, and seasonal changes may influence gut microbiome composition, diversity, and functionality, along with epigenetic alterations and thereby affect social behavior. Next, we consider how gut microbiome-derived metabolites, diet, probiotics, and fecal microbiome transplantation may reduce impairments in social interactions through the adjustment of epigenetic aberrations (e.g., DNA methylation, histone modifications, and microRNAs expression) which may suppress or increase gene expression patterns. Finally, we present the potential benefits and unresolved challenges with the use of gut microbiome-targeted therapeutics in reducing social deficits.

Frailty is an ageing-associated geriatric syndrome that severely affects the functional status, quality of life and life expectancy of older adults. Immune dysfunction and chronic inflammation play crucial roles in frailty, and this study aimed to explore the correlation between the intestinal microbiota and frailty.

A cross-sectional survey was conducted using a comprehensive geriatric assessment of older individuals who underwent medical checkups at the Health Management Center from April 2023 to May 2024. A total of 672 older individuals who met the inclusion criteria were included and divided into a healthy control group and a frail case group. Clinical data, as well as blood and stool samples, were collected. The data from the two groups were analysed with 16S rRNA sequencing in 20 and 30 cases, respectively. SPSS 25.0 was used for statistical analysis.

There were significant differences in income, smoking, and globulin levels between the two groups, while there were no differences in age or sex. There was no significant difference in the abundance or species evenness of intestinal bacteria between the two groups. However, the abundance of accessory bacteria, bifidobacteria, and Escherichia coli in the frail group was greater than that in the control group. Specifically, Escherichia-Shigella was significantly upregulated and fit well into the prediction model of frailty.

The gut microbiota of frail older individuals underwent significant changes in structural composition, and the presence of Escherichia-Shigella may be a diagnostic marker for debilitating diseases. These findings provide an essential clinical reference value for developing methods for preventing or alleviating frailty based on specific microbial communities.

The gut microbiome influences physiological responses to exercise by modulating inflammatory markers and metabolite production. Athletes typically exhibit greater microbial diversity, which may be associated with improved performance, but the mechanisms linking different exercise modalities to the gut microbiome are not fully understood. In this study, blood and stool samples were collected from endurance athletes, strength athletes, and non-athletic controls performing two maximal exercise tests (the anaerobic Wingate test and the aerobic Bruce Treadmill Test) to integrate serum biomarker data with gut bacterial metagenomic profiles. While most biochemical markers showed similar post-exercise trends across groups, SPARC (secreted protein acidic and rich in cysteine) and adiponectin levels showed modality-specific responses. Strength-trained participants showed unique microbiome-biomarker associations after the Wingate test. In addition, baseline enrichment of certain bacterial taxa, including Clostridium phoceensis and Catenibacterium spp., correlated with reduced Bruce Treadmill test response in strength-trained individuals. These findings, while requiring further validation, indicate the complex interplay between exercise type, training background, and the gut microbiome, and suggest that specific microbial species may help shape recovery and adaptation.

This chapter examines how human biology and microbial "secondary genomes" have co-evolved to shape neurodevelopment through the gut-brain axis. Microbial communities generate metabolites that cross blood-brain and placental barriers, influencing synaptogenesis, immune responses, and neural circuit formation. Simultaneously, Human Accelerated Regions (HARs) and Endogenous Retroviruses (ERVs) modulate gene expression and immune pathways, determining which microbes thrive in the gut and impacting brain maturation. These factors converge to form a dynamic host-microbe dialogue with significant consequences for neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. Building on evolutionary perspectives, the chapter elucidates how genetic and immune mechanisms orchestrate beneficial and pathological host-microbe interactions in early brain development. It then explores therapeutic strategies, such as probiotics, prebiotics, fecal microbiota transplantation, and CRISPR-driven microbial engineering, targeting gut dysbiosis to mitigate or prevent neurodevelopmental dysfunctions. Furthermore, innovative organ-on-chip models reveal mechanistic insights under physiologically relevant conditions, offering a translational bridge between in vitro experiments and clinical applications. As the field continues to evolve, this work underscores the translational potential of manipulating the microbiome to optimize neurological outcomes. It enriches our understanding of the intricate evolutionary interplay between host genomes and the microbial world.

Aging-associated dysbiosis leads to chronic inflammation and the development of a range of aging-related diseases. The gut microbiota crosstalks with the host by providing lipid metabolites and modulating metabolic functions. However, the precise mechanism by which the gut microbiota regulates aging is unknown. The objective of this study was to examine the impact of the gut microbiota on the transcriptome and lipidome associated with aging in mouse liver.

RNA-sequencing was conducted on the livers of young and aged male and female-specific pathogen-free (SPF) and germ-free (GF) mice to comprehensively analyze transcriptomic alterations with aging. We also reanalyzed our previously reported results on aging-associated changes in the hepatic lipidome to investigate the gut microbiota-dependent hepatic lipidome signatures associated with aging.

In contrast to the findings in male mice, the changes in hepatic transcriptome associated with aging were attenuated in female GF mice compared with those in SPF mice. In particular, the gene sets associated with inflammatory signatures (i.e., inflammation and tissue remodeling) were found to be suppressed in female GF mice. The ChIP-Atlas database predicted that transcription factors associated with sex differences may be involved in the gene signature of aged female GF mice. Significant differences in the lipid profile were observed between aged SPF and GF female mice, including in bile acids, sterol sulfates, lysophospholipids, oxidized triacylglycerols, vitamin D, and phytoceramides. Moreover, notable alterations were identified in the quality of phospholipids and sphingolipids. Integrated transcriptomic and lipidomic analysis identified candidate enzymes responsible for the change of lipid profiles in aged female mice.

The findings of this study offer new insights into the molecular mechanisms through which the gut microbiota regulates aging-related phenotypes such as inflammation in the liver, possibly through modulating lipid metabolism in a sex-dependent manner.

Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization of young dams with microbiome from aged female donors significantly increased fetal loss. There were significant differences in the composition of the gut microbiome in pups born from dams recolonized with aged female biome that persisted through middle age. Offspring born from dams colonized with aged microbiome also had significant changes in levels of neurotransmitters and metabolites in the blood and the brain. Adult offspring from dams colonized with an aged microbiome displayed persistent depressive- and anxiety-like phenotypes. Collectively, these results demonstrate that age-related changes in the composition of the maternal gut microbiome contribute to chronic alterations in the behavior and physiology of offspring. This work highlights the potential of microbiome-targeted approaches, even prior to birth, may reduce the risk of neuropsychiatric disorders.

As the population ages, problems pertaining to health and life expectancy due to the aging heart have become increasingly prominent. The gut microbiota has become a potential therapeutic target in several diseases, including cardiovascular diseases. Current studies on the roles of the gut microbiota in the cardiovascular system have focused mainly on cardiovascular diseases; therefore, the effects of the gut microbiota on the natural aging of myocardial tissue remain unclear. The present study aimed to explore the roles and mechanisms of the gut microbiota and related metabolites in the natural aging of the heart. Animal models of fecal microbiota transplantation (FMT) were established in elderly and young rats. 16S rRNA sequencing revealed that the gut microbiota of the recipients shifted toward the profile of the donors, with concomitant cardiac structure and diastolic function changes detected via ultrasound and positron emission tomography-computed tomography (PET-CT). A group of significantly enriched myocardial metabolites detected by LC/MS were involved in the fatty acid β-oxidation process. Together with altered glucose uptake, as revealed by PET-CT, changes in ATP content and mitochondrial structure further verified a metabolic difference related to energy among rats transplanted with the gut microbiota from donors of different ages. This study demonstrated that gut microbes may participate in the physiological aging process of the rat heart by regulating oxidative stress and autophagy. The gut microbiota has been shown to be involved in the natural aging of the heart at multiple levels, from the organ level to the metabolically plastic myocardiocytes and associated molecules.

In the process of aging, adverse changes such as weakened intestinal barrier function, increased chronic inflammation, and decreased gut microbiota diversity often occur. We explored the protective effects of Oat β-glucan (BG) on the gut homeostasis of naturally aging mice. The study shows that daily intervention with 400 mg/kg BG effectively modulates the intestinal mucosal structure, mechanical barrier function [Zonula occludens-1 (ZO-1), occludin, and claudin], and anti-inflammatory [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1β], as well as antioxidant responses in aging mice. Spearman correlation analyses showed that BG supplementation increased acetate levels by 1.8-fold, propionate levels by 2.5-fold, and butyrate-derived GABA levels by 2.5-fold. Additionally, BG supplementation improved the gut microbiota, increasing the abundance of beneficial bacteria like Bacteroidota, Prevotellaceae, Coprobacillaceae, and Faecalibacterium. These microbes metabolize BG to produce short-chain fatty acids (SCFAs), activating butanoate and propanoate metabolic pathways to maintain intestinal homeostasis. In conclusion, this study identifies the therapeutic effects of BG in regulating intestinal barrier homeostasis and gut microbiota, providing new insights for nutritional intervention strategies in the elderly.

Menopause is characterized by the cessation of menstruation and a decline in reproductive function, which is an intrinsic component of the aging process. However, it has been a frequently overlooked field of women's health. The oral and gut microbiota, constituting the largest ecosystem within the human body, are important for maintaining human health and notably contribute to the healthy aging of menopausal women. Therefore, a comprehensive review elucidating the impact of the gut and oral microbiota on menopause for healthy aging is of paramount importance. This paper presents the current understanding of the microbiome during menopause, with a particular focus on alterations in the oral and gut microbiota. Our study elucidates the complex interplay between the microbiome and sex hormone levels, explores microbial crosstalk dynamics, and investigates the associations between the microbiome and diseases linked to menopause. Additionally, this review explores the potential of microbiome-targeting therapies for managing menopause-related diseases. Given that menopause can last for approximately 30 years, gaining insights into how the microbiome and menopause interact could pave the way for innovative interventions, which may result in symptomatic relief from menopause and an increase in quality of life in women.

Wearables have evolved into accessible tools for sports, research, and interventions. Their use has expanded to real-time monitoring of behavioural parameters related to ageing and health. This paper provides an overview of the literature on wearables in disease prevention and healthcare over the life course (not only in the older population), based on insights from the Future of Diagnostics Workshop (Leiden, January 2024). Wearable-generated parameters include blood glucose, heart rate, step count, energy expenditure, and oxygen saturation. Integrating wearables in healthcare is protracted and far from mainstream implementation, but promises better diagnosis, biomonitoring, and assessment of medical interventions. The main lifestyle factors monitored directly with wearables or through smartphone applications for disease prevention include physical activity, energy expenditure, gait, sleep, and sedentary behaviour. Insights on dietary consumption and nutrition have resulted from continuous glucose monitors. These factors are important for healthy ageing due to their effect on underlying disease pathways. Inclusivity and engagement, data quality and ease of interpretation, privacy and ethics, user autonomy in decision making, and efficacy present challenges to but also opportunities for their use, especially by older people. These need to be addressed before wearables can be integrated into mainstream medical and public health strategies. Furthermore, six key considerations need to be tackled: 1) engagement, health literacy, and compliance with personalised feedback, 2) technical and standardisation requirements for scalability, 3) accountability, data safety/security, and ethical concerns, 4) technological considerations, access, and capacity building, 5) clinical relevance and risk of overdiagnosis/overmedicalisation, and 6) the clinician's perspective in implementation.

Background/Objectives: The aim of this study was to qualitatively and quantitatively assess the bacterial domain of the gut microbiome in elderly patients with type 2 diabetes (T2D), with a focus on sex differences, glycemic control, and lipid disorders. Methods: This study included 60 older adults with T2D (38 women and 22 men) treated with metformin or a combination of metformin and insulin. The gut microbiota was profiled using 16S rRNA gene sequencing. Statistical analyses, including correlation analysis and multiple regression, were performed to identify the associations between microbial taxa, sex, and metabolic parameters. Results: No statistically significant differences in alpha or beta diversity were observed between the sexes. Multiple regression analysis indicated a positive relationship between Tenericutes and HbA1c in male participants (β = 2.22931, CI [0.75, 3.70], R = 0.67; R2 = 0.36; unadjusted p = 0.0052; adjusted p = 0.0496). In female participants, G0' (β = -2.24107, CI [-3.19, -1.30], R = 0.78; R2 = 0.58; unadjusted p = 0.00003; adjusted p = 0.0005) and HbA1c (β = -1.86670, CI [-2.61, -1.12], R = 0.78; R2 = 0.58; unadjusted p = 0.00001; adjusted p = 0.0003) correlated negatively with Verrucomicrobia as well G0' (β = -1.90427, CI [-2.95, -0.85], R = 0.46; R2 = 0.17; unadjusted p = 0.0008; adjusted p = 0.007) and HbA1c (β = -1.69561, CI [-2.52, -0.87], R = 0.46; R2 = 0.17; unadjusted p = 0.0002; adjusted p = 0.002) correlated negatively with OD1 bacteria, known as Parcubacteria. Conclusions: In this elderly population with type 2 diabetes, biological sex did not significantly affect the gut microbiota diversity. However, several exploratory associations between microbial taxa and metabolic parameters differed between men and women, suggesting that sex may influence specific aspects of microbiota-metabolism interactions. These preliminary findings underscore the importance of considering both age- and sex-related factors when investigating the gut microbiome in the context of type 2 diabetes.

With the increased use of fermented products and probiotic foods, interest in knowing their benefits and safety of their intake is increasing.

The current systematic review investigated the effects of probiotics supplementation on short-chain fatty acid (SCFA) levels.

A systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Medline/PubMed, Scopus, Web of Science, and Embase databases were searched from inception to February 2024, including only randomized controlled trials.

A total of 30 studies were included, involving 1499 participants. The vast majority of trials investigated Bifidobacterium and Lactobacillus strains. These were categorized into healthy adults (n = 6), gastrointestinal/inflammatory diseases (n = 7), metabolic diseases (n = 6), elderly individuals (n = 3), children (n = 4), and infant formula (n = 4). Most studies evaluated isolated strain supplementation (n = 12), followed by fermented beverages (n = 11) and probiotic mixes (n = 3). Globally, 16 studies (53.3%) revealed an increase in at least 1 SCFA in participants supplemented with probiotics. In comparison, 5 studies (16.7%) reported a reduction and 9 studies showed no statistically significant impact in their findings (30%). The subgroup evaluation showed heterogeneity in the results, with low to moderate evidence grading levels.

Probiotics supplementation during childhood was the intervention period more effective in increasing fecal SCFAs and immunoglobulin A (IgA) levels (GRADE: moderate/high-certainty evidence).

PROSPERO registration no. CRD42024513221.

SUMMARYRecent advances in therapeutic probiotics have shown promising results across various health conditions, reflecting a growing understanding of the human microbiome's role in health and disease. However, comprehensive reviews integrating the diverse therapeutic effects of probiotics in human subjects have been limited. By analyzing randomized controlled trials (RCTs) and meta-analyses, this review provides a comprehensive overview of key developments in probiotic interventions targeting gut, liver, skin, vaginal, mental, and oral health. Emerging evidence supports the efficacy of specific probiotic strains and combinations in treating a wide range of disorders, from gastrointestinal (GI) and liver diseases to dermatological conditions, bacterial vaginosis, mental disorders, and oral diseases. We discuss the expanding understanding of microbiome-organ connections underlying probiotic mechanisms of action. While many clinical trials demonstrate significant benefits, we acknowledge areas requiring further large-scale studies to establish definitive efficacy and optimal treatment protocols. The review addresses challenges in standardizing probiotic research methodologies and emphasizes the importance of considering individual variations in microbiome composition and host genetics. Additionally, we explore emerging concepts such as the oral-gut-brain axis and future directions, including high-resolution microbiome profiling, host-microbe interaction studies, organoid models, and artificial intelligence applications in probiotic research. Overall, this review offers a comprehensive update on the current state of therapeutic probiotics across multiple domains of human health, providing insights into future directions and the potential for probiotics to revolutionize preventive and therapeutic medicine.

Beneficial short-chain fatty acids (SCFAs) are produced through intestinal microbial fiber fermentation. Using stable tracer methodology and compartmental modeling, we observed lower SCFA production in older (OAs) than in young adults (YAs) in both an accessible [that is, systemic circulation; whole-body production] and inaccessible [potentially representing intestine absorbing microbially produced SCFAs (U2)] pool.

We now investigated whether fiber supplementation increases SCFA production in OAs and whether concentrations reflect production rate changes.

In this randomized, placebo-controlled, double-blind crossover study, 21 YAs (20-29 y) and 40 OAs (59-87 y) adults were supplemented with inulin or placebo (maltodextrin) for 7 d (final intake: 30 g/d). Before and after interventions, participants collected stool and received an intravenous pulse containing [U-13C]-labeled SCFAs followed by blood draws. We measured plasma tracer enrichments, plasma and fecal concentrations by gas chromatography-mass spectrometry and performed compartmental analysis. Data are mean (95% confidence interval).

Inulin evoked a 44% increase in butyrate production (μmol/min) in the inaccessible pool {YA: 28-44 [+16.2 (4.3, 28.1); P = 0.038], OA: 14-20 [+6.1 (2.2, 9.9); P = 0.011]} and were not different between YAs and OAs. In addition, a 34% increase in propionate production in YA only. We found a 50%-60% increase in fecal acetate, propionate, and butyrate and a 34% increase in plasma butyrate in OA, whereas in YA only 34% increase in fecal acetate. Plasma but not fecal concentrations correlated positively with SCFA production in the inaccessible pool (R2 = 0.20-0.45; P < 0.001).

OAs have a lower SCFA production. Inulin intake increases SCFA production. Tracer pulse approach detects SCFA metabolism changes more sensitively than plasma or fecal concentration measurements (NCT04459156).

Billions of microorganisms inhabit the human gut and maintain overall health. Recent research has revealed the intricate interaction between the brain and gut microbiota through the microbiota-gut-brain axis (MGBA) and its effect on neurodegenerative disorders (NDDs). Alterations in the gut microbiota, known as gut dysbiosis, are linked to the development and progression of several NDDs. Studies suggest that the gut microbiota may be a viable target for improving cognitive health and reducing hallmarks of brain aging. Numerous pathways including hypothalamic-pituitary-adrenal axis stimulation, neurotransmitter release disruption, system-wide inflammation, and increased intestinal and blood-brain barrier permeability connect gut dysbiosis to neurological conditions. Metabolites produced by the gut microbiota influence neural processes that affect brain function. Clinical interventions depend on the capacity to understand the equilibrium between beneficial and detrimental gut microbiota, as it affects both neurodegeneration and neuroprotection. The importance of the gut microbiota and its metabolites during brain aging and the development of neurological disorders is summarized in this review. Moreover, we explored the possible therapeutic effects of the gut microbiota on age-related NDDs. Highlighting various pathways that connect the gut and the brain, this review identifies several important domains where gut microbiota-based interventions could offer possible solutions for age-related NDDs. Furthermore, prebiotics and probiotics are discussed as effective alternatives for mitigating indirect causes of gut dysbiosis. These therapeutic interventions are poised to play a significant role in improving dysbiosis and NDDs, paving the way for further research.