Anaerobutyricum soehngenii (previously Eubacterium hallii) is a butyrate-producing next-generation beneficial microbe generally recognized as safe. Several short-term intervention trials by A. soehngenii L2-7 have shown improvement of insulin sensitivity in prediabetic subjects and type 2 diabetes patients. To determine the long-term cardiometabolic benefits and safety, we performed a 3-month double-blind, randomized placebo-controlled intervention in 98 prediabetic insulin-resistant adults in Europe and U.S. with daily administration of encapsulated cells of A. soehngenii CH-106, a tetracycline-sensitive isogenic derivative of strain L2-7. Compared to placebo, A. soehngenii-treated subjects showed significantly reduced glycemic variability (1% reduction in the coefficient of variation; p = 0.01) and improved glycemic control (6% reduction in the overall net glycemic action-1; p < 0.05), including reduced serum glycated hemoglobin (HbA1c) levels when including the 4-week washout period (1 mmol/mol reduction; p < 0.05). Moreover, diastolic blood pressure was significantly reduced in all A. soehngenii-treated subjects (3 mm Hg; p < 0.05). The study product was well-tolerated and had no effect on the global intestinal microbiota composition, including alpha and beta-diversity, besides an increased abundance of A. soehngenii in the treatment group, indicative of compliance. The U.S. participants, compared to those in Europe, responded best, notably in the oral glucose tolerance tests (15% improvement in the area-under-the curve of plasma glucose levels; p = 0.039) or coefficient of variation (reduction of 3.1%; p < 0.05). This potentially relates to a more severe prediabetic state in U.S. subjects, associated with significantly reduced (1.5-3.5-fold) relative abundance of Bifidobacterium, Coprococcus, Ruminococcus spp. and two-fold increased relative abundance of Lachnoclostridium spp. In conclusion, daily oral supplementation with A. soehngenii was safe and improved various markers of glycemic control, reduced HbA1c levels and diastolic blood pressure, indicating a novel microbiome-based approach to improve cardio-metabolic health in adults at risk for developing type 2 diabetes.Clinical trial reg. no. NCT04529473, clinicaltrials.govSocial media summary 120 characters: Anaerobutyricum soehngenii supplementation improves #cardio-metabolic health in subjects at risk for type 2 #diabetes.

Assessing causality is undoubtedly one of the key questions in microbiome studies for the upcoming years. Since randomized trials in human subjects are often unethical or difficult to pursue, analytical methods to derive causal effects from observational data deserve attention. As simple covariate adjustment is not likely to account for all potential confounders, the idea of instrumental variable (IV) analysis is worth exploiting. Here we propose a novel framework of antibiotic instrumental variable regression (AB-IVR) for estimating the causal relationships between microbiome and various diseases. We rely on the recent studies showing that antibiotic treatment has a cumulative long-term effect on the microbiome, resulting in individuals with higher antibiotic usage to have a more perturbed microbiome. We apply the AB-IVR method on the Estonian Biobank data and show that the microbiome has a causal role in numerous diseases including migraine, depression and irritable bowel syndrome. We show with a plethora of sensitivity analyses that the identified causal effects are robust and propose ways for further methodological developments.

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

Insulin resistance (IR) is an early marker of cardiometabolic deterioration which may develop heterogeneously in key metabolic organs, including the liver (LIR) and skeletal muscle (MIR). This tissue-specific IR is characterized by distinct metabolic signatures, but the role of the gut microbiota in its etiology remains unclear. Here, we profiled the gut microbiota, its metabolites and the plasma metabolome in individuals with either a LIR or MIR phenotype (n = 233). We observed distinct microbial community structures LIR and MIR, and higher short-chain fatty acid (SCFA) producing bacteria, fecal SCFAs and branched-chain fatty acids and a higher postprandial plasma glucagon-like-peptide-1 response in LIR. In addition, we found variations in metabolome profiles and phenotype-specific associations between microbial taxa and functional metabolite groups. Overall, our study highlights association between gut microbiota and its metabolites composition with IR heterogeneity that can be targeted in precision-based strategies to improve cardiometabolic health. Clinicaltrials.gov registration: NCT03708419.

On the basis of the contribution of the gut microbiota to hypertension development, a novel strategy involving fecal microbiota transplantation (FMT) has been proposed to treat hypertension, but its efficacy has not been investigated in the clinic.

In a randomized, blinded, placebo-controlled clinical trial (2021/03-2021/12, ClinicalTrials.gov, NCT04406129), hypertensive patients were recruited from seven centers in China, and received FMT or placebo capsules orally at three visits. The patients were randomized at a 1:1 ratio in blocks of four and stratified by center by an independent statistician. The intention-to-treat principle was implemented, as all randomized participants who received at least one intervention were included. The primary outcome was the decrease in office systolic blood pressure (SBP) from baseline to the day 30 visit. Adverse events (AEs) were recorded through the 3-month follow-up to assess safety measures. Alterations in BP, the fecal microbiome, and the plasma metabolome were assessed via exploratory analyses.

This study included 124 patients (mean age 43 years, 73.4% men) who received FMT (n = 63) or placebo (n = 61) capsules. The numbers of participants who experienced AEs (13 (20.6%) vs. 9 (14.8%), p = 0.39) and the primary outcome (6.28 (11.83) vs. 5.77 (10.06) mmHg, p = 0.62) were comparable between the groups. The FMT group presented a decrease in SBP after 1 week of FMT, with a between-arm difference of - 4.34 (95% CI, - 8.1 to - 0.58; p = 0.024) mmHg, but this difference did not persist even after repeated intervention. After FMT, shifts in microbial richness and structure were identified and the abundance of the phyla Firmicutes and Bacteroidetes was altered. Decreases in the abundances of Eggerthella lenta, Erysipelatoclostridium ramosum, Anaerostipes hadrus, Gemella haemolysans, and Streptococcus vestibularis and increases in the abundances of Parabacteroides merdae, Prevotella copri, Bacteroides galacturonicus, Eubacterium sp. CAG 180, Desulfovibrio piger, Megamonas hypermegale, Collinsella stercoris, Coprococcus catus, and Allisonella histaminiformans were identified and correlated with office SBP. Those species were also correlated with responding and inversely office SBP-associated metabolites including tyrosine, glutamine, aspartate, phenylalanine, methionine, serine, sarcosine, and/or asparagine.

Safety but unsustainable BP reduction was observed in the first trial of the effects of FMT on hypertension. Additional intervention studies on specific microbes with metabolite-targeting and BP-modulating features are needed. Video Abstract.

Exercise and diet modulate the gut microbiota, which is involved in the regulation of orthopaedic diseases and synthesises a wide range of metabolites that modulate cellular function and play an important role in bone development, remodelling and disease. G protein-coupled receptors (GPCRs), the largest family of transmembrane receptors in the human body, interact with gut microbial metabolites to regulate relevant pathological processes. This paper provides a review of different dietary and exercise effects on the pathogenic gut microbiota and their metabolites associated with GPCRs in orthopaedic diseases. RESULTS: Generally, metabolites produced by gut microbiota contribute to the maintenance of bone health by activating the corresponding GPCRs, which are involved in bone metabolism, regulation of immune response, and maintenance of gut flora homeostasis. Exercise and diet can influence gut microbiota, and an imbalance in gut microbiota homeostasis can trigger a series of adverse immune and metabolic responses by affecting GPCR function, ultimately leading to the onset and progression of various orthopaedic diseases. Understanding these relationships is crucial for elucidating the pathogenesis of orthopaedic diseases and developing personalised probiotic-based therapeutic strategies. In the future, we should further explore how to prevent and treat orthopaedic diseases through GPCR-based modulation of gut microbes and their interactions. The development of substances that precisely modulate gut microbes through different exercises and diets will provide more effective interventions to improve bone health in patients.

Type 2 diabetes presents significant public health challenges. The gut microbiome has emerged as a potential factor influencing glucose metabolism.

We performed a randomized, double-blind, single-center trial involving patients with type 2 diabetes and glycated hemoglobin (HbA1c) concentration of 7 % or greater. Patients were randomly assigned to receive 100 billion colony-forming units (CFUs) of probiotic supplementation daily or placebo. The primary efficacy endpoint was the change in HbA1c from baseline to 12 weeks, and secondary endpoints included lipid and inflammatory markers.

A total of 130 patients were included. HbA1c was 7.63 ± 0.54 % at baseline and 7.63 ± 0.63 % at 12 weeks in the probiotic group and 7.71 ± 0.74 % and 7.81 ± 0.84 % in the placebo group (p = 0.29 between treatment groups). There were also no significant differences between treatment groups in plasma glucose (p = 0.60) and insulin (p = 0.41), as well as in LDL-cholesterol (p = 0.90) and triglycerides (p = 0.32). The adjusted geometric mean percent change (95 % confidence interval) in high-sensitivity C-reactive protein was 1.59 % (-15.71, 22.44) in the probiotic group and -1.37 % (-18.04, 18.70) in the placebo group (p = 0.82). Gastrointestinal adverse events occurred in 38.5 % and 46.2 % of patients in the probiotic group and placebo group respectively (p = 0.48).

Probiotic supplementation for 12 weeks did not improve glycemic control, lipid or inflammatory markers in patients with type 2 diabetes. Further research is needed to determine the potential benefits and underlying mechanisms of probiotics in subsets of patients.

gov Identifier no. NCT03239366.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the predominant liver disease and is becoming the paramount contributor to end-stage liver disease and liver-related deaths. Liver sinusoidal endothelial cells (LSECs) located between the hepatic parenchyma and blood from viscera and gastrointestinal tract are the gatekeepers for the hepatic microenvironment and normal function. In normal physiological conditions, LSECs govern the substance exchange between hepatic parenchyma and blood through dynamic regulation of fenestration and maintain the quiescent state of Kupffer cells (KCs) and hepatic stellate cells. In MASLD, lipotoxicity, insulin resistance, gastrointestinal microbiota dysbiosis, and mechanical compression caused by fat-laden hepatocytes result in LSECs capillarization and dysfunction. The altered LSECs progressively shift from healer to injurer, exacerbating liver inflammation and advancing liver fibrosis. This review focuses on the deteriorative roles of LSECs and related molecular mechanisms involved in MASLD and their contribution to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis development and progression. Furthermore, in this review, we propose that targeting LSECs dysfunction is a prospective therapeutic strategy to restore the physiological function of LSECs and mitigate MASLD progression.

The microbiota in humans consists of trillions of microorganisms that are involved in the regulation of the gastrointestinal tract and immune and metabolic homeostasis. The gut microbiota (GM) has a prominent impact on the pathogenesis of metabolic syndrome (MetS). This process is reciprocal, constituting a crosstalk process between the GM and MetS. In this review, GM directly or indirectly inducing MetS via the host-microbial metabolic axis has been systematically reviewed. Additionally, the specifically altered GM in MetS are detailed in this review. Moreover, short-chain fatty acids (SCFAs), as unique gut microbial metabolites, have a remarkable effect on MetS, and the role of SCFAs in MetS-related diseases is highlighted to supplement the gaps in this area. Finally, the existing therapeutics are outlined, and the superiority and shortcomings of different therapeutic approaches are discussed, in hopes that this review can contribute to the development of potential treatment strategies.

Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications-including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities-and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.

Over time, extensive research has underscored the pivotal role of gut microbiota in the onset and progression of various diseases, with a particular focus on fecal microbiota transplantation (FMT) as a potential therapeutic approach. The practice of transferring fecal matter from a healthy donor to a patient provides valuable insights into how alterations in gut microbiota can impact disease development and how rectifying dysbiosis may offer therapeutic benefits. Re-establishing a balanced symbiotic relationship in the gastrointestinal tract has shown positive results in managing both intestinal and systemic conditions. Currently, one of the most pressing global health issues is metabolic syndrome-a cluster of conditions that includes insulin resistance, lipid imbalances, central obesity and hypertension. In this context, FMT has emerged as a promising strategy for addressing key components of metabolic syndrome, such as improving insulin sensitivity, body weight and lipid profiles. However, further well-structured studies are needed to refine treatment protocols and establish the long-term safety and efficacy of this intervention.

The concept of the gut microbes-muscle axis underscores the impact of intestinal microbiota on the muscular system, an area that is increasingly coming to light. However, current interpretations and applications of this concept remain underdeveloped. In this review, we concluded and discussed factors, such as short-chain fatty acids, amino acids, vitamins, bile acids, antibiotics, cytokines, hormones, and extracellular vesicles that mediate gut microbes-muscle crosstalk and influence the gut microbes-muscle axis. Additionally, we examined how the gut microbes-muscle axis affects muscle mass, muscle strength, muscle metabolism, as well as muscle oxidative and immune status. Furthermore, we reviewed the influence of the microbes-muscle axis on muscle fiber type transition, muscle fat deposition, and meat quality. These insights illuminate the potential mechanisms by which the gut microbes-muscle axis operates in humans and animals. Thus, this review provides a theoretical foundation for future research and offers practical guidance for its application in biomedical and livestock industries.

Obesity is a highly prevalent chronic multisystem disease associated with shortened life expectancy due to a number of adverse health outcomes. Epidemiological data link body weight and parameters of central fat distribution to an increasing risk for type 2 diabetes, hypertension, fatty liver diseases, cardiovascular diseases including myocardial infarction, heart failure, atrial fibrillation, stroke, obstructive sleep apnoea, osteoarthritis, mental disorders and some types of cancer. However, the individual risk to develop cardiometabolic and other obesity-related diseases cannot entirely be explained by increased fat mass. Rather than excess fat accumulation, dysfunction of adipose tissue may represent the mechanistic link between obesity and adverse health outcomes. There are people living with obesity who seem to be protected against the premature development of cardiometabolic diseases. On the other hand, people with normal weight may develop typical obesity diseases upon dysfunction of adipose tissue and predominantly visceral fat distribution. The mechanisms linking impaired function of adipose tissue in people with obesity include adipocyte hypertrophy, altered cellular composition, limited expandability of safe subcutaneous fat stores, ectopic fat deposition in visceral depots, the liver and other organs, hypoxia, a variety of stresses, inflammatory processes, and the release of pro-inflammatory, diabetogenic and atherogenic signals. Genetic and environmental factors might contribute either alone or via interaction with intrinsic biological factors to variation in adipose tissue function. There are still many open questions regarding the mechanisms of how increased body weight causes obesity-related disorders and whether these pathologies could be reversed. Evidence-based weight loss interventions using behaviour change, pharmacological or surgical approaches have clarified the beneficial effects of realistic and sustained weight loss on obesity-related complications as hard outcomes. This review focusses on recent advances in understanding epidemiological trends and mechanisms of obesity-related diseases. PLAIN LANGUAGE SUMMARY: Obesity is a chronic complex and progressive disease characterized by excessive fat deposition that may impair health and quality of life. Worldwide, the number of adults living with obesity has more than doubled since 1990. Obesity may lead to reduced life expectancy, because it increases the risk for type 2 diabetes, cardiovascular diseases (e.g., myocardial infarction, high blood pressure, stroke), fatty liver diseases, musculoskeletal diseases, chronic respiratory diseases, depression and certain types of cancer. However, not every person with obesity develops these diseases. For better prevention and treatment, it is important to understand the mechanisms linking high fat mass to obesity related diseases. It has become clear that fat mass alone cannot explain the higher risk of obesity complications. People with obesity can have either high or low risk of developing complications. Compared to people with a low risk for obesity complications those with a high risk to develop obesity related diseases are characterized by higher central fat deposition in the abdominal region, on average bigger fat cells, higher number of immune cells in adipose tissue and altered signals released from adipose tissue that may directly affect the brain, liver, vasculature and other organs. Both inherited and environment factors may cause these abnormalities of adipose tissue function. However, weight loss through behaviour changes (e.g., lower calorie intake, higher physical activity), medications or obesity surgery can improve health, quality of life and reduce the risk for obesity related diseases.

The gut bacteriome influences host metabolic and physiological functions. However, its relationship with reproductive performance remains unclear. In this study, we evaluated the relationship between the gut bacteriome and reproductive performance in beef cattle, such as Japanese black heifers. Artificial insemination (AI) was performed after 300 days of age, and the number of AI required for pregnancy (AI number) was evaluated. The relationship of the fecal bacteriome at 150 and 300 days of age and reproductive performance was visualized using statistical structural equation modelling between traits based on four types of machine-learning algorithms (linear discriminant analysis, association analysis, random forest, and XGBoost).

The heifers were classified into superior (1.04 ± 0.04 cycles, n = 26) and inferior groups (3.87 ± 0.27 cycles, n = 23) according to the median frequency of AI. The fecal bacteria of the two groups were examined and compared using differential analysis, which demonstrated that the genera Rikenellaceae RC9 gut group and Christensenellaceae R-7 group were increased in the superior group. Subsequently, correlation analysis evaluated the interrelationships between bacteriomes, which demonstrated that the patterns exhibited distinct characteristics. Therefore, four machine-learning algorithms were employed to identify the distinctive factors between the two groups. The directed acyclic graphs carried out by DirectLiNGAM based on these extracted factors inferred that the family Erysipelotrichaceae and the genera Clostridium sensu stricto 1 and Family XIII AD3011 group at 150 days of age were strongly associated with an increase in AI number. Furthermore, a pathway involved in creatinine degradation (PWY-4722) at 150 days of age was related to an increase in AI number. However, bacteriomes and/or pathways at 300 days of age were not necessarily related to AI number.

In this study, a causal inference methodology was applied to investigate AI-dependent gut bacterial communities in pregnant cattle. These findings suggest that AI numbers, which are crucial for beef cattle production management, could be inferred from the fecal bacterial patterns nearly six months before the AI, rather than immediately before. This study provides a novel perspective of the gut environment and its role in reproductive performance.

To investigate the causal relationships between gut microbiota and novel adult-onset type 2 diabetes mellitus(T2DM) subtypes.

We conducted Mendelian randomization (MR) analyses using genome-wide association data from European populations. Initial MR analyses examined associations between gut microbiota and four T2DM subtypes, followed by validation analyses using type 1 diabetes mellitus(T1DM) and T2DM GWAS data. We also performed bidirectional MR analyses and tested for heterogeneity and pleiotropy across all analyses.

Our MR analyses revealed distinctive associations between gut microbiota and T2DM subtypes: six bacterial taxa with severe insulin-deficient diabetes (SIDD), four with severe insulin-resistant diabetes (SIRD), eight with mild obesity-related diabetes (MOD), and eight with mild age-related diabetes (MARD). These associations were distinct from T1DM findings. Six bacterial taxa were validated in T2DM analyses, with four showing directionally consistent effects: Class Clostridia (OR = 0.57, P = 0.045) and Order Clostridiales (OR = 0.57, P = 0.045) were associated with reduced MOD risk, while species Catus (OR = 1.80, P = 0.007) was associated with increased MOD risk, and genus Holdemania (OR = 2.51, P = 0.004) was associated with increased SIRD risk. No significant heterogeneity or pleiotropy was observed across analyses.

Our MR analyses reveal novel causal relationships between gut microbiota and adult-onset T2DM subtypes, though further validation studies are warranted.

Numerous factors are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which are responsible for its development and progression as an independent entity, but also thanks to their simultaneous action. This is explained by the hypothesis of multiple parallel hits. These factors are insulin resistance, lipid metabolism alteration, oxidative stress, endoplasmic reticulum stress, inflammatory cytokine liberation, gut microbiota dysbiosis or gut-liver axis activation. This is a systematic review which has an aim to show the connection between intestinal microbiota and the role of its disbalance in the development of NAFLD. The gut microbiota is made from a wide spectrum of microorganisms that has a systemic impact on human health, with a well-documented role in digestion, energy metabolism, the stimulation of the immune system, synthesis of essential nutrients, etc. It has been shown that dysbiosis is associated with all three stages of chronic liver disease. Thus, the modulation of the gut microbiota has attracted research interest as a novel therapeutic approach for the management of NAFLD patients. The modification of microbiota can be achieved by substantial diet modification and the application of probiotics or prebiotics, while the most radical effects are observed by fecal microbiota transplantation (FMT). Given the results of FMT in the context of metabolic syndrome (MetS) and NAFLD in animal models and scarce pilot studies on humans, FMT seems to be a promising treatment option that could reverse intestinal dysbiosis and thereby influence the course of NAFLD.

Recent advancements in multi-omics technologies have provided unprecedented opportunities to identify biomarkers associated with prediabetes, offering novel insights into its diagnosis and management. This review synthesizes the latest findings on prediabetes from multiple omics domains, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and radiomics. We explore how these technologies elucidate the molecular and cellular mechanisms underlying prediabetes and analyze potential biomarkers with predictive value in disease progression. Integrating multi-omics data helps address the limitations of traditional diagnostic methods, enabling early detection, personalized interventions, and improved patient outcomes. However, challenges such as data integration, standardization, and clinical validation and translation remain to be resolved. Future research leveraging artificial intelligence and machine learning is expected to further enhance the predictive power of multi-omics technologies, contributing to the precision diagnosis and tailored management of prediabetes.

The crisis of metabolic and mental disorders continues to escalate worldwide. A growing body of research highlights the influence of tryptophan and its metabolites, such as serotonin, beyond their traditional roles in neural signaling. Serotonin acts as a key neurotransmitter within the brain-gut-microbiome axis, a critical bidirectional communication network affecting both metabolism and behavior. Emerging evidence suggests that the gut microbiome regulates brain function and behavior, particularly through microbial influences on tryptophan metabolism and the serotonergic system, both of which are essential for normal functioning. Additionally, sex differences exist in multiple aspects of serotonin-mediated modulation within the brain-gut-microbiome axis, affecting feeding and affective behaviors. This review summarizes the current knowledge from human and animal studies on the influence of tryptophan and its metabolite serotonin on metabolic and behavioral regulation involving the brain and gut microbiome, with a focus on sex differences and the role of sex hormones. We speculate that gut-derived tryptophan and serotonin play essential roles in the pathophysiology that modifies neural circuits, potentially contributing to eating and affective disorders. We propose the gut microbiome as an appealing therapeutic target for metabolic and affective disorders, emphasizing the importance of understanding sex differences in metabolic and behavioral regulation influenced by the brain-gut-microbiome axis. The therapeutic targeting of the gut microbiota and its metabolites may offer a viable strategy for treating serotonin-related disorders, such as eating and affective disorders, with potential differences in treatment efficacy between men and women. This review would promote research on sex differences in metabolic and behavioral regulation impacted by the brain-gut-microbiome axis.

As unhealthy aging continues to rise globally, there is a pressing need for effective strategies to promote healthy aging, extend health span, and address aging-related complications. Gerobiotics, an emerging concept in geroscience, offers a novel approach to repurposing selective probiotics, postbiotics, and parabiotics to modulate key aging processes and enhance systemic health. This review explores recent advancements in gerobiotics research, focusing on their role in targeting aging hallmarks, regulating longevity-associated pathways, and reducing risks of multiple age-related chronic conditions. Despite their promise, significant challenges remain, including optimizing formulations, ensuring safety and efficacy across diverse populations, and achieving successful clinical translation. Addressing these gaps through rigorous research, well-designed clinical trials, and advanced biotechnologies can establish gerobiotics as a transformative intervention for healthy aging and chronic disease prevention.

The effect of the gut microbiota extends beyond their habitant place from the gastrointestinal tract to distant organs, including the cardiovascular system. Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (H2S), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, H2S by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, H2S, and PAGln.

Non-communicable diseases (NCDs), such as type 2 diabetes (T2D) and metabolic dysfunction-associated fatty liver disease, have reached epidemic proportions worldwide. The global increase in dietary sugar consumption, which is largely attributed to the production and widespread use of cheap alternatives such as high-fructose corn syrup, is a major driving factor of NCDs. Therefore, a comprehensive understanding of sugar metabolism and its impact on host health is imperative to rise to the challenge of reducing NCDs. Notably, fructose appears to exert more pronounced deleterious effects than glucose, as hepatic fructose metabolism induces de novo lipogenesis and insulin resistance through distinct mechanisms. Furthermore, recent studies have demonstrated an intricate relationship between sugar metabolism and the small intestinal microbiota (SIM). In contrast to the beneficial role of colonic microbiota in complex carbohydrate metabolism, sugar metabolism by the SIM appears to be less beneficial to the host as it can generate toxic metabolites. These fermentation products can serve as a substrate for fatty acid synthesis, imposing negative health effects on the host. Nevertheless, due to the challenging accessibility of the small intestine, our knowledge of the SIM and its involvement in sugar metabolism remains limited. This review presents an overview of the current knowledge in this field along with implications for future research, ultimately offering potential therapeutic avenues for addressing NCDs.

Atrial fibrillation (AF) is a prevalent clinical arrhythmia associated with a high incidence and severe complications such as cerebral embolism and heart failure. While the etiology and pathogenesis of AF involve numerous factors, recent research emphasizes the significant role of intestinal microbiota imbalance in the emergence and progression of AF, particularly among older adults. This review investigates the mechanisms by which intestinal flora and their metabolites contribute to the onset of AF in the elderly, highlighting novel interactions between gut health and cardiac function. Current literature often overlooks these critical connections, indicating a substantial research gap in understanding how dysbiosis may exacerbate AF and hinder recovery. Furthermore, exploring the bidirectional relationship between the gut microbiome and systemic inflammation in the context of AF provides a unique perspective that has yet to be thoroughly investigated. Future research should focus on longitudinal studies assessing gut microbiota composition and function in AF patients and consider probiotics or prebiotics as potential adjunctive therapies for mitigating AF. This comprehensive approach may pave the way for innovative treatments integrating cardiology with gastroenterology, enhancing patient outcomes through a holistic understanding of health.

Diabetes mellitus is a complex metabolic disorder and one of the fastest-growing global public health concerns. The gut microbiota is implicated in the pathophysiology of various diseases, including diabetes. This study utilized 16S rRNA metagenomic data from a volunteer citizen science initiative to investigate microbial markers associated with diabetes status (positive or negative) and type (type 1 or type 2 diabetes mellitus) using supervised machine learning (ML) models. The diversity of the microbiome varied according to diabetes status and type. Differential microbial signatures between diabetes types and negative group revealed an increased presence of Brucellaceae, Ruminococcaceae, Clostridiaceae, Micrococcaceae, Barnesiellaceae and Fusobacteriaceae in subjects with diabetes type 1, and Veillonellaceae, Streptococcaceae and the order Gammaproteobacteria in subjects with diabetes type 2. The decision tree, elastic net, random forest (RF) and support vector machine with radial kernel ML algorithms were trained to screen and type diabetes based on microbial profiles of 76 subjects with type 1 diabetes, 366 subjects with type 2 diabetes and 250 subjects without diabetes. Using the 1000 most variable features, tree-based models were the highest-performing algorithms. The RF screening models achieved the best performance, with an average area under the receiver operating characteristic curve (AUC) of 0.76, although all models lacked sensitivity. Reducing the dataset to 500 features produced an AUC of 0.77 with sensitivity increasing by 74% from 0.46 to 0.80. Model performance improved for the classification of negative-status and type 2 diabetes. Diabetes type models performed best with 500 features, but the metric performed poorly across all model iterations. ML has the potential to facilitate early diagnosis of diabetes based on microbial profiles of the gut microbiome.

The world is experiencing a sudden surge in urban population, especially in developing Asian and African countries. Consequently, the global burden of cardio-metabolic disease (CMD) is also rising owing to gut microbiome dysbiosis due to urbanization factors such as mode of birth, breastfeeding, diet, environmental pollutants, and soil exposure. Dysbiotic gut microbiome indicated by altered Firmicutes to Bacteroides ratio and loss of beneficial short-chain fatty acids-producing bacteria such as Prevotella, and Ruminococcus may disrupt host-intestinal homeostasis by altering host immune response, gut barrier integrity, and microbial metabolism through altered T-regulatory cells/T-helper cells balance, activation of pattern recognition receptors and toll-like receptors, decreased mucus production, elevated level of trimethylamine-oxide and primary bile acids. This leads to a pro-inflammatory gut characterized by increased pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin-2, Interferon-ϒ and elevated levels of metabolites or metabolic endotoxemia due to leaky gut formation. These pathophysiological characteristics are associated with an increased risk of cardio-metabolic disease. This review aims to comprehensively elucidate the effect of urbanization on gut microbiome-driven cardio-metabolic disease. Additionally, it discusses targeting the gut microbiome and its associated pathways via strategies such as diet and lifestyle modulation, probiotics, prebiotics intake, etc., for the prevention and treatment of disease which can potentially be integrated into clinical and professional healthcare settings.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

Over the past 50 years, the incidence of obesity has gradually increased, necessitating investigation into the multifactorial contributors to this disease, including the gut microbiota. Bacteria within the human gut microbiome communicate using a density-dependent process known as quorum sensing (QS), in which autoinducer (AI) molecules (e.g., N-acyl-homoserine lactones [AHLs]) are produced to enable bacterial interactions and regulate gene expression.

We aimed to disrupt QS using quorum quenching (QQ) lactonases GcL and SsoPox, which cleave AHL signaling molecules in a taxa-specific manner based on differing enzyme affinities for different substrates. We hypothesized that QQ hinders signals from obesity-associated pathobionts, thereby slowing or preventing obesity.

In a murine model of diet-induced obesity, we observed GcL and SsoPox treatments have separate sex-dependent and dose-dependent effects on intestinal community composition and diversity. Notably, male mice given 2 mg/mL SsoPox exhibited significant changes in the relative abundances of gram-negative taxa, including Porphyromonadaceae, Akkermansiaceae, Muribaculaceae, and Bacteroidales (Kruskal-Wallis p < 0.001). Additionally, we used covariance matrix network analysis to model bacterial taxa co-occurrence due to QQ enzyme administration. There were more associations among taxa in control mice, particularly among gram-negative bacteria, whereas mice receiving SsoPox had the fewest associations.

Overall, our study establishes proof of concept that QQ is a targetable strategy for microbial control in vivo. Further characterization and dosage optimization of QQ enzymes are necessary to harness their therapeutic capability for the treatment of chronic microbial-associated diseases.

Evidence is accumulating that short-chain fatty acids (SCFAs) produced by the gut microbiota play pivotal roles in host metabolism. They contribute to the metabolic regulation and energy homeostasis of the host not only by preserving intestinal health and serving as energy substrates but also by entering the systemic circulation as signaling molecules, affecting the gut-brain axis and neuroendocrine-immune network. This review critically summarizes the current knowledge regarding the effects of SCFAs in the fine-tuning of the pathogenesis of type 2 diabetes mellitus (T2DM) and insulin resistance, with an emphasis on the complex relationships among diet, microbiota-derived metabolites, T2DM inflammation, glucose metabolism, and the underlying mechanisms involved. We hold an optimistic view that elucidating how diet can influence gut bacterial composition and activity, SCFA production, and metabolic functions in the host will advance our understanding of the mutual interactions of the intestinal microbiota with other metabolically active organs, and may pave the way for harnessing these pathways to develop novel personalized therapeutics for glucometabolic disorders.

Numerous recent studies have suggested that the composition of the intestinal microbiota can trigger metabolic disorders, such as diabetes, prediabetes, obesity, metabolic syndrome, sarcopenia, dyslipidemia, hyperhomocysteinemia, and non-alcoholic fatty liver disease. Since then, considerable effort has been made to understand the link between the composition of intestinal microbiota and metabolic disorders, as well as the role of probiotics in the modulation of the intestinal microbiota. The aim of this review was to summarize the reviews and individual articles on the state of the art regarding ideal therapy with probiotics and prebiotics in order to obtain the reversion of dysbiosis (alteration in microbiota) to eubiosis during metabolic diseases, such as diabetes, prediabetes, obesity, hyperhomocysteinemia, dyslipidemia, sarcopenia, and non-alcoholic fatty liver diseases. This review includes 245 eligible studies. In conclusion, a condition of dysbiosis, or in general, alteration of the intestinal microbiota, could be implicated in the development of metabolic disorders through different mechanisms, mainly linked to the release of pro-inflammatory factors. Several studies have already demonstrated the potential of using probiotics and prebiotics in the treatment of this condition, detecting significant improvements in the specific symptoms of metabolic diseases. These findings reinforce the hypothesis that a condition of dysbiosis can lead to a generalized inflammatory picture with negative consequences on different organs and systems. Moreover, this review confirms that the beneficial effects of probiotics on metabolic diseases are promising, but more research is needed to determine the optimal probiotic strains, doses, and administration forms for specific metabolic conditions.

Osteoarthritis (OA) is a chronic, progressive degenerative joint disease that affects the entire synovial joint, leading to the progressive degeneration of articular cartilage. It seriously affects the quality of life and global disability of patients. OA is affected by a variety of factors; the most significant risk factor for OA is age. As individuals age, the risk and severity of OA increase due to the exacerbation of cartilage degeneration and wear and tear. In recent years, research has indicated that the gut microbiota may play a significant role in the aging and OA processes. It is anticipated that regulating the gut microbiota may offer novel approaches to the treatment of OA. The objective of this paper is to examine the relationship between the gut microbiota and senile OA, to investigate the potential mechanisms involved. This review also summarizes the therapeutic strategies related to gut flora in OA management, such as prebiotics and probiotics, diet, exercise, traditional Chinese medicine (TCM) modification, and fecal microbiota transplantation (FMT), highlighting the potential clinical value of gut flora and elucidating the current challenges. The foundation for future research directions is established through the summarization of current research progress.

Tryptophan is an essential amino acid that is metabolized in the intestine by gut bacteria into indole derivatives, including tryptamine. However, little is known about which bacterial tryptophan metabolites directly influence obesity. In this study, we identified tryptamine as a bacterial metabolite that significantly reduced fat mass following the intraperitoneal injection of five bacterial tryptophan end-products in a diet-induced obese mouse model. Interestingly, tryptamine, a serotonin analog, inhibited both lipogenesis and lipolysis in adipose tissue, which was further confirmed in a 3T3-L1 adipocyte cell culture study. Moreover, oral tryptamine supplementation markedly reduced fat mass and improved insulin sensitivity in a long-term, high-fat-diet, pair-feeding model. These studies demonstrate the therapeutic potential of tryptamine, a bacterial tryptophan metabolite, in ameliorating obesity and insulin resistance by directly regulating lipogenesis and lipolysis in white adipose tissue.

Metabolic Syndrome (MS) is a cluster of metabolic abnormalities closely associated with hypertension, diabetes, hyperlipidemia, obesity, etc. Our previous research indicated that fecal microbiota transplantation (FMT) could improve MS, but the factors influencing the efficacy of washed microbiota transplantation (WMT) in treating MS patients remain unclear. The objective of this study is to analyze the influencing factors of WMT in treating MS patients.

The clinical data and influencing factors related to MS patients were collected retrospectively. Not only the changes in body mass index [BMI = weight (kg)/height (m)2], blood glucose, blood lipids, and blood pressure were analyzed, but also the influencing factors of WMT in treating MS patients were carried out based on Logistic Regression. The 16S rRNA gene amplicon sequencing was performed on fecal samples before and after WMT treatment.

A total of 210 patients were included, including 68 patients in the WMT group and 142 patients in the drug treatment (DT) group. WMT had a significant improvement and ASCVD downregulation effect on MS patients, and 42.65% of MS patients removed the label of MS after WMT treatment. Independent influencing factors for treating MS patients through WMT include age < 60 years old, high smoking index, infection, single donor selection, single-course WMT treatment, and having hypertension, diabetes, or obesity. WMT treated MS patients by maintaining the balance of gut microbiota.

WMT has a significant effect in improving MS and downregulating ASCVD risk stratification. The therapeutic effect of WMT on MS patients is closely related to their age, smoking index, infection, chronic disease status, donor type, and WMT courses. Therefore, we can improve the efficacy of WMT by reducing independent influencing factors that affect gut microbiota homeostasis.

Sugar preference is a key contributor to the overconsumption of sugar and the concomitant increase in the incidence of diabetes. However, the exact mechanism of its development remains ambiguous. Here we show that the expression of free fatty acid receptor Ffar4, a receptor for long-chain fatty acids, is decreased in patients and mouse models with diabetes, which is associated with high sugar intake. Deletion of intestinal Ffar4 in mice resulted in reduced gut Bacteroides vulgatus and its metabolite pantothenate, leading to dietary sugar preference. Pantothenate promoted the secretion of GLP-1 which inhibited sugar preference by stimulating hepatic FGF21 release, which in turn regulates energy metabolism. These findings uncover a previously unappreciated role of Ffar4 in negatively regulating sugar preference and suggest B. vulgatus-derived pantothenate as a potential therapeutic target for diabetes.

Obesity is a major public health concern and burden on individuals and healthcare systems. Due to the challenges and limitations of lifestyle adjustments, it is advisable to consider pharmacological treatment for people affected by obesity. However, the side effects and limited efficacy of available drugs make the obesity drug market far from sufficient. Drug repurposing involves identifying new applications for existing drugs and offers some advantages over traditional drug development approaches including lower costs and shorter development timelines. This review aims to provide an overview of drug repurposing for anti-obesity medications, including the rationale for repurposing, the challenges and approaches, and the potential drugs that are being investigated for repurposing. Through advanced computational techniques, researchers can unlock the potential of repurposed drugs to tackle the global obesity epidemic. Further research, clinical trials, and collaborative efforts are essential to fully explore and leverage the potential of drug repurposing in the fight against obesity.