Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus; however, many patients respond poorly to this drug in clinical practice. The potential involvement of microbiota-mediated intestinal immunity and related signals in metformin responsiveness has not been previously investigated. In this study, we successfully constructed a humanized mouse model by fecal transplantation of the gut microbiota from clinical metformin-treated - responders and non-responders, and reproduced the difference in clinical phenotypes of responsiveness to metformin. The abundance of Bacteroides thetaiotaomicron, considered a representative differential bacterium of metformin responsiveness, and the level of secretory immunoglobulin A (SIgA) in intestinal immunity increased significantly in responder recipient mice following metformin treatment. In contrast, no significant alterations in B. thetaiotaomicron and SIgA were observed in non-responder recipient mice. The study of IgA-/- mice confirmed that downregulated expression or deficiency of SIgA resulted in non-response to metformin, meaning that metformin was unable to improve dysfunctional glucose metabolism and reduce intestinal and adipose tissue inflammation, ultimately leading to systemic insulin resistance. Furthermore, supplementation with succinate, a microbial product of B. thetaiotaomicron, potentially reversed the non-response to metformin by inducing the production of SIgA. In conclusion, we demonstrated that upregulated SIgA, which could be regulated by succinate, was functionally involved in metformin response through its influence on immune cell-mediated inflammation and insulin resistance. Conversely, an inability to regulate SIgA may result in a lack of response to metformin.

Patients with type 2 diabetes mellitus (T2DM) often exhibit reduced Lactobacillus abundance, dysregulated immune responses, disrupted intestinal barrier integrity, and increased insulin resistance. Consumption of non-digestible oligosaccharides has been shown to support the persistence of Lactobacillus in the gut and improve gut homeostasis. Lactiplantibacillus plantarum ZDY2013, a probiotic capable of metabolizing various oligosaccharides, serves as a potent regulator of intestinal mucosal immunity. In this study, we investigated the potential ameliorative effects of xylooligosaccharides combined with L. plantarum ZDY2013 (synbiotic) on T2DM-induced intestinal injury and explored the underlying mechanisms. Our results showed that synbiotic improved glucose metabolism, reduced lipid accumulation, and alleviated insulin resistance in T2DM rats. Moreover, synbiotic outperformed L. plantarum ZDY2013 alone in restoring intestinal barrier integrity by suppressing oxidative stress and intestinal inflammation, while significantly enhancing the colonization of L. plantarum ZDY2013 and altering the abundance of key bacterial genera. Interestingly, synbiotic treatment also increased the production of short-chain fatty acids (SCFAs), which were strongly associated with specific bacterial taxa. Furthermore, gut microbiota-derived SCFAs were confirmed to ameliorate insulin resistance by promoting glucose uptake and glycogen synthesis in IR-HepG2 cells. Collectively, these findings suggest the potential use of synbiotics as a clinical intervention to ameliorate T2DM. This study provides a rationale for exploring dietary approaches as a mitigating strategy for managing long-standing diabetes.

Xiexin Tang (XXT) is a classic Chinese medicine formula that can be used to treat Atherosclerosis (AS). This study aimed to investigate the mechanism by which XXT regulated AS lipid levels. Firstly, the mixture components of XXT were analyzed by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Then, the AS model based on Apolipoprotein E knockout (ApoE-/-) mice was established. Cytokines related to lipid metabolism and bile acid metabolism were detected by Quantitative Real-time PCR (qRT-PCR). 16S rDNA gene sequencing was performed to analyze differential bacterial populations, and the mechanism of XXT regulation of bile acids affecting lipid metabolism was further explored by targeted metabolomics. Further, antibiotic-treated mice were used to investigate the role of gut microbiota in the anti-AS effect of XXT. The results showed that XXT attenuated the lipid levels and reversed the abnormal elevation of cytokines, such as hepatic lipid metabolism and inflammatory reaction in AS mice. XXT also repaired the gut barrier damage and reversed gut microbiota disorders in AS mice. Furthermore, the metabolic levels of bile acids were reshaped by XXT. Whereas, in the absence of gut microbiota, XXT failed to attenuate lipid levels and inhibit the expression of cytokines related to inflammation and bile acid metabolism in AS mice and failed to play a role in ultimately treating AS. In conclusion, XXT could effectively inhibit the inflammatory reaction and lipid accumulation in AS mice, and this effect was closely related to its remodeling of gut microbiota to regulate bile acid metabolism.

To investigate the impact of diet-induced gut microbiota alterations on type 2 diabetes and assess the therapeutic potential of Fecal Microbiota Transplantation (FMT) in restoring a balanced gut microenvironment.

To induce type 2 diabetes, rats were fed a high-sugar high-fat diet (HSFD) for 90 days. After diabetes induction, animals were divided into an HSFD control group, a metformin group (100 mg/kg), and an FMT group (100 mg/kg), receiving treatment for an additional 90 days. Fasting blood glucose levels, glucose tolerance, serum markers (HbA1C, free fatty acids, lipopolysaccharides, pro-inflammatory and anti-inflammatory cytokines), and gut microbiota profiles via cecal metagenome sequencing were analyzed post-treatment.

FMT effectively restored gut microbiota composition to a profile similar to healthy controls, rebalancing the Firmicutes/Bacteroidetes ratio and increasing beneficial taxa, including Prevotella ruminicola, Akkermansia muciniphila, Roseburia, and Faecalibacterium prausnitzii. These microbial shifts corresponded with significant metabolic improvements: FMT reduced inflammatory markers (LPS and FFA), lowered HbA1c, and improved glucose tolerance. Enhanced gut barrier integrity observed in FMT-treated animals likely contributed to reduced endotoxemia and systemic inflammation, distinguishing FMT's metabolic effects from those of metformin. Notably, FMT addressed the dysbiosis associated with HSFD, promoting microbial resilience and mitigating the metabolic disruptions linked to type 2 diabetes.

These findings underscore the potential of FMT as a targeted therapeutic approach to modulate gut microbiota composition and mitigate metabolic dysregulation induced by high sugar high fat diet.

Colonic permeability is a major consequence of dysbiosis and diseases affecting the colon, further contributing to inflammation and extraintestinal diseases. Recent advances have shed light on the association between colonocyte energy utilization and the mechanisms that support epithelial function and homeostasis. One unifying theme is the induction of colonocyte hypoxia, driven by the aerobic oxidation of microbial-derived butyrate, as a critical factor promoting multiple cellular processes that support intestinal barrier function, mucus secretion, and the maintenance of synergistic luminal microbes. Particular attention will be focused on experimental evidence supporting beta-oxidation via activation of peroxisome proliferators-activated receptor-γ (PPAR) and upregulation and activation of processes that promote barrier function by hypoxia-inducible factor (HIF) signaling. Growing evidence suggests that colonocyte energy utilization is tightly regulated and switches between beta-oxidation of butyrate and anaerobic glycolysis, the latter being associated with several disease states. As most of the primary literature associated with colonocyte energy utilization has focused on adult models, evidence supporting butyrate oxidation in the neonatal gut is lacking. Thus, this review details the current state of knowledge linking colonocyte substrate utilization to mechanisms supporting gut health, but also highlights the counterindications of colonic butyrate availability and utilization in developmental periods.

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.

Obesity is a significant health concern, significantly contributing to increased morbidity and mortality by disrupting multiple physiological systems. It is strongly associated with metabolic dysfunctions, including impaired glycemic homeostasis, compromised intestinal barrier integrity, and gut microbiota imbalances, all exacerbating the risk of chronic diseases. The hydroalcoholic extract of açaí seeds (ASE), rich in phenolic compounds, has demonstrated beneficial effects on obesity and hyperglycemia; however, its impacts on gut health and gut-hypothalamus communication remain unclear. This study aimed to investigate the therapeutic effect of ASE in intestinal and hypothalamic alterations associated with obesity and compare it with Metformin. Male C57BL/6 mice were fed a high-fat or standard diet for 14 weeks. The ASE (300mg/Kg/day) and Metformin (300mg/Kg/day) treatments started in the tenth week until the fourteenth week, totaling four weeks of treatment. Our data show that the treatment with ASE and Metformin reduced body weight, ameliorated lipid profile, hyperglycemia, and plasma hyperleptinemia, and decreased the oxidative damage in the gut by reducing immunostaining of 8-isoprostane and NOX-4 expression, and improved the intestinal parameters and hypothalamic gene expression. Obesity-induced dysbiosis in the HF group was marked by reduced Proteobacteria and elevated LPS plasma levels, which were improved by treatments with ASE and Metformin. These findings suggest that ASE and Metformin are promising strategies to counteract the adverse effects of obesity on intestinal health and gut-hypothalamus communication, though they act through distinct mechanisms. Therefore, we can suggest that ASE is a promising natural product for treating the intestinal alterations associated with obesity.

Metformin is frequently prescribed to treat type 2 diabetes. Its primarily regulates hepatic and colonic glucose metabolism, but recent studies have suggested an anti-inflammatory effect, especially in colitis. It has been suggested that metformin may enhance immune checkpoint inhibition (ICI) efficacy for cancer treatment. Our study aims to explore the impact of metformin on ICI efficacy and the risk for colitis.

This was a single center, retrospective analysis of consecutive patients at a tertiary cancer center who received ICI between 01/2010-12/2022 and developed immune-mediated colitis (IMC). Patients were screened for colitis based on stool tests, then divided into two groups depending on metformin use prior to colitis onset. We collected data on demographic and colitis clinical information including treatments, and outcomes.

A total of 953 patients were included. The incidence of IMC was higher among metformin users (7.6 %) than non-metformin users (4.9 %; p < 0.01). There were no significant differences in colitis features and outcomes, except for longer hospital stay among metformin users (8 days vs 6 for non-metformin users; p = 0.03). Metformin use was associated with shorter overall survival vs non-metformin users among patients with IMC (p = 0.03).

Our study is among the first to explore the impact of metformin on IMC and overall survival. We found that metformin use may be associated with higher risk of IMC. We also found an association between metformin use and shorter overall survival among patients who developed IMC. Larger studies with risk-stratified analysis are needed to validate our findings.

The composition of the microbiota in patients has been shown to correlate with cancer progression and response to therapy, highlighting unique opportunities to improve patient outcomes. In this review, we discuss the challenges and advancements in understanding the chemical mechanisms of specific microbiota species, pathways, and molecules involved in cancer progression and treatment. We also describe the modulation of cancer and immunotherapy by the microbiota, along with approaches for investigating microbiota enzymes and metabolites. Elucidating these specific microbiota mechanisms and molecules should offer new opportunities for developing enhanced diagnostics and therapeutics to improve outcomes for cancer patients. Nonetheless, many microbiota mechanisms remain to be determined and require innovative chemical genetic approaches.

Healthcare professionals face increasing challenges when managing older patients, a group characterized by significant interindividual variability in comorbidity patterns, homeostatic capacity, frailty status, cognitive function, and life expectancy. Complex therapeutic decisions may increase the risk of inappropriate polypharmacy, drug-drug, and drug-disease interactions in the context of age-associated pharmacokinetic and pharmacodynamic alterations, with consequent drug accumulation and toxicity.

This state-of-the-art narrative review article summarizes and critically appraises the results of original research studies and reviews published in PubMed, Scopus, and Web of Science, from inception to 9 April 2025, on age-associated changes in critical organs and systems and relevant pharmacokinetic and pharmacodynamic alterations. It also discusses the emerging role of frailty and the gut microbiota in influencing such alterations and the potential utility of machine learning techniques in identifying new signals of drug efficacy and toxicity in older patients.

The available knowledge regarding specific age-associated pharmacokinetic and pharmacodynamic alterations applies to a limited number of drugs, some of which are not frequently prescribed in contemporary practice. Future studies investigating a wider range of drugs and their patterns of use will likely enhance therapeutic efficacy and minimize toxicity in the older patient population.

Interindividual variability in drug exposure can significantly influence treatment outcomes and may lead to drug concentration-related side effects during tuberculosis (TB) treatment. Although the gut microbiota is known to affect drug metabolism, its impact on anti-TB drugs has not been thoroughly explored. This study sought to elucidate the relationship between pre-treatment gut microbiota and drug exposure levels among patients with pulmonary TB. Two cohorts were analyzed: a discovery cohort (N = 99) and a validation cohort (N = 32), both comprising patients undergoing anti-TB therapy with rifampicin, isoniazid, pyrazinamide, and ethambutol. The gut microbiota patterns of participants from the discovery cohort and the validation cohort were profiled by 16S rRNA gene sequencing and metagenomics, respectively. Analyses of both cohorts robustly established a positive association between pre-treatment microbial diversity and drug exposure, as well as significant differences in gut microbiota composition across various drug exposure groups. At the species level, Faecalibacterium prausnitzii was positively associated with drug exposure to rifampicin. Moreover, functional analysis revealed that starch and sucrose metabolism and secondary bile acid biosynthesis were more abundant in the high drug exposure group. To identify biomarkers capable of stratifying patients based on their drug exposure levels, 11 taxa, represented by Faecalibacterium, were selected in the discovery cohort (AUC = 0.992) and were confirmed in the validation cohort with high predictive accuracy (AUC = 0.894). This study demonstrated a correlation between microbial dysbiosis and reduced exposure to anti-TB medications. Optimizing treatment by regulating gut microbiota to improve drug exposure levels requires further validation through larger scale multicenter clinical trials.

Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness among individuals with diabetes mellitus. Current clinical diagnostic criteria mainly base on visible vascular structure changes, which are insufficient to identify diabetic patients without clinical DR (NDR) but with dysfunctional retinopathy. This review focuses on retinal endothelial cells (RECs), the first cells to sense and respond to elevated blood glucose. As blood glucose rises, RECs undergo compensatory and transitional phases, and the correspondingly altered molecules are likely to become biomarkers and targets for early prediction and treatment of NDR with dysfunctional retinopathy. This article elaborated the possible pathophysiological processes focusing on RECs and summarized recently published and reliable biomarkers for early screening and emerging intervention strategies for NDR patients with dysfunctional retinopathy. Additionally, references for clinical medication selection and lifestyle recommendations for this population are provided. This review aims to deepen the understanding of REC biology and NDR pathophysiology, emphasizes the importance of early detection and intervention, and points out future directions to improve the diagnosis and treatment of NDR with dysfunctional retinopathy and to reduce the occurrence of DR.

Aim    To evaluate the effect of extended-release metformin (metformin long) on plasma concentrations of short-chain fatty acids (SCFA), physical performance and muscle strength in patients with chronic heart failure (CHF), sarcopenia and prediabetes.Material and methods    The study included 27 patients (mean age 68±9.8 years) with CHF, sarcopenia and prediabetes randomized into the groups of intervention (n=14) (metformin long + healthy lifestyle, HLS) and control (n=13) (HLS). Measurement of SCFA (C3, iC4, C4, αC5, βC5, C5, iC6, C6) concentrations, bioimpedancemetry, Short Physical Performance Battery (SPPB) test, and dynamometry were performed at the beginning of the study and after 6 months. R language and RStudio software were used for statistical analysis.Results    The study groups were comparable in clinical characteristics. The SCFA concentrations were significantly increased, except for iC6. After 6 months of treatment, the SCFA concentrations were decreased, except for C5, iC6, C3. Metformin long improved the physical performance and strength index. The median SPPB score in the control group was 4 [3.0; 9.5] and in the metformin group, 9 [7.25; 9.75], p = 0.0014. In the control group, the change in Δ strength index was -4.65 [-11.09; 17.66], in the metformin group, 18.75 [8.17; 33.03], p = 0.031.Conclusion    Metformin exerts a beneficial effect on plasma SCFA and physical performance in patients with prediabetes, CHF, and sarcopenia.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex metabolic disorder characterized by hepatic lipid accumulation and subsequent inflammation. This condition is closely linked to metabolic syndrome and obesity, with its prevalence rising due to sedentary lifestyles and high-calorie diets. The pathogenesis of MAFLD involves multiple factors, including insulin resistance, lipotoxicity, oxidative stress, and inflammatory responses. The gut microbiota plays a crucial role in MAFLD development, with dysbiosis contributing to liver inflammation through various mechanisms, such as enhanced intestinal permeability and the translocation of bacterial products like lipopolysaccharide (LPS). Microbial metabolites, including short-chain fatty acids (SCFAs) and bile acids, influence hepatic function and immune responses, with potential implications for disease progression. Specific gut microbiome signatures have been identified in MAFLD patients, offering potential diagnostic and therapeutic targets. Moreover, gut-derived toxins, such as endotoxins, lipopolysaccharides, trimethylamine-N-oxide and bacterial metabolites, significantly influence liver damage and inflammation, highlighting the complex interplay between the gut microbiome and hepatic health. This review comprehensively examines the complex interplay between the gut microbiota and MAFLD, focusing on underlying pathogenic mechanisms, potential biomarkers, and emerging microbiome-targeted therapeutic strategies for disease management.

Type 2 diabetes (T2D) is a complex disease shaped by genetic and environmental factors, including the gut microbiome. Recent research revealed pathophysiological heterogeneity and distinct subgroups in both T2D and prediabetes, prompting exploration of personalized risk factors. Using metabolomics in two Swedish cohorts (n = 1,167), we identified over 500 blood metabolites associated with impaired glucose control, with approximately one-third linked to an altered gut microbiome. Our findings identified metabolic disruptions in microbiome-metabolome dynamics as potential mediators of compromised glucose homeostasis, as illustrated by the potential interactions between Hominifimenecus microfluidus and Blautia wexlerae via hippurate. Short-term lifestyle changes, for example, diet and exercise, modulated microbiome-associated metabolites in a lifestyle-specific manner. This study suggests that the microbiome-metabolome axis is a modifiable target for T2D management, with optimal health benefits achievable through a combination of lifestyle modifications.

Human dipeptidyl peptidase 4 (hDPP-4) has been a pharmacological target for metabolic diseases, particularly diabetes, since the early 2000s. As a ubiquitous enzyme found in both prokaryotic and eukaryotic organisms, hDPP-4 plays crucial roles in host homeostasis and disease progression. While many studies have explored hDPP-4's properties, research on gut microbially derived DPP-4 (mDPP-4) remains limited. This review discusses the significance of mDPP-4 and its health implications, analyzing crystal structures of mDPP-4 in comparison to human counterparts. We examine how hDPP-4 inhibitors could influence gut microbiome composition and mDPP-4 activity. Additionally, this review connects ongoing discussions regarding DPP-4 substrate specificity and potential access routes for mDPP-4, emphasizing the urgent need for further research on mDPP-4's role in health and improve the precision of DPP-4 inhibitor therapies.

Oral microbiome dysbiosis has been proposed as a potential contributing factor to rising rates of diabetes in pregnancy, with oral health previously associated with an increased risk of numerous chronic diseases and complications in pregnancy, including gestational diabetes mellitus (GDM). However, whilst most studies examining the relationship between GDM and the oral microbiome identify significant differences, these differences are highly variable between studies. Additionally, no previous research has examined the oral microbiome of women with pre-existing type 2 diabetes mellitus (T2DM), which has greater risks of complications to both mother and baby. In this study, we compared the oral microbiome of 11 pregnant women with pre-existing T2DM with 28 pregnant normoglycaemic controls. We used shotgun metagenomic sequencing to examine buccal swab and saliva rinse samples at two time points between 26 and 38 weeks of gestation. To reduce variation caused by the choice of differential abundance analysis tool, we employed a consensus approach to identify differential taxa and pathways due to diabetes status. Differences were identified at the late time point only. In swab samples, there was increased Flavobacteriaceae, Capnocytophaga, Capnocytophaga gingivalis SGB2479, Capnocytophaga leadbetteri SGB2492 and Neisseria elongata SGB9447 abundance in T2DM as well as increased Shannon diversity and richness. In rinse samples, there was an increased abundance of Haemophilus, Pasteurellaceae, Pasteurellales and Proteobacteria. In contrast to studies of the oral microbiome in T2DM or GDM that use a single differential abundance analysis tool, our consensus approach identified few differences between pregnant women with and without T2DM.

Metformin, an oral antihyperglycemic drug that has been in use for over 60 years, remains a first-line therapy for type 2 diabetes (T2D). Numerous studies have suggested that metformin promotes health benefits beyond T2D management, including weight loss, cancer prevention and treatment, and anti-aging, through several proposed mechanistic targets. Here we discuss the established effects of metformin and the progress made in identifying its direct targets. Additionally, we emphasize the importance of elucidating the structural bases of the drug and its direct targets. Ultimately, this review aims to highlight the current state of knowledge regarding metformin and its related emerging discoveries, while also outlining critical future research directions.

FCP-2-1, a water-soluble polysaccharide isolated and purified from Finger Citron, demonstrated hypoglycemic effect in vitro in our previous study. However, its antidiabetic effect and underlying mechanism in vivo remain to be elucidated. In this study, the antidiabetic effect of FCP-2-1 and its effects on the gut microbiota, short-chain fatty acids (SCFAs), and glucagon-like peptide-1 (GLP-1) in high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice were investigated. The results showed that FCP-2-1 could significantly alleviate diabetic symptoms in diabetic mice, restore the balance of the gut microbiota, and increase the content of acetic acid and propionic acid. In particular, FCP-2-1 was found to be able to promote the secretion of GLP-1, a new therapeutic target for diabetes. Moreover, propionic acid and FCP-2-1 were able to promote GLP-1 secretion in NCI-H716 cells, suggesting that FCP-2-1 could stimulate the secretion of GLP-1 through itself and propionic acid produced by the gut microbiota. These findings indicated that the antidiabetic mechanism of FCP-2-1 might be related to the gut microbiota-GLP-1 pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.

An increased rate of gastrointestinal (GI) symptoms is reported in patients with type 2 diabetes receiving imeglimin plus metformin vs monotherapy or in combination with other antidiabetic drugs. This post-hoc analysis explored GI symptom incidence, risk factors for their occurrence, and the impact on therapeutic efficacy during imeglimin and metformin combination therapy.

Data were derived from the 52-week, open-label, phase 3 TIMES-2 trial in Japanese type 2 diabetes patients. Patients in the imeglimin plus metformin group were divided into two subgroups based on the presence of GI symptoms and diarrhea, with efficacy and safety assessed. Factors associated with their occurrence were explored using multivariate logistic regression analysis.

Of 64 patients analyzed, GI symptoms and diarrhea occurred in 40.6% (n = 26) and 17.2% (n = 11) of patients, respectively. Metformin dose and patient age did not significantly affect their incidence. Events occurred more frequently within the first 4 months of treatment. Approximately half resolved within 1 week, and most were mild. Type 2 diabetes duration <5 years was significantly associated with diarrhea (odds ratio = 5.979; P = 0.039). Significant hypoglycemic effects were observed from baseline, irrespective of GI symptoms or diarrhea. However, the degree of HbA1c improvement tended to be greater in patients with GI symptoms and diarrhea.

Increased awareness regarding the potential for GI symptoms, including diarrhea, during imeglimin plus metformin combination therapy is warranted. This data will provide clinicians with useful information regarding symptomatic treatment when it occurs and help determine whether to continue treatment administration and is expected to improve patient adherence.

Type 2 diabetes mellitus (T2DM) is a rapidly increasing metabolic disorder that poses a significant threat to global public health. Recent evidence suggests that targeting the gut microbiota through dietary and pharmaceutical interventions can effectively manage T2DM. In this study, we developed a novel Chinese herbal formula, CCM, specifically for T2DM, composed of Coptis rhizoma, Cinnamomi cortex, and Mume fructus. To evaluate CCM's efficacy and explore its underlying mechanisms, particularly the role of the gut microbiota, diabetic C57/db/db mice were administered different doses of CCM (low, medium, high) for 4 weeks, with normal C57 mice as healthy controls and metformin as a positive control. Comprehensive clinical indicators of T2DM were measured before and after treatment. High-throughput sequencing was used to assess changes in gut microbiome composition and function. Our results showed that CCM treatment, especially at medium and high doses, resulted in more significant improvements in blood glucose, lipid profiles, and body weight compared to metformin. The CCM-treated group also exhibited more significant changes in the microbial community structure compared to the metformin group, notably enriching three beneficial microbes (>40%): Bacteroidetes spp., Akkermansia spp., and Parabacteroides spp., which correlated with improved diabetic parameters. Further analysis identified that all four microbial metabolic pathways linked to lowering blood glucose were exclusively enriched in the CCM-treated group. Of the 10 pathways related to improved blood lipid levels, five were unique to CCM. These unique pathways enriched by CCM may explain its superior therapeutic effects, indicating its distinct mechanisms in modulating gut microbiota.IMPORTANCEOur study demonstrates that CCM outperforms metformin in managing key clinical indicators in type 2 diabetes mellitus (T2DM) model mice and induces more significant alterations in gut microbiota composition and function. Notably, the uniquely enriched beneficial microbes and microbial metabolic pathways in the CCM samples may explain its enhanced therapeutic effects compared to metformin. Consequently, these findings suggest that CCM offers a promising therapeutic strategy for T2DM, and further provide valuable insights into potential probiotic candidates (such as Bacteroidetes spp., Akkermansia spp., and Parabacteroides spp.) and newly identified functional pathways (such as chondroitin sulfate degradation, geraniol degradation, biotin biosynthesis, colonic acid building blocks biosynthesis, and the biosynthesis of vancomycin group antibiotics) that could be targeted for therapeutic intervention.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a decade-long preclinical pathological period that can be divided into several stages. Emerging evidence has revealed that the microbiota-gut-brain axis plays an important role in AD pathology. However, the role of gut microbiota in different AD stages has not been well characterized. In this study, we performed fecal shotgun metagenomic analysis on a Chinese cohort with 476 participants across five stages of AD pathology to characterize stage-specific alterations in gut microbiota and evaluate their diagnostic potential. We discovered extensive gut dysbiosis that is associated with neuroinflammation and neurotransmitter dysregulation, with over 10% of microbial species and gene families showing significant alterations during AD progression. Furthermore, we demonstrated that microbial gene families exhibited strong diagnostic capabilities, evidenced by an average AUC of 0.80 in cross-validation and 0.75 in independent external validation. In the optimal model, the most discriminant gene families are primarily involved in the metabolism of carbohydrates, amino acids, energy, glycan and vitamins. We found that stage-specific microbial gene families in AD pathology could be validated by an in vitro gut simulator and were associated with specific genera. We also observed that the gut microbiota could affect the progression of cognitive decline in 5xFAD mice through fecal microbiota transplantation, which could be used for early intervention of AD. Our multi-stage large cohort metagenomic analysis demonstrates that alterations in gut microbiota occur from the very early stages of AD pathology, offering important etiological and diagnostic insights.

This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin's effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, and multiple sclerosis. Key findings demonstrate that metformin's neuroprotective effects operate through multiple pathways: AMPK activation enhancing cellular energy metabolism and autophagy; upregulation of antioxidant defenses; suppression of inflammation; inhibition of protein aggregation; and improvement of mitochondrial function. These mechanisms collectively address common pathological features in neurodegeneration and neuroinflammation, including oxidative stress, protein accumulation, and mitochondrial dysfunction. Clinical and preclinical evidence supporting metformin's association with improved cognitive performance, reduced risk of dementia, and modulation of pathological hallmarks of neurodegenerative diseases is critically evaluated. While metformin shows promise as a therapeutic agent, this review emphasizes the need for further investigation to fully understand its mechanisms and optimal therapeutic applications in neurodegenerative diseases.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by T cell-mediated pancreatic β cell destruction. To evaluate the effects of metformin on immune cells in autoimmune diabetes, we administered metformin intraperitoneally to two T1D mouse models and analyzed autoimmune diabetes progression. In a cyclophosphamide (CY)-induced T1D model in male non-obese diabetic (NOD) mice, intraperitoneal administration of metformin significantly prevented autoimmune diabetes. Treatment with metformin showed a decrease in activated T cells, CD44hiCD62Llo effector memory cells, macrophages, and dendritic cells (DCs), and an increase in CD44hiCD62Lhi central memory cells, B cells, and regulatory T cells (Tregs) in splenocytes. Interestingly, metformin treatment showed a decrease in activated T cells, CD4+ effector memory T cells and Th1-type antigen-specific cells in PLN cells. IL-17 production was significantly suppressed in metformin-treated mice. TNF-α production from DCs in vitro was dose-dependently suppressed by metformin. Activity of mTOR signaling was significantly reduced in CD4+ T cells, CD8+ T cells, and B220+ B cells. In addition, activities of mTOR and STAT3 signaling in DCs were also reduced significantly. Furthermore, metformin treatment in female NOD mice, a spontaneous T1D model, significantly suppressed autoimmune diabetes onset as well and an increase in Tregs was observed. Our results suggest that metformin may suppress autoimmunity and have therapeutic potential in T1D progression as an immunomodulator.

Metformin shows potential in combating clozapine-induced weight gain (CIWG). However, current evidence for its use remains limited. Through an audit we determined the prevalence of metformin use among clozapine-treated patients and its impact on weight and waist circumference (WC).

This retrospective cohort study examined electronic medical records of community-based clozapine patients under the care of metropolitan community mental health teams within the Central Adelaide Local Health Network (CALHN) from January 2014 to June 2023. We included patients treated with clozapine both with and without metformin, above 18 years of age, with complete physical monitoring data at baseline, 6, and 12 months.

There were 357 patients, who met study criteria. Metformin was prescribed to 23% of patients, of whom 78% had diabetes. At baseline, WC was > 101 cm in 71% of males and > 87 cm in 86% of females, placing them at increased risk of weight-related comorbidities, including cardiovascular disease, cancer, and death. After 1 year, males and females in the highest risk group for WC-related comorbidities increased to 76.3% and 95.4%, respectively. Co-prescription of metformin with clozapine was associated with unadjusted mean weight loss (-1.67 kg) and decrease in WC (-1.00 cm). Patients not using metformin gained weight (0.68 kg) and WC (2.49 cm). Using a linear mixed-effects models adjusting for repeated measurements, age, sex, and type 2 diabetes, over 12 months, patients treated with metformin were 3.08 kg lighter than those not taking metformin (95% confidence interval [CI]: 0.54-5.62, p = 0.018). Similar models suggested patients treated with metformin showed an average 2.83 cm decrease in WC compared with those not taking metformin (CI: 0.26-5.40, p = 0.03). There was no significant interaction between difference from baseline in weight or WC and metformin dose (p > 0.05).

The prevalence of metformin use for CIWG appears low in this cohort, where over 84% of patients were overweight or obese. Metformin use was associated with a significantly lower incidence of weight and WC gain over 12 months. Pharmacists are crucial for educating clinicians and patients about the benefits of metformin for reducing CIWG.

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

Akkermansia muciniphila is a promising target for managing obesity and type 2 diabetes (T2D), but human studies are limited. We conducted a 12-week randomized, double-blind, placebo-controlled trial involving 58 participants with overweight or obese T2D, who received A. muciniphila (AKK-WST01) or placebo, along with routine lifestyle guidance. Both groups showed decreases in body weight and glycated hemoglobin (HbA1c), without significant between-group differences. In participants with low baseline A. muciniphila, AKK-WST01 supplementation showed high colonization efficiency and significant reductions in body weight, fat mass, and HbA1c, which were not found in the placebo group. However, AKK-WST01 supplementation showed poor colonization and no significant clinical improvements in participants with high baseline A. muciniphila. These findings were verified in germ-free mice receiving feces with low or high A. muciniphila. Our study indicates that metabolic benefits of A. muciniphila supplementation could depend on its baseline intestinal levels, supporting the potential for gut microbiota-guided probiotic supplementation. (ClinicalTrials.gov number, NCT04797442).

Through a retrospective analysis of existing FDG PET-MRI images, we recently demonstrated that metformin increases the accumulation of FDG in the intestinal lumen, suggesting that metformin stimulates glucose excretion into the intestine. However, the details of this phenomenon remain unclear. We here investigate the detailed dynamics of intestinal glucose excretion, including the rate of excretion and the metabolism of excreted glucose, in both the presence and absence of metformin.

We quantified intestinal glucose excretion using newly developed FDG PET-MRI-based bioimaging in individuals with type 2 diabetes, both treated and untreated with metformin. The metabolism of excreted glucose was analyzed through mass spectrometry of fecal samples from mice intravenously injected with 13C-labeled glucose.

Continuous FDG PET/MRI image taking reveals that FDG is initially observed in the jejunum, suggesting its involvement in FDG excretion. Metformin-treated individuals excrete a significant amount of glucose (~1.65 g h-1 per body) into the intestinal lumen. In individuals not receiving metformin, a certain amount of glucose (~0.41 g h-1per body) is also excreted into the intestinal lumen, indicating its physiological importance. Intravenous injection of 13C-labeled glucose in mice increases the content of 13C in short-chain fatty acids (SCFAs) extracted from feces, and metformin increased the incorporation of 13C into SCFAs.

A previously unrecognized, substantial flux of glucose from the circulation to the intestinal lumen exists, which likely contributes to the symbiosis between gut microbiota and the host. This flux represents a potential target of metformin's action in humans.

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.

Contradictory results for the association between metformin intake and changes in cognitive function have been reported. We attempted to overview systematic reviews and meta-analyses showing the role of metformin, as mono or combination therapy, in cognitive performance alterations among patients with type 2 diabetes mellitus (T2DM) and to determine the quality of the evidence as well. To find the English-written reviews, a literature search was conducted on PubMed, Web of Science, Scopus, Cochrane Library, Trip, and Google Scholar by May 1, 2023. The literature search unearthed 2672 records, 10 of which were included in the study. Metformin may provide cognitive benefits for patients with type 2 diabetes, as evidence suggests potential improvements in memory and a reduced risk of neurodegenerative diseases. Even though the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score alterations correspond to raising concerns about cognitive decline, Mini-Mental State Examination (MMSE) and selective reminding test (SRT) score improvements support metformin's role in improving specific cognitive domains. As such, metformin may exert differential impacts on various aspects of cognitive performance in these patients. However, the inconsistency and low quality of current evidence point toward the need for accurate research to elucidate whether metformin's cognitive effects are protective, neutral, or context-dependent based on patient profiles.

More effective treatments are needed for impaired fasting glucose or glucose intolerance, known as prediabetes. Sulforaphane is an isothiocyanate that reduces hepatic gluconeogenesis in individuals with type 2 diabetes and is well tolerated when provided as a broccoli sprout extract (BSE). Here we report a randomized, double-blind, placebo-controlled trial in which drug-naive individuals with prediabetes were treated with BSE (n = 35) or placebo (n = 39) once daily for 12 weeks. The primary outcome was a 0.3 mmol l-1 reduction in fasting blood glucose compared with placebo from baseline to week 12. Gastro-intestinal side effects but no severe adverse events were observed in response to treatment. BSE did not meet the prespecified primary outcome, and the overall effect in individuals with prediabetes was a 0.2 mmol l-1 reduction in fasting blood glucose (95% confidence interval -0.44 to -0.01; P = 0.04). Exploratory analyses to identify subgroups revealed that individuals with mild obesity, low insulin resistance and reduced insulin secretion had a pronounced response (0.4 mmol l-1 reduction) and were consequently referred to as responders. Gut microbiota analysis further revealed an association between baseline gut microbiota and pathophysiology and that responders had a different gut microbiota composition. Genomic analyses confirmed that responders had a higher abundance of a Bacteroides-encoded transcriptional regulator required for the conversion of the inactive precursor to bioactive sulforaphane. The abundance of this gene operon correlated with sulforaphane serum concentration. These findings suggest a combined influence of host pathophysiology and gut microbiota on metabolic treatment response, and exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov registration: NCT03763240 .

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.

Background: Obesity contributes to cardiometabolic risk, including subclinical atherosclerosis and insulin resistance. This study examines the predictive roles of trimethylamine N-oxide (TMAO) and resistin in relation to carotid intima-media thickness and metabolic parameters; Methods: Sixty adults (18-71 years) with varying body weights were assessed for body composition, subclinical atherosclerosis, and blood biomarkers, including TMAO and resistin; Results: TMAO correlated strongly with CIMT (r = 0.674, p < 0.001), indicating its role in subclinical atherosclerosis. Logistic regression identified TMAO (threshold 380; AUC = 0.880, accuracy = 91.7%) as a predictor of cardiometabolic risk. Resistin was associated with CIMT, WHR, and total cholesterol, inversely linked to LDL cholesterol (p = 0.003). Less active participants exhibited higher TMAO (p = 0.001) and resistin (p = 0.02). Family histories of obesity and diabetes correlated with elevated TMAO, while resistin linked to shorter sleep duration and diabetes history, highlighting their importance in obesity-related cardiometabolic risks; Conclusions: TMAO is strongly linked to abdominal fat, insulin resistance, and subclinical atherosclerosis, while resistin is associated with lipid metabolism and aging. Their combined assessment enhances the prediction of obesity-related cardiometabolic risk, supporting their role in risk stratification and targeted interventions.

Metabolic syndrome (MetS) constitutes a spectrum of interconnected conditions comprising obesity, dyslipidemia, hypertension, and insulin resistance (IR). While a singular, all-encompassing treatment for MetS remains elusive, an integrative approach involving tailored lifestyle modifications and emerging functional food therapies holds promise in preventing its multifaceted manifestations. Our main objective was to scrutinize the efficacy of cranberry proanthocyanidins (PAC, 200 mg/kg/day for 12 weeks) in mitigating MetS pathophysiology in male mice subjected to standard Chow or high-fat/high-fructose (HFHF) diets while unravelling intricate mechanisms. The administration of PAC, in conjunction with an HFHF diet, significantly averted obesity, evidenced by reductions in body weight, adiposity across various fat depots, and adipocyte hypertrophy. Similarly, PAC prevented HFHF-induced hyperglycemia and hyperinsulinemia while also lessening IR. Furthermore, PAC proved effective in alleviating key risk factors associated with cardiovascular diseases by diminishing plasma saturated fatty acids, as well as levels of triglycerides, cholesterol, and non-HDL-C levels. The rise in adiponectin and drop in circulating levels of inflammatory markers showcased PAC's protective role against inflammation. To better clarify the mechanisms behind PAC actions, gut-liver axis parameters were examined, showing significant enhancements in gut microbiota composition, microbiota-derived metabolites, and marked reductions in intestinal and hepatic inflammation, liver steatosis, and key biomarkers associated with endoplasmic reticulum (ER) stress and lipid metabolism. This study enhances our understanding of the complex mechanisms underlying the development of MetS and provides valuable insights into how PAC may alleviate cardiometabolic dysfunction in HFHF mice.

Emerging evidence highlights the central role of gut microbiota in maintaining physiological homeostasis within the host. Disruptions in gut microbiota can destabilize systemic metabolism and inflammation, driving the onset and progression of cardiometabolic diseases. In heart failure (HF), intestinal dysfunction may induce the release of endotoxins and metabolites, leading to dysbiosis and exacerbating HF through the gut-heart axis. Understanding the relationship between gut microbiota and HF offers critical insights into disease mechanisms and therapeutic opportunities. Current research highlights promising potential to improve patient outcomes by restoring microbiota balance. In this review, we summarize the current studies in understanding the gut microbiota-HF connection and discuss avenues for future investigation.