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Aims/hypothesisIndividuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1–7.0 mmol/l or HbA1c of 42–48 mmol/mol [6.0–6.5%]) and a range of clinical biomarkers of poor metabolic health.MethodsIn the present case–control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation.ResultsWe found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log2 fold change −0.64 (SEM 0.23), padj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), padj = 5 × 10−4; 0.51 (SEM 0.11), padj = 1 × 10−4; 0.60 (SEM 0.21), padj = 0.0497; and 0.92 (SEM 0.21), padj = 4 × 10−4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log2 fold change −1.74 (SEM 0.41), padj = 2 × 10−3 and −1.65 (SEM 0.34), padj = 4 × 10−4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.Conclusions/interpretationCollectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.

Accumulating evidence has suggested that the gut microbiome plays an important role in depression. Akkermansia muciniphila (AKK), a next-generation probiotic, shows a beneficial effect on immune and metabolic homeostasis. The relative abundance of AKK was found negatively correlated with depressive symptoms in both clinical and pre-clinical studies. To evaluate the potential antidepressant effect of AKK and explore the possible mechanism, we used chronic alcohol exposure and chronic unpredictable mild stress (CUMS) to induce depressive-like behaviors in mice. We found that oral AKK administration significantly reduced the immobility time in the force swimming test (FST) and tail suspension test (TST) in the mice with chronic alcohol exposure and the CUMS mice. The sucrose preference in the mice receiving AKK was significantly increased in the sucrose preference test (SPT). More importantly, AKK implantation significantly increased the level of 5-HT in the gut and PFC of both the alcohol exposure mice and the CUMS mice. Furthermore, AKK had inhibited the expression of SERT in the gut but not in the brain for both NIAAA and the CUMS model mice. Interestingly, the expression of cFos in enteric nerves in the gut significantly decreased after AKK administration. In conclusion, our study demonstrated the antidepressant effect of AKK in mice exposed to alcohol exposure and CUMS, with the potential mechanism that AKK implantation might lead to an increased level of 5-HT and inhibited SERT expression in the gut, and might alter the gut-to-brain signal through suppression of enteric nerves activation.

BackgroundOlanzapine (OLZ) is one of the most effective atypical antipsychotics but is associated with severe metabolic side effects, in which the gut microbiota plays an important role. Akkermansia muciniphila (A. muciniphila; Akk), a Gram-negative anaerobic bacterium in the intestine, can potentially improve metabolic syndrome.ObjectiveThis study investigated the effect and underlying mechanisms of an A. muciniphila subtype (A. muciniphilasub; Akksub) on OLZ-induced metabolic dysfunction in lean and obese mice.MethodsC57BL/6 female mice were fed a high-fat diet to induce obesity or normal chow for 8 weeks before OLZ treatment for 16 weeks. During the treatment period, mice in each group were orally administrated A. muciniphilasub. Weight gain, glucose and lipid metabolism, and inflammation were evaluated.ResultsA. muciniphilasub decreased OLZ-related weight gain only at week 16 in lean mice and significantly alleviated OLZ-induced hyperglycemia irrespective of diet. This was accompanied by reduced levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)—key enzymes in hepatic gluconeogenesis—and OLZ-associated insulin resistance. Moreover, OLZ-induced increases in serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels were improved by A. muciniphilasub in both obese and lean mice. OLZ did not increase serum lipid levels or hepatic fat accumulation.ConclusionsA. muciniphilasub improves OLZ-related hyperglycemia via regulation of G6Pase and PEPCK levels and insulin resistance. Moreover, A. muciniphilasub alleviates systemic inflammation caused by OLZ. A. muciniphilasub is a promising probiotic treatment for OLZ-induced metabolic dysfunction.

A prior retrospective analysis demonstrated that quantifying Programmed Cell Death Ligand 1 (PD-L1) expression using a phosphor-integrated dot (PID) score effectively predicted immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC) and other cancers. However, PD-L1 expression proved unreliable in some patients with low PD-L1 levels, highlighting the need for alternative biomarkers. A previous cohort study in NSCLC patients linked intestinal (Akk) presence to improved ICI efficacy, particularly in low PD-L1 subgroups. Here, we evaluated tumor tissue Akk expression via immunohistochemical staining as a potential biomarker for ICI response in NSCLC. We retrospectively analyzed tumor tissues from 60 metastatic or recurrent NSCLC patients treated with ICIs. Immunohistochemical (IHC) staining was performed to assess Akk and PD-L1 expression, along with CD3 and CD68 in PD-L1-low samples. Transcriptomic profiling using RNA-sequencing was conducted on tumor samples to identify Akk-related gene expression patterns. Tumor Akk expression showed no correlation with PD-L1 levels assessed via PID. Survival and multivariable Cox regression analyses revealed no association between Akk expression and progression-free survival (PFS) or overall survival (OS). In high PD-L1 patients, Akk status did not influence outcomes. However, among low PD-L1 patients, Akk-positive cases exhibited significantly worse PFS compared to Akk-negative cases (OS remained unchanged). Transcriptome analysis indicated that Akk positivity in low PD-L1 samples exhibited enrichment in oxidative phosphorylation and amyotrophic lateral sclerosis-related pathways and downregulation of spliceosome-associated pathways. No significant differences in tumor-infiltrating CD3+ T cells or CD68+ macrophages were observed between Akk-positive and Akk-negative tumors in the PD-L1-low group. Tumor-associated Akk may serve as a negative predictive biomarker for ICI efficacy in NSCLC patients with low PD-L1 expression. Our findings suggest that tumor microbiota profiling, particularly targeting Akk, could refine patient stratification and therapeutic decision-making.

Aim Overweight and obesity are global public health challenges characterized by chronic low-grade inflammation, metabolic dysregulation, and gut microbiota imbalance. This study evaluated the safety and efficacy of a synbiotic formulation containing Akkermansia muciniphila Akk11 on gut microbiota composition, metabolic regulation, and obesity-associated inflammation. Methods A randomized, double-blind, placebo-controlled trial was conducted at Henan University of Technology. Adults aged 18–45 years with overweight or obesity ( n  = 110) were randomly assigned (1:1) to receive either a prebiotic placebo (control) or the synbiotic formulation containing A. muciniphila Akk11 (3.0 × 10 10 active fluorescent units [AFU] daily). Over 8 weeks, gut-microbiota composition was profiled by 16 S ribosomal RNA gene sequencing, and serum biomarkers were quantified by enzyme-linked immunosorbent assay. Emotional well-being, sleep quality, and anthropometric measures were also assessed. Results After the 8-week intervention, the Akk11 group showed significant reductions in tumor necrosis factor-α, interleukin-6, and C-reactive protein and a significant increase in interleukin-25 versus baseline (all p <  0.001). Relative to placebo, circulating Glucagon-Like Peptide-1 and Peptide YY (PYY) concentrations were higher ( p <  0.05), and Malondialdehyde levels were lower ( p <  0.01). Akk11 reduced the enrichment of Escherichia coli / Shigella and promoted the enrichment of beneficial genera, indicating a more favorable gut-microbiota structure. Waist-to-hip ratio decreased significantly ( p <  0.05), and significant reductions were observed in both Patient Health Questionnaire-9 and Pittsburgh Sleep Quality Index scores. No significant changes were detected in routine hematology, clinical chemistry, or blood glucose following Akk11 treatment. Conclusion The synbiotic formulation containing A. muciniphila Akk11 was well tolerated and may serve as a safe adjunctive strategy targeting microbiota-immune-metabolic interactions to alleviate obesity-associated metabolic and inflammatory disorders.

Aims/hypothesis Metabolic dysfunction–associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally and is closely associated with type 2 diabetes (T2D) and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer partial therapeutic benefits in MASLD, but their efficacy is often limited in advanced insulin-resistant states, highlighting the need for adjunctive strategies to improve treatment responsiveness. Methods We investigated the metabolic and mechanistic effects of combining semaglutide (GLP-1RA) with Akkermansia muciniphila 11 (Akk11) in db/db mice, a model of T2D-associated MASLD. Mice were treated with semaglutide alone or in combination with Akk11. Metabolic parameters, hepatic and adipose tissue morphology, gut microbiota composition, transcriptomic profiles, and inflammatory signaling were evaluated. Results GLP-1RA monotherapy elicited only modest improvements in glycemia and hepatic lipid accumulation, with effects waning over time. However, Akk11 supplementation significantly enhanced semaglutide therapeutic effects, leading to reduced subcutaneous and visceral fat, improved liver histology, and decreased serum triglycerides. Mechanistically, combination treatment suppressed fatty acid synthesis, promoted mitochondrial function, and remodeled the gut microbiota. Notably, both GLP-1RA and AKK attenuated intestinal pyroptosis pathways, and the combination further suppressed pro-inflammatory markers in the liver and intestine. Conclusions/interpretation Our findings highlight a synergistic interaction between GLP-1RA and Akk11, likely mediated through microbiota remodeling and parallel improvements in lipid metabolism across intestinal, hepatic, and adipose compartments. This study supports the development of microbiota-guided strategies to enhance therapies for MASLD and other metabolic diseases.

Akkermansia muciniphila is increasingly regarded as a next‐generation probiotic with clinical and commercial potential. This study aimed to evaluate the strain‐specific safety and probiotic characteristics of Akk11, isolated from the feces of healthy infants. The genotypic profile of Akk11 was assessed via whole‐genome sequencing, including antibiotic resistance, virulence factors, and metabolic pathway annotations. Phenotypic analyses included antibiotic susceptibility, mucin degradation, biogenic amine and D‐/L‐lactic acid production, and hemolytic activity. Stress tolerance and cytotoxicity were performed using simulated gastrointestinal conditions and Caco‐2 cells. In vivo safety was further evaluated through acute oral toxicity, bacterial reverse mutation, mammalian erythrocyte micronucleus, and 90‐day sub‐chronic toxicity, following international guidelines. Akk11 showed 98.36% genomic similarity to the type strain adeF with no mobile genetic elements or transferable resistance. Phenotypically, Akk11 exhibited intrinsic resistance to several antibiotics while lacking harmful metabolic activities and excellent simulated gastrointestinal stress tolerance with non‐cytotoxicity. No adverse effects were observed in any of the in vivo toxicity studies, even under long‐term oral administration of bacterial powder preparations containing both viable and non‐viable cells. The NOAEL was 9 × 1011 AFU/kg/day, the highest dose tested in both sexes, using a lyophilized preparation that contained approximately 20%–30% non‐viable Akk11 cells (n‐AFU). Akk11 possesses a robust, strain‐specific safety profile and probiotic potential, providing a scientific basis for its application in next‐generation probiotic products. Akkermansia muciniphila Akk11 showed strain‐specific safety: 98.36% genomic similarity to the type strain, with no mobile elements, no harmful metabolites, strong simulated GI tolerance, and no Caco‐2 cytotoxicity. Acute, reverse‐mutation, micronucleus, and 90‐day studies found no adverse effects; NOAEL was 9 × 1011 AFU/kg/day using a lyophilized powder containing 20%–30% non‐viable cells. Findings support Akk11's robust safety and next‐generation probiotic potential.

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with escalating global incidence. Conventional therapies face limitations including substantial costs and adverse effects, while live probiotics pose safety risks in vulnerable populations. Postbiotics—inactivated microorganisms conferring health benefits—offer therapeutic potential without viable bacterial risks. This study investigated inactivated Akkermansia muciniphila AKK PROBIO in dextran sulfate sodium (DSS)-induced colitis mice. Inactivated AKK PROBIO significantly ameliorated disease manifestations, restoring body weight and food intake during days 10–14 (p < 0.01) and reducing Disease Activity Index scores (p < 0.0001). Treatment preserved colonic architecture, enhanced tight junction proteins (Claudin-1, Occludin, ZO-1), and elevated mucin 2 expression. Mechanistically, AKK PROBIO modulated inflammatory responses by increasing anti-inflammatory interleukin-10 (p < 0.05) while decreasing pro-inflammatory cytokines IL-1β, IL-6, and TNF-α (all p < 0.05). 16S rRNA sequencing revealed selective microbiota remodeling with enriched beneficial genera (Ligilactobacillus, Lachnospiraceae_NK4A136_group, Bacteroides, Akkermansia) and depleted pathobionts (Escherichia-Shigella). Functional profiling demonstrated enhanced microbial metabolic capacity in carbohydrate and amino acid metabolism pathways. Gas chromatography–mass spectrometry analysis confirmed elevated short-chain fatty acid production, particularly butyrate and isocaproate (p < 0.05). Correlation analyses revealed interconnected relationships among beneficial microbiota, short-chain fatty acids, and anti-inflammatory mediators, while showing inverse associations with pro-inflammatory cytokines. In summary, our findings demonstrate that inactivated AKK PROBIO alleviates colitis, supporting its development as a safe, food-derived postbiotic.

Polyethylene glycol (PEG) is a commonly used dispersant for oral administration of hydrophobic agents. PEG is partly absorbed in the small intestine, and the unabsorbed fraction reaches the large intestine; thus, oral administration of PEG may impact the gut microbial community. However, to the best of our knowledge, no study evaluated the effects of PEG on gut commensal bacteria. Herein, we aimed to determine whether oral administration of PEG modifies the gut microbiota. Administration of PEG400 and PEG4000 altered gut microbial diversity in a concentration-dependent manner. Taxonomic analysis revealed that Akkermansia muciniphila and particularly Parabacteroides goldsteinii were overrepresented in mice administered with 40% PEG. PEG400 administration ameliorated the high-fat diet (HFD)-induced obesity and adipose tissue inflammation. Fecal microbiome transplantation from PEG400-administered donors counteracted the HFD-induced body and epididymal adipose tissue weight gain, indicating that PEG400-associated bacteria are responsible for the anti-obesity effect. Conversely, carboxymethyl cellulose, also used as a dispersant, did not affect the abundance of these two bacterial species or HFD-induced obesity. In conclusion, we demonstrated that oral administration of a high concentration of PEG400 (40%) alters the gut microbiota composition and ameliorates HFD-induced obesity.

Extensive research has been conducted to investigate the impact of capsaicin (CAP) on lipid metabolism, focusing specifically on its interaction with the vanilloid subtype 1 (TRPV1) ion channel. Additionally, studies have illuminated the role of Akkermansia muciniphila (A. muciniphila), a specific strain of intestinal microbiota, in lipid metabolism. In this study, a model utilizing resiniferatoxin (RTX) was employed to deactivate TRPV1 ion channels in germ-free mice, followed by the administration of A. muciniphila via gavage. Following the collection of intestinal tissues for a comprehensive analysis, employing histopathology, qPCR, and ELISA techniques, our findings revealed a significant upregulation of MUC2 and MUC3 expression induced by CAP. This upregulation resulted in the thickening of the colonic mucus layers. Notably, this effect was absent when TRPV1 was selectively inhibited. Moreover, there was no discernible impact on goblet cells. The findings strongly indicate that CAP influences the system by activating the TRPV1 ion channel, thereby enhancing the expression of mucin MUC2 and promoting an augmentation in the thickness of the mucous layer. This activation, in turn, supplies A. muciniphila with an ample source of carbon and nitrogen. This insight potentially clarify the underlying mechanism through which CAP facilitates the increase in A. muciniphila abundance