Imbalanced nutrition, such as a high-fat/high-carbohydrate diet, is associated with negative effects on human health. The composition and metabolic activity of the human gut microbiota are closely related to the type of diet and have been shown to change significantly in response to changes in food content and food supplement administration. Alkylresorcinols (ARs) are lipophilic molecules that have been found to improve lipid metabolism and glycemic control and decrease systemic inflammation. Furthermore, alkylresorcinol intake is associated with changes in intestinal microbiota metabolic activity. However, the exact mechanism through which alkylresorcinols modulate microbiota activity and host metabolism has not been determined. In this study, alterations in the small intestinal microbiota (SIM) and the large intestinal microbiota (LIM) were investigated in mice fed a high-fat diet with or without pentadecylresorcinol (C15) supplementation. High-throughput sequencing was applied for jejunal and colonic microbiota analysis. The results revealed that C15 supplementation in combination with a high-fat diet could decrease blood glucose levels. High-throughput sequencing analysis indicated that C15 intake significantly increased (p < 0.0001) the abundance of the probiotic bacteria Akkermansia muciniphila and Bifidobacterium pseudolongum in both the small and large intestines and increased the alpha diversity of LIM (p < 0.05), but not SIM. The preliminary results suggested that one of the mechanisms of the protective effects of alkylresorcinol on a high-fat diet is the modulation of the content of SIM and LIM and metabolic activity to increase the probiotic bacteria that alleviate unhealthy metabolic changes in the host.

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.

This comprehensive review delineates the extensive roles of Akkermansia muciniphila in various health domains, spanning from metabolic and inflammatory diseases to neurodegenerative disorders. A. muciniphila, known for its ability to reside in the mucous layer of the intestine, plays a pivotal role in maintaining gut integrity and interacting with host metabolic processes. Its influence extends to modulating immune responses and potentially easing symptoms across several non-communicable diseases, including obesity, diabetes, inflammatory bowel disease, and cancer. Recent studies highlight its capacity to interact with the gut-brain axis, suggesting a possible impact on neuropsychiatric conditions. Despite the promising therapeutic potential of A. muciniphila highlighted in animal and preliminary human studies, challenges remain in its practical application due to stability and cultivation issues. However, the development of pasteurized forms and synthetic mediums offers new avenues for its use in clinical settings, as recognized by regulatory bodies like the European Food Safety Authority. This narrative review serves as a crucial resource for understanding the broad implications of A. muciniphila across different health conditions and its potential integration into therapeutic strategies.

Pomegranate juice (PJ) and inulin have been reported to ameliorate diet-induced metabolic disorders by regulating gut microbiota dysbiosis. However, there was a lack of clinical evidence for the combined effects of PJ and inulin on regulating gut microbiota in individuals with metabolic disorders. A double-blind, parallel, randomized, placebo-controlled trial was conducted, and 68 overweight/obese individuals (25 ≤ BMI ≤ 35 kg/m2) were randomly assigned to receive 200 mL/d PJ, PJ supplemented with inulin, or placebo for 3 weeks. Our results showed that PJ and PJ+inulin did not significantly alter the levels of anthropometric and blood biochemical indicators after 3 weeks of treatment. However, there was an increasingly significant impact from placebo to PJ to PJ+inulin on the composition of gut microbiota. Detailed bacterial abundance analysis further showed that PJ+inulin treatment more profoundly resulted in significant changes in the abundance of gut microbiota at each taxonomic level than PJ. Moreover, PJ+inulin treatment also promoted the production of microbiota-associated short-chain fatty acids and pomegranate polyphenol metabolites, which correlated with the abundance of the bacterial genus. Our results suggested that PJ supplemented with inulin modulates gut microbiota composition and thus promotes the production of microbiota-associated metabolites that exert potential beneficial effects in overweight/obese subjects.

The Mediterranean diet (MD) and its bioactive constituents have been advocated for their neuroprotective properties along with their capacity to affect gut microbiota speciation and metabolism. Mediated through the gut brain axis, this modulation of the microbiota may partly contribute to the neuroprotective properties of the MD. To explore this potential interaction, we evaluated the neuroprotective properties of a novel bioactive blend (Neurosyn240) resembling the Mediterranean diet in a rodent model of chronic low-grade inflammation. Behavioral tests of cognition, brain proteomic analysis, 16S rRNA sequencing, and 1H NMR metabolomic analyses were employed to develop an understanding of the gut-brain axis interactions involved. Recognition memory, as assessed by the novel object recognition task (NOR), decreased in response to LPS insult and was restored with Neurosyn240 supplementation. Although the open field task performance did not reach significance, it correlated with NOR performance indicating an element of anxiety related to this cognitive change. Behavioral changes associated with Neurosyn240 were accompanied by a shift in the microbiota composition which included the restoration of the Firmicutes: Bacteroidota ratio and an increase in Muribaculum, Rikenellaceae Alloprevotella, and most notably Akkermansia which significantly correlated with NOR performance. Akkermansia also correlated with the metabolites 5-aminovalerate, threonine, valine, uridine monophosphate, and adenosine monophosphate, which in turn significantly correlated with NOR performance. The proteomic profile within the brain was dramatically influenced by both interventions, with KEGG analysis highlighting oxidative phosphorylation and neurodegenerative disease-related pathways to be modulated. Intriguingly, a subset of these proteomic changes simultaneously correlated with Akkermansia abundance and predominantly related to oxidative phosphorylation, perhaps alluding to a protective gut-brain axis interaction. Collectively, our results suggest that the bioactive blend Neurosyn240 conferred cognitive and microbiota resilience in response to the deleterious effects of low-grade inflammation.

Hepcidin is a crucial regulator of iron homeostasis with protective effects on liver fibrosis. Additionally, gut microbiota can also affect liver fibrosis and iron metabolism. Although the hepatoprotective potential of Akkermansia muciniphila and Faecalibacterium duncaniae, formerly known as F. prausnitzii, has been reported, however, their effects on hepcidin expression remain unknown. We investigated the direct and macrophage stimulation-mediated effects of active, heat-inactivated, and cell-free supernatant (CFS) forms of A. muciniphila and F. duncaniae on hepcidin expression in HepG2 cells by RT-qPCR analysis. Following stimulation of phorbol-12-myristate-13-acetate (PMA) -differentiated THP-1 cells with A. muciniphila and F. duncaniae, IL-6 concentration was assessed via ELISA. Additionally, the resulting supernatant was treated with HepG2 cells to evaluate the effect of macrophage stimulation on hepcidin gene expression. The expression of genes mediating iron absorption and export was also examined in HepG2 and Caco-2 cells via RT-qPCR. All forms of F. duncaniae increased hepcidin expression while active and heat-inactivated/CFS forms of A. muciniphila upregulated and downregulated its expression, respectively. Active, heat-inactivated, and CFS forms of A. muciniphila and F. duncaniae upregulated hepcidin expression, consistent with the elevation of IL-6 released from THP-1-stimulated cells as a macrophage stimulation effect in HepG2 cells. A. muciniphila and F. duncaniae in active, inactive, and CFS forms altered the expression of hepatocyte and intestinal iron-mediated absorption /exporter genes, namely dcytb and dmt1, and fpn in HepG2 and Caco-2 cells, respectively. In conclusion, A. muciniphila and F. duncaniae affect not only directly but also through macrophage stimulation the expression of hepcidin gene in HepG2 cells. These findings underscore the potential of A. muciniphila and F. duncaniae as a potential therapeutic target for liver fibrosis by modulating hepcidin and intestinal and hepatocyte iron metabolism mediated gene expression.

Type 2 diabetes (T2DM) significantly diminishes people\'s quality of life and imposes a substantial economic burden. This pathological progression is intimately linked with specific gut microbiota, such as Akkermansia muciniphila. Pasteurized A. muciniphila (P-AKK) has been defined as a novel food by the European Food Safety Authority and exhibited significant hypoglycemic activity. However, current research on the hypoglycemic activity of P-AKK is limited to the metabolic level, neglecting systematic exploration at the pathological level. Consequently, its material basis and mechanism of action for hypoglycemia remain unclear. Drawing upon this foundation, we utilized high-temperature killed A. muciniphila (H-K-AKK) with insignificant hypoglycemic activity as the control research object. Assessments were conducted at pathological levels to evaluate the hypoglycemic functions of both P-AKK and H-K-AKK separately. Our study unveiled for the first time that P-AKK ameliorated symptoms of T2DM by enhancing the generation of glucagon-Like Peptide 1 (GLP-1), with pasteurized A. muciniphila total proteins (PP) being a pivotal component responsible for this activity. Utilizing SDS-PAGE, proteomics, and molecular docking techniques, we deeply analyzed the material foundation of PP. We scientifically screened and identified a protein weighing 77.85 kDa, designated as P5. P5 enhanced GLP-1 synthesis and secretion by activating the G protein-coupled receptor (GPCR) signaling pathway, with free fatty acid receptor 2 (FFAR-2) being identified as the pivotal target protein for P5\'s physiological activity. These findings further promote the widespread application of P-AKK in the food industry, laying a solid theoretical foundation for its utilization as a beneficial food ingredient or functional component.

The intestinal anaerobic bacterium Akkermansia muciniphila is specialized in the degradation of mucins, which are heavily O-glycosylated proteins that constitute the major components of the mucus lining the intestine. Despite that adhesion to mucins is considered critical for the persistence of A. muciniphila in the human intestinal tract, our knowledge of how this intestinal symbiont recognizes and binds to mucins is still limited. Here, we first show that the mucin-binding properties of A. muciniphila are independent of environmental oxygen concentrations and not abolished by pasteurization. We then dissected the mucin-binding properties of pasteurized A. muciniphila by use of a recently developed cell-based mucin array that enables display of the tandem repeats of human mucins with distinct O-glycan patterns and structures. We found that A. muciniphila recognizes the unsialylated LacNAc (Galβ1-4GlcNAcβ1-R) disaccharide selectively on core2 and core3 O-glycans. This disaccharide epitope is abundantly found on human colonic mucins capped by sialic acids, and we demonstrated that endogenous A. muciniphila neuraminidase activity can uncover the epitope and promote binding. In summary, our study provides insights into the mucin-binding properties important for colonization of a key mucin-foraging bacterium.

Akkermansia muciniphila is a mucin-degrading probiotic that colonizes the gastrointestinal tract. Genomic analysis identified a set of genes involved in the biosynthesis of corrin ring, including the cobalt factor II methyltransferase CbiL, in some phylogroups of A. muciniphila, implying a potential capacity for de novo synthesis of cobalamin. In this work, we determined the crystal structure of CbiL from A. muciniphila at 2.3 Å resolution. AmCbiL exists as a dimer both in solution and in crystal, and each protomer consists of two α/β domains, the N-terminal domain and the C-terminal domain, consistent with the folding of typical class III MTases. The two domains create an open trough, potentially available to bind the substrates SAM and cobalt factor II. Sequence and structural comparisons with other CbiLs, assisted by computer modeling, suggest that AmCbiL should have cobalt factor II C-20 methyltransferase activity. Our results support that certain strains of A. muciniphila may be capable of synthesizing cobalamin de novo.

Mucin is a glycoprotein secreted throughout the mammalian gastrointestinal tract that can support endogenous microorganisms in the absence of complex polysaccharides. While several mucin-degrading bacteria have been identified, the interindividual differences in microbial communities capable of metabolizing this complex polymer are not well described. To determine whether community assembly on mucin is deterministic across individuals or whether taxonomically distinct but functionally similar mucin-degrading communities are selected across fecal inocula, we used a 10-day in vitro sequential batch culture fermentation from three human donors with mucin as the sole carbon source. For each donor, 16S rRNA gene amplicon sequencing was used to characterize microbial community succession, and the short-chain fatty acid profile was determined from the final community. All three communities reached a steady-state by day 7 in which the community composition stabilized. Taxonomic comparisons amongst communities revealed that one of the final communities had Desulfovibrio, another had Akkermansia, and all three shared other members, such as Bacteroides. Metabolic output differences were most notable for one of the donor\'s communities, with significantly less production of acetate and propionate than the other two communities. These findings demonstrate the feasibility of developing stable mucin-degrading communities with shared and unique taxa. Furthermore, the mechanisms and efficiencies of mucin degradation across individuals are important for understanding how this community-level process impacts human health.