The Role of Akkermansia muciniphila on Improving Gut and Metabolic Health Modulation: A Meta-Analysis of Preclinical Mouse Model Studies

Abstract

Akkermansia muciniphila (A. muciniphila) and its derivatives, including extracellular vesicles (EVs) and outer membrane proteins, are recognized for enhancing intestinal balance and metabolic health. However, the mechanisms of Akkermansia muciniphila's action and its effects on the microbiome are not well understood. In this study, we examined the influence of A. muciniphila and its derivatives on gastrointestinal (GI) and metabolic disorders through a meta-analysis of studies conducted on mouse models. A total of 39 eligible studies were identified through targeted searches on PubMed, Web of Science, Science Direct, and Embase until May 2024. A. muciniphila (alive or heat-killed) and its derivatives positively affected systemic and gut inflammation, liver enzyme level, glycemic response, and lipid profiles. The intervention increased the expression of tight-junction proteins in the gut, improving gut permeability in mouse models of GI and metabolic disorders. Regarding body weight, A. muciniphila and its derivatives prevented weight loss in animals with GI disorders while reducing body weight in mice with metabolic disorders. Sub-group analysis indicated that live bacteria had a more substantial effect on most analyzed biomarkers. Gut microbiome analysis using live A. muciniphila identified a co-occurrence cluster, including Desulfovibrio, Family XIII AD3011 group, and Candidatus Saccharimonas. Thus, enhancing the intestinal abundance of A. muciniphila and its gut microbial clusters may provide more robust health benefits for cardiometabolic, and age-related diseases compared with A. muciniphila alone. The mechanistic insight elucidated here will pave the way for further exploration and potential translational applications in human health.

Keywords: Akkermansia muciniphila; Candidatus Saccharimonas; Desulfovibrio; Family XIII AD3011 group; gut; inflammation; metabolic health.

Figure 1

The PRISMA flowchart of the approach employed in this study. The relevant studies were identified through comprehensive database searches in PubMed, Embase, Web of Science, and Science Direct up to May 2024. The search criteria encompassed studies exploring the impact of A. muciniphila on gut microbiota and metabolic response, specifically in mice models, which are used to study metabolic and GI disorders.

Figure 2

Effect of A. muciniphila on systemic and gut inflammation [15,17,25,26,29,30,31,32,33,35,37,38,39,41,42,43,46,47,50,52,56,57,58,59]. Forest plot of individual SMD of serum inflammatory markers (TNFα, IL6, IL10, and LPS) and expression of inflammatory factors (TNFα, IL6, and IL10) in the gut of aging mice and mice with GI and metabolic disorders. A green diamond indicates significance, while the white diamond indicates not statistical differences.

Figure 3

Effect of A. muciniphila on gut epithelial health markers [15,17,23,26,27,28,29,30,31,32,34,35,36,37,38,41,43,44,50,52,54,56,57,58,59]. Forest plot of individual SMD of colon length, mucus thickness, and tight-junction expression (protein and mRNA) in the gut of aging mice and mice with GI and metabolic disorders. A green diamond indicates significance, while the white diamond indicates not statistical differences.

Figure 4

Effect of A. muciniphila on metabolic profiles and liver health [15,17,40,41,42,43,44,45,46,48,49,50,51,53,55,57,58,59]. Forest plot of individual SMD of glycemic control (blood glucose, insulin level, and HOMA.IR), lipid profile (TG and cholesterol), and liver enzymes (ALT and AST) of mice with metabolic disorders. A green diamond indicates significance.

Figure 5

Effect of A. muciniphila on body weight [17,26,31,36,38,40,44,48,50,55,56,57,58]. Forest plot of individual SMD of body weight of mice with GI and metabolic disorders. A green diamond indicates significance.

Figure 6

The treatment with A. muciniphila induces alterations in microbial co-regulation ecological niches. (A) Microbial alpha-diversity. Microbial composition at (B) phylum, (C) family, and (D) genus level. (E) The top 15 genera are more abundant in each group (ALDEx2). (F) Significantly correlated genus with A. muciniphila (Spearman correlation coefficient (ρ) > 0.3). Correlational network between genera in (G) CTL and (H) AKK group. Each node represents one genus, and only significant links are shown (Spearman coefficient (ρ) > 0.7, Benjamini–Hochberg corrected p-value < 0.05). CTL: control group; AKK: A. muciniphila-treated group.

Figure 7

Relative abundance of taxa showing co-occurrence association with Akkermansia (Akk) in network analysis of the AKK group. Comparison of the relative abundance of (A) Desulfovibrio, (B) Candidadus Saccharimonas, and (C) Family XIII AD3011 group (Anaerovoracaceae family) between treatment groups (CTL and AKK), Akk non-detected (Akk-; n = 43) and Akk detected (Akk+; n = 33) samples. (D–F) Akk detected and non-detected samples within treatment groups (CTL/Akk− n = 21, CTL/Akk+ n = 14, AKK/Akk− n = 22, AKK/Akk+ n = 19). p-values were calculated using the Mann–Whitney U test (Wilcoxon rank sum test). Bar plots are presented as mean ± SE. * p < 0.05; *** p < 0.001.

Figure 8

Model of the proposed mechanism by which A. muciniphila improves host health. Oral administration of A. muciniphila remodels the gut microbiota, increasing the abundance of Desulfovibrio, Candidatus Saccharimonas, and Family_XIII_AD3011. Desulfovibrio produces H₂S, which inhibits inflammation and protects the cardiovascular system. However, H₂S overproduction has been reported in Parkinson’s disease (PD) patients. Candidatus Saccharimonas produces lactate and acetate and reduces inflammation in macrophages. Less is known of the function of Family_XIII_AD3011. These changes were associated with reduced intestinal inflammation and improved gut permeability, likely through the activation of TLR and the inhibition of NF-kB. Upregulation of intestinal IL10 likely reduces pro-inflammatory cytokines and upregulates tight junction proteins. In circulation, A. muciniphila reduced inflammation (TNFα, IL6), cholesterol, TG, and LPS while increasing HDL and improving glucose control. In the liver, A. muciniphila, reduced ALT, AST, and IL1β. The known activation of FXR (dotted line) by A. muciniphila may explain the reduction in TG and improved glucose sensitivity. FXR activation, along with the reduction in cholesterol, is also expected to reduce bile acid and fatty acid (FA) synthesis in the liver. Blue and red arrowheads indicate reduced and increased expression, respectively. The model was generated using BioRender.