Introduction
Human microbiota,which is also called the hidden organ includes a variety of microorganisms dominated by bacterial community. Microbiota coexists and coevolves in various sites of human body mainly gut, skin and oral cavity. It contributes genetic information, surpassing 150 times that of the entire human genome (Hou et al., 2022). It plays an important role in host’s health status through physiological metabolic and immune modulations such as food fermentation, protection against the pathogens, vitamins production and immune response stimulation (Fujimura et al., 2010).
Gastrointestinal tract has a diverse microbial ecology where two bacterial phyla Bacteroidetes and Firmicutes predominate, while Actinobacteria, Proteobacteria, and Verrucomicrobia are typically present in lower abundance (Lozupone et al., 2012). Among the gut microbiota, Akkermansia is notable for its mucin-degrading capacity, involvement in metabolic homeostasis, and potential as a therapeutic agent in metabolic disorders.
Akkermansia muciniphila (referred as AKK hereafter) has been consistently associated with host health, and its reduced abundance is linked to a range of pathological conditions in both murine models and humans. Although the precise molecular signaling pathways through which this probiotic confers benefits to the host are still being explored actively, its preventive and therapeutic potential in conditions such as obesity, aging, diabetes and various other metabolic syndromes is well established (Hasnain et al., 2024). Importantly, AKK plays a central role in preserving gut barrier integrity and modulating immune responses, thereby limiting chronic low-grade inflammation-a key contributor to the pathogenesis of numerous diseases (Aja et al., 2025).
This mini-review aims to provide a concise overview of the current understanding of AKK as a next-generation probiotic, with a focus on its roles in metabolic regulation, immune modulation, and gut barrier function. We explore emerging evidence linking AKK to various health conditions, including metabolic disorders, inflammation, and neurodegeneration. Additionally, we highlight the underlying mechanisms by which this bacterium may exert its beneficial effects, discuss and identify key concerning areas that warrant further investigation.
Taxonomy, Genomics and Physiology
AKK is a Gram-negative, oval-shaped, non-motile oxygen-tolerant anaerobe which was first discovered in 2004 in human fecal samples. It belongs to phylum Verrucomicrobia and was the 1st cultivated member of Akkermansia genus (Aja et al., 2025). While it’s most abundant in colon, mucus layer of small intestine is also inhabited by AKK (Hasnain et al., 2024). First genome of AKK was sequenced in 2011. With a total size of 2.7 Mb, 11% of its large secretome (61 proteins) were involved in mucus degradation along with 43% other proteins with no known function which might also play role in mucin modification/processing (van Passel et al., 2011). In addition, its genome analysis revealed the presence of two CRISPR loci and many phage-derived sequences highlighting the vital role of viral infections in their evolution. Analysis of various other AKK isolates have demonstrated the possibility of horizonal gene transfer since the CRISPR genes are located close to predicted phage genes (Becken et al., 2021; van Passel et al., 2011). While a type-strain, MucT (ATCC BAA-835) remains most extensively studied, pangenome analysis of 234 isolates revealed the presence of significant genomic diversity in AKK strains based on which these can be categorized into separate clades and subspecies with diverse attributes (Mueller et al., 2024).
Since it colonizes intestinal mucosa, its energy harvesting and synthesis pathways are based on mucin degradation and processing. It thrives by degrading mucin, its main energy and nitrogen source. It metabolizes mucin-derived monosaccharides such as fucose, galactose and N-acetylgalactosamine, with enhanced growth observed when mucin is co-metabolized with these sugars (Ottman et al., 2017). Although it can ferment some non-mucin sugars like fructose and human milk oligosaccharides, it does not efficiently utilize sugars like maltose, melibiose or trehalose, despite genomic indications of potential metabolism (Aja et al., 2025; Ottman et al., 2017). Notably, threonine is the only essential amino acid AKK cannot produce, likely due to its abundance in mucin, reflecting its adaptation to the mucosal niche (Ottman et al., 2017; Schrager 1970).
Role in Gut Health
Intestinal tight junctions and mucus are important in keeping the damage from digestive secretions and pathogens. AKK is involved in improving the intestinal barrier integrity through i) enhancement of mucus-producing goblet cells and regulating their autophagy process, ii) intestinal stems cell stimulation and differentiation to intestinal epithelial cells and Paneth/ goblet cells, iii) upregulation of tight junction proteins e.g. Occludin, Claudin-3, ZO-1 directly or through its extra extracellular vesicles (EVs) mainly via inhibition of NF-κB pathway and yet-to-establish mechanisms (Mo et al., 2024). In addition, AKK improves the leaky gut situation through suppressing the production of inflammatory cytokines like TNF-α and IL-8. Short-chain fatty acids (SCFAs), and proteins like Amuc_1100 and P9 stimulate L cells to secrete glucagon-like peptide-1 (GLP-1) which improves barrier function and reduces inflammation (Mo et al., 2024; Yoon et al., 2021). AKK and its out-membrane protein i.e. Amuc_1100 have been shown to induce CD8+ cytotoxic T lymphocytes activity and Treg differentiation thereby inhibiting colitis-associated colorectal cancer (Wang et al., 2020). Two other membrane proteins from AKK, namely Amuc_2172 and Amuc_2173 further reprogram tumor immune microenvironments in intestinal tumors (Jiang et al., 2023; Mo et al, 2024). Further, through TLR2/NLRP3 signaling, AKK shifts macrophages toward M1 phenotype in anti-cancer immunity (Fan et al., 2021).
Implications in Metabolic Disorders and Cardiovascular Health
Recent research has found changes in the abundance of AKK to be associated with various metabolic disorders like obesity, type 2 diabetes mellitus (T2D), nonalcoholic fatty liver disease and cardiovascular diseases (Everard et al., 2013; Shi et al., 2021; Zhang et al., 2021).
Obesity and its associated disorders have become a serious health issue. The role of gut microbiota in metabolism and energy harvesting process is well established and gut dysbiosis has been linked to imbalance in energy intake and expenditure leading to obesity and related disorders. Recent research has suggested that AKK is a promising candidate for preventing or ameliorating obesity and associated diseases (Hasnain et al., 2024). Live and pasteurized AKK and its EVs plays a protective role against obesity primarily by enhancing gut barrier integrity and modulating host metabolism. In high-fat diet (HFD)-induced models, it reduces intestinal permeability, lowers plasma lipopolysaccharide (LPS) levels, and mitigates systemic inflammation (Ashrafian et al., 2021; Depommier et al., 2020). Mechanistically, AKK promotes thermogenesis, increases GLP-1 secretion, elevates endocannabinoid levels, and downregulates genes involved in adipogenesis and carbohydrate transport. These actions collectively reduce fat accumulation, improve insulin sensitivity, and decrease energy efficiency. While animal studies demonstrate consistent anti-obesity effects with live, pasteurized, or EVs derived from AKK, clinical evidence in humans remains limited and warrants further investigation (Zhao et al., 2024).
T2D is a heterogeneous metabolic disorder characterized by hyperglycemia, insulin resistance, obesity, and low-grade inflammation, with a rapidly increasing global prevalence. If left uncontrolled, T2D leads to severe complications such as diabetic nephropathy, cardiomyopathy, retinopathy, and cognitive impairment, significantly contributing to mortality (Gregg et al., 2014). AKK exerts multifaceted beneficial effects in T2D through several interconnected mechanisms. It modulates host glucose metabolism by enhancing GLP-1 secretion via microbial metabolites such as propionate and direct interaction of outer membrane protein P9 with intercellular adhesion molecule (ICAM)-2, which together stimulate insulin release and improve glycemic control (Li et al., 2023; Psichas et al., 2015; Yoon et al., 2021). The bacterium also activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and promotes lipid oxidation through upregulation of the liver kinase B1 (LKB1)-AMPK signaling axis, thereby mitigating hepatic steatosis (Huang et al 2018; Jiafeng et al; 2022; Rao et al., 2021). Furthermore, it influences bile acid metabolism by modulating farnesoid X receptor signaling and fibroblast growth factor 15/19 (FGF15/19) pathways, contributing to improved lipid and glucose homeostasis (Li et al., 2023). AKK strengthens the gut barrier by increasing mucin (Muc2) production, tight junction protein expression (e.g., ZO-1, occludin), and stimulating Wnt signaling in intestinal stem cells, which collectively reduce metabolic endotoxemia by limiting LPS translocation (Guo et al., 2022; Li et al., 2023). Additionally, AKK contributes to microbiota homeostasis by enhancing microbial diversity and rebalancing the Firmicutes/Bacteroidetes ratio, which is often disrupted in T2D. Its beneficial effects are not limited to live bacteria; components such as pasteurized cells, outer membrane protein Amuc_1100, and extracellular vesicles also retain immunomodulatory and metabolic regulatory properties, supporting its potential as a next-generation probiotic for T2D.
AKK supports cardiovascular health by reducing endothelial inflammation through downregulation of TNF-α, MCP-1, and ICAM-1, thereby inhibiting macrophage adhesion and atherosclerotic plaque formation (Gofron et al., 2024; Li et al., 2016). It lowers systemic inflammatory markers such as CRP and TNF receptor II without altering lipid or glucose levels, reducing atherosclerosis severity (Gofron et al., 2024). The bacterium also produces propionate, which inhibits arterial calcification, and reduces TMAO synthesis, thereby protecting against atrial fibrillation and cardiomyocyte pyroptosis. These benefits are primarily observed with live bacterial supplementation. Additionally, AKK improves gut barrier function and lipid metabolism, contributing to weight reduction and blood pressure control, indirectly mitigating cardiovascular risk (Gofron et al., 2024; Luo et al., 2022; Yan et al., 2022). Table 1 enlists recent research regarding the ameliorative potential of AKK in different disease conditions.
| Type of disorder | Type of model | Main observation | Reference |
|---|---|---|---|
| Depression | CRS mouse model | ↓ Depression-like behavior; ↑ BDNF, ↑ dopamine, regulation of gut microbiota and metabolic pathways | Ding et al., 2021 |
| Antibiotic-treated mouse model | ↓ Depression-like behavior, ↑ BDNF and 5-HT, modulated gut-brain axis, normalized HPA axis | Sun et al., 2023 | |
| Murine alcohol + LPS model | ↓ Depression-like symptoms, ↑ occludin, BDNF, and 5-HT; ↓ LPS, TNF-α, IL-1α, and IL-6 | Guo et al., 2022 | |
| Alzheimer’s disease (AD) | APP/PS1 transgenic mouse model | ↓ Aβ plaques and levels; Improved cognition and gut barrier integrity | Ou et al., 2020 |
| Cardiovascular disease | Atherosclerosis (ApoE−/− mice) | ↓ Atherosclerotic lesions; Improved lipid profiles, and restored gut microbial balance | Xiao et al., 2024 |
| Abdominal aortic aneurysm (mice) | ↓ Aneurysm development, restored microbiota diversity, ↓ systemic inflammation | He et al., 2022 | |
| Metabolic disease | HFD-fed rats | Protected β-cells from apoptosis, promoted differentiation, ↑ gut barrier function | Yan et al., 2024 |
| Obesity & T2D | Meta-analysis of animal studies | ↓ Body weight by 10.4%, fasting glucose by 21.2%; ↑ insulin by 26.9%, improved glucose tolerance | Liu et al., 2024 |
| Colorectal cancer | Mouse tumorigenesis model | Amuc_2172 inhibits tumorigenesis by upregulating HSP70 and enhancing CD8+ T cell activity | Jiang et al., 2023 |
| Sepsis | Mouse sepsis model | Arg-Lys-His tripeptide from AKK reduces inflammation via TLR4 inhibition | Xie and Prasad, 2020 |
| Metabolic syndrome/gut barrier integrity | Mouse gut permeability model | AKK-EVs promote gut barrier integrity | Chelakkot et al., 2018 |
| Type 2 diabetes | Clinical trial (probiotic formulation) | ↓ Postprandial glucose levels; ↑ insulin sensitivity and metabolic markers | Perraudeau et al., 2020 |
| Age-related muscle decline | Clinical trial (pasteurized AKK HB05) | ↑ Muscle strength, function, and physical performance | Kang et al., 2024 |
| Chronic respiratory symptoms | Clinical trial (ETB-F01, heat-killed AKK) | Improved respiratory symptoms and lung function | Lee et al., 2024 |
| Obesity and diabetes | HFD mouse model | ↓ Body weight gain, fat mass, insulin resistance, lowered plasma leptin and triglycerides; ↑ glucose tolerance, gut barrier integrity | Plovier et al., 2017 |
| Obesity, insulin resistance | Randomized, double-blind, placebo-controlled pilot study | ↑ Insulin sensitivity; ↓ plasma total cholesterol, fat mass, plasma LPS, creatine kinase | Depommier et al., 2019 |
AKK and Neurological Disorders
In neuropsychiatric conditions, AKK modulates host physiology through multifaceted mechanisms involving metabolic, immunological, and gut-brain signaling pathways. Its outer membrane protein Amuc_1100 and secreted protein P9 influence serotonin biosynthesis and brain-derived neurotrophic factor (BDNF) signaling, critical in depression and anxiety-like behaviors (Lei et al., 2023). Amuc_1100 acts via TLR2 to promote 5-HT production and upregulate BDNF, while P9 enhances GLP-1 secretion with downstream neuroprotective effects (Holst et al., 2011; Wang et al., 2021). In Parkinson’s disease (PD) and Alzheimer’s disease (AD), studies consistently report elevated levels of AKK in patient microbiota, but with mixed implications. While some studies suggest AKK may help reduce inflammation, others associate its increased abundance with damage to the gut lining and higher levels of endotoxins in the blood (Lei et al., 2023). Therefore, further research is necessary to clarify the dual role of AKK in PD and determine whether its increased abundance is protective or contributes to disease pathology. In PD and multiple sclerosis (MS), both human and mouse studies show elevated AKK abundance correlating with either beneficial modulation of T-cell responses or exacerbation of inflammation, depending on context and strain (Takewaki et al., 2020). The production of SCFAs, particularly butyrate, by AKK or its microbial consortia, is linked to anti-inflammatory effects, enhanced synaptic plasticity, and modulation of the enteric and central nervous systems (Lei et al., 2023; Yang et al., 2019). Hence, clinical and animal studies across conditions like depression, AD, and stroke reveal alterations in AKK levels, often tied to behavioral and cognitive outcomes. These findings suggest a complex, context-dependent role for AKK in neurological disorders, balancing mucosal health and immune regulation with potential pathogenic effects in dysregulated states (Lei et al., 2023).
Conclusions
AKK is gaining attention as a strong candidate for next-generation probiotics because of its important role in supporting gut and metabolic health. It helps maintain the gut barrier, supports the immune system, and produces useful compounds like SCFAs, which are linked to benefits in conditions such as obesity, type 2 diabetes, and inflammatory bowel disease. Different strains of AKK have shown differences in how they function, suggesting that their health effects may depend on the specific strain used. While animal studies have shown encouraging results, more research in humans is needed to confirm these findings. Future studies should focus on testing the safety of using live AKK, understanding how different strains work, and exploring how it interacts with diet and other gut microbes. There is also potential in combining AKK with other gut-based treatments to manage complex health problems. With more evidence, this microbe could become a valuable tool in future treatments for metabolic and gut-related diseases. Preclinical data substantially supports its therapeutic promise, however, there are still a limited number of human studies. Therefore, further research is needed into strain-specific effects, administration methods, and long-term safety.
