The genera Lactobacillus and Bifidobacterium have long been the workhorses for traditional research into the health benefits of probiotics and are the most common commercialized probiotics. Now, newer techniques of analyzing microbial communities are leading to the identification of novel microbes, some with probiotic potential. These “next-generation probiotics” (NGPs) may offer unique benefits from more established probiotic strains and hence are an area of intense research. While there are many promising NGPs, this blog will explore one in particular: Akkermansia muciniphila.
Next-Generation Probiotics, in brief
Most of the vast array of microorganisms in the human gut has remained unidentified because they are typically anaerobic bacteria that are difficult to cultivate. Recent advances in microbiology— complete genome sequencing, culture techniques, and bioinformatics— have enabled the precise identification and detection of these bacteria, facilitating the development of NGPs with promising health benefits. Examples include Roseburia intestinalis, Eubacterium spp., Faecalibacterium prausnitzii, Bacteroides spp., and Akkermansia muciniphila. Their selection is often prompted by their correlation to health or, their absence, to disease. Although cause and effect often remain to be documented. Turning these species into industrial probiotics is challenging due to their need for specific growth factors and anaerobic conditions, which increase costs and complexity. Another hurdle is the regulatory approval of new probiotic species without a history of use. However, novel regulatory frameworks are emerging, for example, the Live Biotherapeutic Products category being defined by the United States Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines.
Despite these challenges, Akkermansia muciniphila (A. muciniphila) is a particularly promising candidate.
Akkermansia muciniphila
Isolated just two decades ago, A. muciniphila is a commonly found commensal bacterium that constitutes 1 to 4% of the gut microbiota in healthy individuals. With its ability to live in the mucous layer of the intestine, A. muciniphila plays a crucial role in gut integrity maintenance thereby reducing the abundance of pathogens. It degrades intestinal mucins and glycoproteins for use as energy interacting with host metabolic processes. A. muciniphila can also increase the production of mucin, which leads to strengthening of the intestinal barrier.
Abundant in the first year of life, A. muciniphila generally decreases with age but was found to be higher in a study with centenarians. Notably, abundance is associated with healthy aging while being reduced in individuals with comorbidities linked to unhealthy aging.
Mechanisms of action
Research has identified three main actions of A. muciniphila: enhancing gut barrier integrity, improving metabolic health, and modulating the immune system. Together or separately, these mechanisms may have implications in diseases; the primary areas of study follow.
Gut disease
Alterations in intestinal barrier permeability, such as changes in tight junction proteins, are associated with the development of inflammatory bowel disease (IBD). A. muciniphila levels are significantly reduced in patients with ulcerative colitis and Crohn’s disease, and its abundance inversely correlates with inflammation.
One recent study investigated the effects of pasteurized A. muciniphila on alleviating IBS-like symptoms and related behavioral disorders in mice, finding that it significantly reduced colonic hypersensitivity, improved gut barrier function, and enhanced anxiety-like behavior and cognitive performance without significantly altering fecal microbiota composition.
A 2024 review of studies suggested that A. muciniphila supplementation may help reduce inflammation and improve gut health, although further research is needed to fully understand its therapeutic potential.
Metabolic disease
Numerous studies highlight the significance of the microbe A. muciniphila in metabolic health. For example, reduced levels of A. muciniphila are linked to diabetes in mice. In addition, a lower fecal abundance has been observed in obese patients with type II diabetes, hypertension, and liver disorders.
A. muciniphila has shown benefit in the following ways:
Improving gut integrity by enhancing gut barrier function, reducing permeability and endotoxemia.
Supporting immune function by enhancing immune signaling, promoting a balanced immune response, and reducing systemic inflammation. It decreases the levels of pro-inflammatory cytokines and markers, thereby alleviating systemic and gut inflammation.
Improving metabolic parameters: Many animal studies report a significant beneficial effect of A. muciniphila on the development of diabetes of both types and in obesity management. Supplementation was observed to lead to reduced plasma insulin levels, decreased body fat, and improved metabolic parameters. Most studies used animal models, but a clinical trial with 40 overweight or obese subjects showed that 3 months of A. muciniphila supplementation, both live and pasteurized, significantly reduced plasma insulin and improved insulin sensitivity compared to placebo. Pasteurized A. muciniphila also lowered cholesterol, triglycerides, body weight, fat mass, and waist and hip circumference.
Protecting against liver damage by reducing liver enzymes and guarding against liver fibrosis and non-alcoholic fatty liver disease in mice.
Cancer
With its crucial role in gut integrity, A. muciniphila may guard against permeability that allows toxic and pro-inflammatory substances to penetrate which can lead to carcinogenesis.
A study on immunocompetent mice with prostate cancer found that treatment with extracellular vesicles from A. muciniphila significantly slowed tumor growth, increased tumor-fighting immune cell activity, and showed no toxicity to healthy tissues.
In colorectal cancer, A. muciniphila showed potential in reducing tumor growth and improving immune response in mouse models. Notably, treatments with A. muciniphila have demonstrated enhanced efficacy of colorectal cancer therapies, such as certain chemotherapies, by increasing beneficial immune cell activity and decreasing tumor proliferation without significant toxicity.
A comprehensive review cited the studies pointing to high levels of A. muciniphila in the gut microbiota of lung or kidney cancer patients correlating with a positive response to immunotherapy whereas the absence of this bacterium leads to no such response, a finding supported by fecal transplant studies in mice and further linked to better outcomes in immune checkpoint inhibitor treatments. Thus, A. muciniphila positively affects the response to certain immunotherapy and chemotherapy agents. Most studies are in animals, so further human research is needed.
Neurodegenerative diseases
A. muciniphila is considered integral to brain function via the gut-brain axis. Its safeguarding the intestinal mucosal barrier, modulation of the immune system and production of metabolites, such as short-chain fatty acids, amino acids, and amino acid derivatives suggests therapeutic potential in several neurodegenerative disorders, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple sclerosis (MS).
Alzheimer’s disease
In AD mouse models, a decrease in A.muciniphila is linked to intestinal barrier impairment and cognitive deficits, and supplementation can improve gut health and reduce amyloid-β deposition, enhancing cognitive function. However, human study results regarding the effects of A. muciniphila have been inconsistent.
Amyotrophic lateral sclerosis
A. muciniphila is negatively associated with ALS, with decreasing abundance in ALS mice. Research found that its supplementation in an ALS mouse model improved motor function and brain atrophy through nicotinamide accumulation, which supports neuronal health.
Parkinson’s disease
Gut dysbiosis, with an enrichment of A. muciniphila, is observed in both the human prodromal phase of PD and certain PD mouse models, suggesting its role in PD pathogenesis and potential as an early biomarker. While A. muciniphila may contribute to gut inflammation and systemic issues through mucin degradation, it also has anti-inflammatory effects, though its impact on cognitive decline in PD remains uncertain.
Multiple sclerosis
Research indicates that A.muciniphila abundance is significantly higher in MS patients, correlating with a pro-inflammatory T-cell profile that worsens immune response. However, other findings suggest that A. muciniphila may also have beneficial effects, such as reducing the severity of autoimmune encephalomyelitis (the body’s immune system mistakenly attacks the brain and spinal cord) and promoting an anti-inflammatory immune response, suggesting a strain-specific role in MS.
Neuropsychiatric conditions
Research suggests that A.muciniphila may influence neuropsychiatric disorders through its effects on the gut-brain axis, contributing to reduced intestinal imbalances and inflammation. Studies in animal models indicate that supplementation with A. muciniphila can alleviate depressive symptoms and improve mucosal barrier function, potentially enhancing behavioral outcomes and neurochemical profiles. Additional research highlights its potential role in conditions like autism spectrum disorders, where alterations in gut microbiota composition may impact gastrointestinal and neurological function.
Takeaway
A. muciniphila, a gut bacterium isolated two decades ago, plays a crucial role in maintaining gut integrity by living in the intestinal mucous layer and reducing pathogen abundance. It shows promise in improving gut barrier function, enhancing metabolic health, and modulating the immune system, with potential benefits for conditions like inflammatory bowel disease, diabetes, certain cancers, and neurodegenerative and neuropsychiatric disorders. While studies indicate potential therapeutic effects on Alzheimer’s, Parkinson’s, and depressive symptoms, results have been inconsistent, highlighting the need for further research to fully understand its benefits and applications. Partly, these inconsistencies may be explained by strain differences within the species. Despite challenges in industrial production and regulatory approval, A. muciniphila is a focal point of probiotic research due to its significant therapeutic potential across a range of diseases. As many of the studies were conducted in animals, future research in humans should better define its practical potential in health and disease.
Key references
Al-Fakhrany, Omnia Momtaz, and Engy Elekhnawy. “Next-generation probiotics: the upcoming biotherapeutics.” Molecular biology reports vol. 51,1 505. 15 Apr. 2024, doi:10.1007/s11033-024-09398-5
Blacher, Eran et al. “Potential roles of gut microbiome and metabolites in modulating ALS in mice.” Nature vol. 572,7770 (2019): 474-480. doi:10.1038/s41586-019-1443-5
Brodmann, Theodor et al. “Safety of Novel Microbes for Human Consumption: Practical Examples of Assessment in the European Union.” Frontiers in microbiology vol. 8 1725. 12 Sep. 2017, doi:10.3389/fmicb.2017.01725
Cekanaviciute, Egle et al. “Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models.” Proceedings of the National Academy of Sciences of the United States of America vol. 114,40 (2017): 10713-10718. doi:10.1073/pnas.1711235114
Collado, M Carmen et al. “Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly.” Applied and environmental microbiology vol. 73,23 (2007): 7767-70. doi:10.1128/AEM.01477-07
Cox, Laura M et al. “Gut Microbiome in Progressive Multiple Sclerosis.” Annals of neurology vol. 89,6 (2021): 1195-1211. doi:10.1002/ana.26084
Cunningham, Marla et al. “Shaping the Future of Probiotics and Prebiotics.” Trends in microbiology vol. 29,8 (2021): 667-685. doi:10.1016/j.tim.2021.01.003
de Vos, Willem M. “Microbe Profile: Akkermansia muciniphila: a conserved intestinal symbiont that acts as the gatekeeper of our mucosa.” Microbiology (Reading, England) vol. 163,5 (2017): 646-648. doi:10.1099/mic.0.000444
Depommier, Clara et al. “Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.” Nature medicine vol. 25,7 (2019): 1096-1103. doi:10.1038/s41591-019-0495-2
Derrien, Muriel et al. “Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium.” International journal of systematic and evolutionary microbiology vol. 54,Pt 5 (2004): 1469-1476. doi:10.1099/ijs.0.02873-0
Derrien, Muriel et al. “The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract.” Applied and environmental microbiology vol. 74,5 (2008): 1646-8. doi:10.1128/AEM.01226-07
Ding, Yang et al. “A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress-induced depressive-like behavior in mice by regulating gut microbiota and metabolites.” Applied microbiology and biotechnology vol. 105,21-22 (2021): 8411-8426. doi:10.1007/s00253-021-11622-2
Earley, Helen et al. “The abundance of Akkermansia muciniphila and its relationship with sulphated colonic mucins in health and ulcerative colitis.” Scientific reports vol. 9,1 15683. 30 Oct. 2019, doi:10.1038/s41598-019-51878-3
Etienne-Mesmin, Lucie et al. “Experimental models to study intestinal microbes-mucus interactions in health and disease.” FEMS microbiology reviews vol. 43,5 (2019): 457-489. doi:10.1093/femsre/fuz013
Fan, Lina et al. “A. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs.” Cancer immunology research vol. 9,10 (2021): 1111-1124. doi:10.1158/2326-6066.CIR-20-1019
Gopalakrishnan, V et al. “Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.” Science (New York, N.Y.) vol. 359,6371 (2018): 97-103. doi:10.1126/science.aan4236
Hänninen, Arno et al. “Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice.” Gut vol. 67,8 (2018): 1445-1453. doi:10.1136/gutjnl-2017-314508
Hou, Xiaoying et al. “Akkermansia Muciniphila Potentiates the Antitumor Efficacy of FOLFOX in Colon Cancer.” Frontiers in pharmacology vol. 12 725583. 17 Sep. 2021, doi:10.3389/fphar.2021.725583
Kim, Sejeong et al. “Akkermansia muciniphila Prevents Fatty Liver Disease, Decreases Serum Triglycerides, and Maintains Gut Homeostasis.” Applied and environmental microbiology vol. 86,7 e03004-19. 18 Mar. 2020, doi:10.1128/AEM.03004-19
Lei, Wenhui et al. “Akkermansia muciniphila in neuropsychiatric disorders: friend or foe?.” Frontiers in cellular and infection microbiology vol. 13 1224155. 10 Jul. 2023, doi:10.3389/fcimb.2023.1224155
Liu, Qing et al. “Akkermansia muciniphila Exerts Strain-Specific Effects on DSS-Induced Ulcerative Colitis in Mice.” Frontiers in cellular and infection microbiology vol. 11 698914. 4 Aug. 2021, doi:10.3389/fcimb.2021.698914
Liu, Xia et al. “Rescue of social deficits by early-life melatonin supplementation through modulation of gut microbiota in a murine model of autism.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 156 (2022): 113949. doi:10.1016/j.biopha.2022.113949
Luo, Zhong-Wei et al. “Extracellular Vesicles from Akkermansia muciniphila Elicit Antitumor Immunity Against Prostate Cancer via Modulation of CD8+ T Cells and Macrophages.” International journal of nanomedicine vol. 16 2949-2963. 20 Apr. 2021, doi:10.2147/IJN.S304515
Meynier, Maëva et al. “Pasteurized akkermansia muciniphila improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice.” Gut microbes vol. 16,1 (2024): 2298026. doi:10.1080/19490976.2023.2298026
Mruk-Mazurkiewicz, Honorata et al. “Insights into the Mechanisms of Action of Akkermansia muciniphila in the Treatment of Non-Communicable Diseases.” Nutrients vol. 16,11 1695. 29 May. 2024, doi:10.3390/nu16111695
Ou, Zihao et al. “Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease.” Nutrition & diabetes vol. 10,1 12. 22 Apr. 2020, doi:10.1038/s41387-020-0115-8
Palmas, Vanessa et al. “Gut Microbiota Markers and Dietary Habits Associated with Extreme Longevity in Healthy Sardinian Centenarians.” Nutrients vol. 14,12 2436. 12 Jun. 2022, doi:10.3390/nu14122436
Si, Jiyeon et al. “Revisiting the role of Akkermansia muciniphila as a therapeutic bacterium.” Gut microbes vol. 14,1 (2022): 2078619. doi:10.1080/19490976.2022.2078619
Van Herreweghen, Florence et al. “Mucin as a Functional Niche is a More Important Driver of in Vitro Gut Microbiota Composition and Functionality than Supplementation of Akkermansia muciniphila.” Applied and environmental microbiology vol. 87,4 (2021): e02647-20. doi:10.1128/AEM.02647-20
Xu, Ruiling et al. “The role of the probiotic Akkermansia muciniphila in brain functions: insights underpinning therapeutic potential.” Critical reviews in microbiology vol. 49,2 (2023): 151-176. doi:10.1080/1040841X.2022.2044286
Zhang, Yaoyuan et al. “Enhancing intestinal barrier efficiency: A novel metabolic diseases therapy.” Frontiers in nutrition vol. 10 1120168. 2 Mar. 2023, doi:10.3389/fnut.2023.1120168