Akkermansia muciniphila, a commensal bacterium residing in the intestinal niche, has garnered significant attention for its potential beneficial effects on host metabolic health. This oval-shaped, anaerobic Gram-negative bacterium, first isolated in 2004, typically constitutes about 3% of the gut microbial community. It is the only representative member of the Verrucomicrobia phylum found in mammal gastrointestinal samples, and its abundance gradually increases throughout the life course. While accumulating evidence suggests Akkermansia as a promising therapeutic probiotic against metabolic disorders like obesity, type 2 diabetes, and cardiovascular diseases, a nuanced understanding of its role is crucial. In specific intestinal microenvironments, excessive enrichment of Akkermansia may not be beneficial, and its use in certain patient populations requires careful evaluation.
The Role of Akkermansia in the Gut
Akkermansia muciniphila's life cycle and metabolism center around degrading mucin, a major glycoprotein component of the mucus secreted by the gastrointestinal tract's glandular epithelium. Mucin plays a vital role in protecting the gut lining, regulating water passage, and acting as a defense against pathogens and toxins. The bacterium's genome encodes several mucolytic enzymes (glycosyl hydrolases, proteases, sulfatases, and sialidases) that facilitate mucin degradation. This process, when regulated, stimulates the mucosa to produce new mucus, strengthening the epithelial barrier. However, excessive degradation can increase susceptibility to pathogens, inflammatory intestinal diseases, and colorectal cancer.
The scientific community's interest in Akkermansia muciniphila stems from observations linking its abundance in the gut with host health, and its alterations with several dysfunctions. Lower levels of Akkermansia muciniphila are observed in metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and non-alcoholic fatty liver disease (NAFLD). Conversely, an excessive enrichment in Akkermansia muciniphila, in specific intestinal microenvironments, may exacerbate local inflammation caused by damages on the epithelial barrier. Therefore, in light of these controversial points, evaluating the use of Akkermansia on an individual basis should be critically considered.
Potential Benefits of Akkermansia as a Probiotic
Several studies suggest Akkermansia muciniphila as a promising therapeutic agent with a probiotic role and several metabolic applications. Pre-clinical and clinical studies have demonstrated its efficacy in improving the clinical picture of metabolic syndrome and obesity, with beneficial effects on insulin sensitivity, lipoprotein metabolism, and hepatic metabolic inflammation. The ability of Akkermansia to strengthen the integrity of the intestinal barrier, modulate insulin resistance, and protect from metabolic inflammation are among its best-described effects.
Akkermansia helps to preserve the epithelial barrier’s integrity by stimulating anti-inflammatory pathways. From the fermentation of mucin, Akkermansia muciniphila produces short chain fatty acids (SCFAs) such as acetate and propionate, thus improving intestinal integrity and reducing endotoxemia arising, for instance, from a condition of obesity. Notably, such beneficial effects are not related only to live Akkermansia muciniphila, but also to pasteurized Akkermansia. The latter may enhance the gut barrier’s function and lead to the attenuation of metabolic endotoxemia. A clinical trial demonstrated that the oral assumption of pasteurized Akkermansia muciniphila in overweight or obese individuals significantly ameliorated insulin sensitivity, decreased insulinemia and plasma total cholesterol, and slightly reduced body weight compared to the placebo group.
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Overall, the reported studies suggest that Akkermansia muciniphila is a promising probiotic strategy for the treatment of metabolic conditions such as obesity and diabetes. However, extending its wide use in clinical practice needs deeper critical considerations and more clinical trials to test and verify its safety and efficacy.
Cautions and Potential Harms
Despite the beneficial effects on the metabolic profile, it is worth noting that in some cases the abundance of Akkermansia may be not effective to induce a clinical metabolic improvement, as recently reported in a study on bariatric patients. In such patients with severe obesity, the increased relative abundance of Akkermansia observed after bariatric surgery, failed to correlate with improvements in glucose homeostasis compared to the baseline. Furthermore, in some other conditions, orally supplementing Akkermansia may not have the expected effects on intestinal health and clinical conditions, and therefore, considering the safety and efficacy of its widespread application is quite crucial.
In the case of Salmonella typhimurium infection, the procolonization of Akkermansia makes Salmonella a dominant bacterium of microbiota. Inflammatory bowel disease (IBD) is another condition in which the use of Akkermansia should be carefully evaluated. In this condition, the gut barrier function is already compromised, and a mucin-degrader probiotic may not be the appropriate choice. This was evidenced in a preclinical study on a mouse model of IBD (IL-10−/−), in which the supplementation of Akkermansia may be not indicated due to the development of colitis. A condition of prolonged intestinal inflammation, as occurs in the IBD, may be of risk for colonic tumorigenesis, and it is referred to as colitis-associated colorectal cancer (CAC).
IBD may also often occur in women suffering from endocrine and gynecological disorders such as polycystic ovary syndrome (PCOS) or endometriosis. Although patients with PCOS may exhibit glucose and lipid metabolic alterations, the use of Akkermansia needs proper attention in this context. Indeed, these patients may also suffer from dysbiosis of the gut microbiota with chronic intestinal inflammation, which can expose them to a higher risk of developing IBD. A longitudinal study found that women with endometriosis may be 80% more likely to develop IBD compared with women without endometriosis.
The excessive enrichment of Akkermansia may alter the process of mucin degradation, thus impairing the intestinal barrier and inducing the secretion of inflammatory cytokines (IL-1β, IL-6, and TNF-α). The extensive use of Akkermansia in the post-antibiotic reconstitution of the microbial community may further make the intestinal barrier’s functionality even worse. A recent study demonstrated that in the particular context of CAC, post-antibiotic Akkermansia replenishment exacerbates the intestinal barrier damage and increases colonic and systemic inflammation, thus interfering with the reconstitution of the intestinal microbiota and its metabolic function. Once antibiotic treatments are stopped, the microbiota undergoes a dynamic rebuilding process, which is often slow and incomplete. Therefore, stimulating such changing microbiota by using probiotics may be not beneficial in this phase.
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Along with the attention of using Akkermansia muciniphila in compromised intestinal conditions, recent findings from the neurologic field indicated a cautionary use of such probiotic. Different studies revealed an increase in Akkermansia abundance in patients suffering from Parkinson’s disease (PD). The elevated abundance of Akkermansia seems to be one of the features of the intestinal microbiota in such patients. In line with this, in 2017, a study found that individuals with rapid eye movement sleep behavior disorder, which is considered a pre-motor symptom of PD, exhibited elevated intestinal Akkermansia levels. In addition, other studies revealed an increased intestinal abundance of Akkermansia also in subjects with multiple sclerosis (MS). Different studies demonstrated that transplanting into a mouse model of MS fecal microbiota samples from MS-affected mice, exposed to a worse disease progression compared to transplanting fecal microbiota samples from healthy controls. Although speculative, some authors hypothesized that the activation of the Toll-like Receptor 2 (TLR2) or the modulation of glucose and cholesterol homeostasis, induced by Akkermansia, may determine unexpected deleterious consequences for neurological health in certain individuals.
Another crucial aspect to bear in mind, especially when evaluating the safety of Akkermansia, is its evolutionary potential to acquire antimicrobial resistance genes (ARGs) under antibiotic selective pressure. Akkermansia is gaining significant attention for its potential application in food supplements and pharmaceutical formulations as well as other anaerobic gut commensals associated with human health (Bacteroides spp., Clostridium butyricum, Faecalibacterium prausnitzii), however, all these genera and microbial species do not have a history of safe use yet. With the introduction of Akkermansia muciniphila in the food chain, the evaluation of the antimicrobial susceptibility of this bacterium becomes fundamental to meet the safety recommendations of EFSA. Phenotypic tests have confirmed the antibiotic resistance profile of some strains of Akkermansia; however, further studies involving a larger number of Akkermansia strains are necessary to demonstrate the safety of this microbial species, considering that the coexistence of several microbial populations in the gut provides ideal conditions for gene exchange.
Pendulum's Akkermansia Products
Two products developed and manufactured by Pendulum contain A. muciniphila and are available on the market. One is marketed for gut health, and the other is marketed for glucose control. The product for gut health contains A. muciniphila as the only beneficial microbe. The product for glucose control, sold under the trade name Pendulum Glucose Control, contains a proprietary, multistrain probiotic blend that contains A. muciniphila, Clostridium butyricum, Clostridium beijerinckii, Anaerobutyricum hallii, and Bifidobacterium infantis. Both products contain chicory inulin, oligofructose, and hypromellose (vegetarian capsule).
Pendulum’s glucose control product restores the body’s ability to produce butyrate and restores the mucin lining of the gut. Butyrate binds to receptors in the gut mucosa and stimulates the release of GLP-1. One small, short, multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial was conducted in people with type 2 diabetes. This 12-week, parallel study included 76 adults who were previously diagnosed with type 2 diabetes and being treated with metformin and/or a sulfonylurea. Participants were randomized to receive either placebo or one of two different active treatments twice daily with food. One treatment contained three strains and the other contained five strains of probiotics.
In the arm receiving the five-strain treatment, there was a statistically significant reduction in the primary outcome of total glucose area under the curve (AUC) of −36 mg/dL/180 minutes (P = 0.05) when compared with placebo. For a secondary outcome of A1C, there was a nonsignificant reduction in both treatment arms (−0.2% in the three-strain arm [P = 0.4684] and −0.6% in the five-strain arm [P = 0.054]).
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Reassessing the Akkermansia-Obesity Association
Obesity is associated with or even caused by the dysbiosis of gut microbiota. Some beneficial bacteria, such as gut Akkermansia, may play a decisive role in reducing the burden of obesity, via modulation of glucose metabolism and low-grade inflammation.
A study used datasets from the American Gut Project to strictly reassess the association and further examined the effect of aging on it. A total of 10,534 participants aged 20 to 99 years from the United States and the United Kingdom were included. The relative abundance of Akkermansia was assessed based on 16S rRNA sequencing data. Obesity (body mass index, BMI ≥ 30 kg/m2) risks were compared across Akkermansia quintiles in logistic models with adjustment for common confounders.
The median abundance of Akkermansia was 0.08% (interquartile range: 0.006-0.93%), and the prevalence of obesity was 11.03%. Nonlinear association was detected between Akkermansia and obesity risk (P = 0.01). The odds ratios (95% confidence interval) for obesity across the increasing Akkermansia quintiles (referencing to the first quintile) were 1.14 (0.94-1.39), 0.94 (0.77-1.15), 0.70 (0.56-0.85) and 0.79 (0.64-0.96) after adjusting for age and sex (P for trend < 0.001). This association remained unchanged after further controlling for smoking, alcohol drinking, diet, and country.
Practical Recommendations
Given that there is significant evidence of cardiovascular, renal, and heart failure benefits with multiple available pharmacological treatments for diabetes, this probiotic blend product should not be used instead of validated therapies. If this medical probiotic product is recommended, it should be in addition to-not instead of-other proven therapies. This caution is especially important for people with cardiovascular disease, heart failure, or chronic kidney disease who are taking prescription agents with proven outcomes for these conditions, as described and recommended in ADA guidelines.
Ways to Increase Akkermansia Abundance
- Eat foods high in prebiotic fibers and FODMAPs, e.g. onions, garlic, asparagus, pears, dried fruit. Take care if you have IBS, as FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) can exacerbate IBS symptoms.
- Try a ketogenic diet. Caveat: Though this recent study showed Akkermansia increasing with keto (type of high-fat diet), overall microbial diversity and number of Bifidobacteria decreased. Keto diets aren’t recommended for people whose mood and energy tank when they’re on a low-carb regimen.
- Eat more dietary polyphenols from foods like cranberry and pomegranate juices and extracts, green tea and red grapes, or red wine.
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