Akkermansia muciniphila: An essential bacterium for maintaining good health

The gut microbiota plays a crucial role in metabolism, immunity and regulation of the gut-brain axis in animals, including humans. The microbiota is involved in the digestion of non-digestible food components (cellulose, hemicellulose, resistant starch, pectin, complex polysaccharides, certain sugars and alcohols) and generates, via its metabolism, compounds that have multiple beneficial effects on human health.

One of the gut microorganisms that have captured the attention of researchers over the past two decades is the bacterium Akkermansia muciniphila, a member of the phylum Verrucomicrobiota that was first isolated from fecal samples in 2004. This bacterium was named in honour of Dr. Antoon Akkermans (1940–2006), a Dutch microbiologist recognized for his contributions to microbial ecology. Metagenomic analyses carried out since suggest that there are at least eight species of the genus Akkermansia that colonize the intestine of humans, in addition to Akkermansia muciniphila. Moreover, microorganisms related to Akkermansia colonize the intestine of many mammals and non-mammals.

The mucus of the intestinal wall
It has been estimated that Akkermansia muciniphila represents 1-3% of the whole microbiota, and up to 3-5% of the gut microbiota in healthy people. This bacterium colonizes the mucus layer, a viscous layer that covers and protects the epithelial cells that line the intestinal mucosa. Mucus is secreted by specialized epithelial cells, called goblet cells or muciparous cells. The most abundant constituents of mucus are mucins, highly glycosylated proteins whose main characteristic is the ability to form a gel with lubricating properties. Akkermansia muciniphila is one of the intestinal bacteria that have the ability to produce enzymes (mucinases) that degrade mucins, which generates carbon and nitrogen-containing products that are sources of energy for itself, as well as for other microorganisms present in the intestine. In addition, Akkermansia muciniphila generates metabolites, including short-chain fatty acids such as acetate, propionate, butyrate and 1,2-propanediol, which have several beneficial effects on metabolism and immunity (see our article on the subject).

Akkermansia muciniphila colonizes the mucus layer of children soon after birth and reaches the levels seen in adults in as little as a year. However, colonization of the intestine by Akkermansia muciniphila decreases in the elderly (>80 years).

Role in maintaining the intestinal mucosa
The continuous degradation of mucin by the enzymes secreted by Akkermansia muciniphila contributes to maintaining the optimal thickness of the mucus layer and the integrity of the intestinal barrier. This is because mucus breakdown produces nutrients for goblet (mucus-producing) cells and, therefore, stimulates mucus turnover.

Akkermansia muciniphila and chronic diseases
Several studies have shown that Akkermansia muciniphila is present in lower amounts in people with diseases such as type 2 diabetes, obesity, inflammatory bowel disease, colorectal cancer and autism.

Obesity
Obesity is a major risk factor for type 2 diabetes, coronary heart disease, fatty liver disease, certain cancers and premature mortality. A study carried out in mice showed that Akkermansia muciniphila is present in lower quantities (3,300 times less) in the intestine of obese mice (genetically deficient in leptin, a satiety hormone) than in that of thin mice. In addition,Akkermansia muciniphila was 100 times less abundant in the intestine of mice made obese by a very high-fat diet than in that of thin, normally fed mice. Adding prebiotics (oligofructose) to the food of obese mice normalized Akkermansia muciniphila levels and improved their metabolic profile. The administration (by gavage) of Akkermansia muciniphila to obese mice also significantly improved the metabolic disorders found in these mice: reduction of endotoxemia (presence of endotoxins in the blood), adiposity, inflammation of adipose tissue, body weight, fat-to-lean mass ratio, and insulin resistance. Additionally, administration of Akkermansia muciniphila increased intestinal levels of endocannabinoids (acylglycerols) that control inflammation, gut barrier integrity, and gut peptide secretion.

A systematic review published in 2021 listed 10 high-quality randomized controlled studies on the effects of supplementation with Akkermansia muciniphila on obesity in mice. Overall, studies show that supplementation with Akkermansia muciniphila improves insulin sensitivity and blood sugar control and reduces inflammation in obese mice.

Significantly lower levels of Akkermansia muciniphila were measured in overweight or obese preschool children and obese adult women, compared to people of the same age group who were of normal weight. According to a French study, it seems that the levels of Akkermansia muciniphila are even lower in people with severe obesity (BMI: 35-39.9 kg/m²) or morbid obesity (BMI: ≥40 kg/m²) than in those with moderate obesity (BMI: 30-34.9 kg/m²). After bariatric surgery (Roux-en-Y gastric bypass), obese people saw their levels of Akkermansia muciniphila increase significantly, but this was not correlated with metabolic improvement.

Supplementation with Akkermansia muciniphila in humans was tested in 2019 on 32 overweight or obese volunteers. The main purpose of this randomized, controlled study was to establish the safety and tolerability of supplementation and to measure various metabolic parameters related to obesity. Oral supplementation for three months with 10 billion Akkermansia muciniphila bacteria (live or pasteurized) daily has been shown to be safe and well tolerated. Compared to placebo, supplementation with Akkermansia muciniphila improved insulin sensitivity and reduced insulin levels and total blood cholesterol. After the three months of supplementation, Akkermansia muciniphila reduced blood levels of several markers of liver dysfunction and inflammation.

A trend in the use of probiotics is to use non-viable microorganisms (pasteurized, for example), in order to prevent the potential risks associated with the use of live microorganisms. A study showed that in mice fed a normal diet, pasteurized Akkermansia muciniphila was more effective than live (unpasteurized) bacteria in decreasing markers of inflammation and improving several biochemical parameters.

Type 2 diabetes
A clinical study showed that prediabetic, glucose-intolerant patients with had less Akkermansia muciniphila present in their gut than people with normal glucose tolerance. In another study, administration of Akkermansia muciniphila to mice reversed the negative effect of the cytokine IFN-γ on glucose tolerance, suggesting that a reduction in Akkermansia muciniphila may be responsible for the same effects of IFN-γ on glucose tolerance in humans. It should be noted that high levels of IFN-γ are associated with increased severity of coronary heart disease and type 2 diabetes, as well as with the progression of amyotrophic lateral sclerosis and lupus.

Cardiovascular diseases
Atherosclerosis is a chronic inflammatory disease that is the main cause of cardiovascular mortality. Atherosclerotic plaques contain bacteria that normally reside in the gut and mouth, suggesting that microbiota may be involved in the development of this disease. It is also known that cardiovascular risk is inversely associated with the level of Akkermansia muciniphila in the intestine. In an animal model of atherosclerosis (ApoE^–/–, i.e., mice deficient in Apolipoprotein E), administration of Akkermansia muciniphila has been shown to attenuate atherosclerotic lesions by decreasing inflammation induced by endotoxemia. Another study showed that supplementation with berberine (used in traditional Chinese medicine) in ApoE^–/– mice fed a high-fat diet increased intestinal levels of Akkermansia muciniphila and decreased atherosclerosis. Berberine supplementation also decreased endotoxemia and the expression of pro-inflammatory cytokines and chemokines.

Longevity
A Spanish research group examined the role of the gut microbiota in aging and progeria (Hutchinson-Gilford syndrome), a very rare genetic disease characterized by accelerated aging from the first or second year of life. In both mouse models of progeria, there were fewer bacteria from the Verrucomicrobiota phylum and more bacteria from the Proteobacteria and Cyanobacteria phyla than in healthy mice. Transplantation of whole microbiota from healthy mice to progeria model mice improved lifespan and attenuated the manifestations of accelerated aging. Transplantation of the microorganism Akkermansia muciniphila alone also significantly increased the lifespan of mouse models of progeria, although more modestly. In humans, analyses have shown a decrease in bacteria of the phylum Verrucomicrobiota (of which Akkermansia muciniphila is a part) in children with progeria compared to healthy children, and an increase in centenarians compared to healthy adults. This study makes it possible to consider treatments by supplementation with laboratory-grown Akkermansia muciniphila to treat progeria as well as to age in better health and live longer.

Prebiotics
Prebiotics are substances that promote the growth of microorganisms in the intestine. Some examples of prebiotics are fructo-oligosaccharides, galacto-oligosaccharides, arabinose, galactose, inulin, raffinose and mannose. Inulin, a linear polymer of D-fructose, is found in several plants where it constitutes a reserve of carbohydrates. Several studies in mice and a few studies in humans have shown that inulin increases the amount of several intestinal bacteria, including Akkermansia muciniphila. To maximize inulin consumption, it may be useful to know that certain foods contain good amounts, such as Jerusalem artichokes (16-20%), chicory (15-20%), dandelion greens (12-15%), garlic (9-16%), artichokes (3-10%), leeks (3-10%), and onions (2-6%).

Conclusion
The composition of the gut microbiota has very important and numerous effects on human health. The bacterium Akkermansia muciniphila plays an essential role in maintaining the intestinal barrier, and it generates metabolites that have several beneficial effects on metabolism and immunity. Low levels of this bacterium in the gut is an indicator of poor gut health and is associated with several chronic diseases, including obesity, type 2 diabetes, cardiovascular disease and inflammatory bowel disease. Interventions that aim to increase Akkermansia muciniphila (prebiotic or supplementation) in the gut improve metabolic disorders such as endotoxemia, insulin resistance and inflammation. It is still too early to consider treating patients with a metabolic disorder, but this promising avenue will need to be studied in rigorous clinical trials. Adopting a healthy diet, such as the Mediterranean-style diet (consisting mainly of vegetables, legumes, fruits, nuts, olive oil, and some wine and red meat) is an approach that maximizes the chances of having a healthy intestinal microbiota and preventing metabolic disorders and certain chronic diseases.