In 2007, Patrice Cani (FNRS-WELBIO researcher) and his team at the Louvain Drug Research Institute of University of Louvain, in close collaboration with Willem de Vos, professor at UWageningen, discovered the beneficial effects of intestinal bacteria, Akkermansia muciniphila, able to moderate the development of obesity and type 2 diabetes, in mice.
In 2017, the team discovered (still in the mouse) that the use of a pasteurized form of Akkermansia leads to an even greater protection than the living bacterium regarding various cardiovascular disease risk factors such as insulin resistance, hypercholesterolemia, or the storage of fat in adipose tissue.
Following these discoveries, the UCLouvain team, in collaboration with the Cliniques Universitaires Saint-Luc, developed a clinical study in order to administer the bacteria to humans.
For this, it was necessary to develop the capacity to produce the bacterium in large quantity and to make sure that the tests would be without risk for the participants.
The UCLouvain researchers administered Akkermansia to overweight or obese volunteers, all displaying insulin resistance (pre-diabetes type 2) and metabolic syndrome, in other words, having several elevated risk factors for cardiovascular diseases.
The volunteers were randomly divided into 3 groups (placebo, live bacteria and pasteurized bacteria) and were asked not to change their dietary habits or their physical activity. Akkermansia was provided as a nutritional supplement.
The primary goal of this UCLouvain study was to demonstrate the feasibility of daily ingesting Akkermansia for 3 months, without risk. Clara Depommier and Amandine Everard, UCLouvain researchers, observed excellent compliance (the supplements were easy to ingest) and tolerance (there were no side effects) in the groups taking live or pasteurized bacteria.
The conclusions are clear: The tests in humans confirm what had already been observed in mice. Ingestion of the (pasteurized) bacterium prevented the deterioration of the health status of the subjects (pre-diabetes, cardiovascular risks).
Even better, the researchers observed a decrease in inflammation markers in the liver, a slight decrease in the body weight of the subjects (2.3 kg on average) as well as a lowering of cholesterol levels.
In contrast, the metabolic parameters (insulin resistance or hypercholesterolemia) in placebo subjects continued to deteriorate over time.
Who does it benefit?
According to the WHO, one in three people die every day from cardiovascular disease worldwide.
In Western countries, one in two people is overweight and has increased cardiovascular risks.
This research of the UCLouvain would limit these risks and therefore potentially have an impact (limit the effects) on half of the population, if properly used.
In conclusion, this pilot study demonstrates the feasibility of administrating (pasteurized) Akkermansia bacteria to humans in the form of a food supplement and reports encouraging results on the effectiveness of the Akkermansia-based dietary supplements to reduce cardio-metabolic risk factors.
These results pave the way for a large-scale study, to confirm/elaborate these first results, but also endorse the commercialization of the bacteria as food supplements, by 2021.
The study is published in Nature Medicine.
In 2004, Muriel Derrien in her Ph.D. research at Wageningen University of the Netherlands isolated from a sample of healthy human feces a species of bacteria that can grow on a viscogenic substrate such as mucin and use it a single nutrient source, especially on the mucosal surface of the gastrointestinal tract.(1)
From the name of microbial ecologist Antoon DL Akkermans and 6“preferring mucin”, this bacterium was named Akkermansia muciniphila(Akkermansia).
It accounts for 1 to 4% of intestinal bacteria in adults and is a species of bacteria that inhabits the large intestine.(2)
Akkermansia a is a gram-negative, obligate anaerobic, non-motile, nonspore-forming elliptical eubacterium, classified under the phylum Verrucomicrobia.
In this review, we summarized recent studies that have indicated that Akkermansia is involved in obesity, glucose metabolism, and intestinal immunity, as well as reports on the associated role of food factors.(3,4)
Glucose Metabolism and Akkermansia
In humans with high body weight, body mass index (BMI), blood cholesterol level, and fasting blood glucose level, it is suggested that the abundance of Akkermansia in the gut is lower than that in the gut of healthy humans.(5)
In addition, when overweight or obese people undergo calorie-restricted diet therapy, the effect of improving insulin resistance has been reported to be more pronounced in humans with a higher abundance of Akkermansia in the intestine.
It is reported that Akkermansia increases when metformin, which is one of the therapeutic agents for diabetes, is administered to obese mice, and the action of metformin is partly mediated by the action of Akkermansia.(6)
In recent years, it has been revealed that, in the diabetic state, the breakdown of the intestinal mucosal barrier mechanism modifies the pathological condition; it has been reported that Akkermansia promotes mucus secretion and makes the barrier mechanism more robust. Chelakkot et al.(7) demonstrated that Akkermansia-derived extracellular vesicles may act as functional moieties for controlling gut permeability and that the regulation of intestinal barrier integrity can improve metabolic functions in high-fat diet-fed mice.
Blood lipopolysaccharide (LPS) concentration, an indicator of intestinal permeability, was also observed to be high in obese subjects (high-fat diet and diabetes mellitus mouse models), and the administration of Akkermansia was shown to decrease it.(8)
In mice, many studies have been carried out towards showing how Akkermansia more directly influences glucose/lipid metabolism.
The precise molecular mechanisms underlying how Akkermansia physiologically influences the human body are gradually being elucidated.
It is thought that Akkermansia produces short-chain fatty acids such as acetic acid from mucin and supplies energy to goblet cells that produce mucin.
Metformin, an antidiabetic drug, is suggested to increase the number of goblet cells, thereby enhancing mucin production, thickening the intestinal mucus layer, and maintaining the intestinal barrier mechanism; this contributes to an anti-inflammatory effect and, consequently, its antidiabetic action.(6)
Studies analyzing the bacterial cell proteins of Akkermansia have also been carried out. Amuc-1100, an outer membrane protein of Akkermansia, has been identified and found to activate intracellular signals mediated by the Toll-like receptor 2 (TLR2) of intestinal epithelial cells, contributing to the enhancement of the intestinal barrier.(9)
It has also been demonstrated that Amuc-1100 of Akkermansia is involved in the immune response, specifically in the induction of the production of interleukin-10 (IL-10), which is an anti-inflammatory cytokine.(9)
As previously mentioned, it has become clear that Akkermansia is either directly or indirectly involved in the metabolic and immune responses of humans, thus attracting attention as a next-generation beneficial bacterium.(3)
Polyphenol Functionality and Akkermansia
The health-promoting and disease-preventing effects of polyphenols have attracted attention.
There are many polyphenols in nature, including catechins found in wine, tea, apples, grape leather, mussels and blueberries; isoflavones found in soybeans; and chlorogenic acid found in coffee.
Polyphenols generally have low absorption rates, and there previously suggested to not work effectively in the body.
However, it has recently been reported that polyphenols are metabolized by intestinal bacteria to change its absorption rate and bioavailability; conversely, polyphenols can change the composition of the intestinal bacterial bacteria.
Intestinal bacteria that degrade polyphenols such as quercetin have been reported, and the relationship between polyphenols and the gut microbiota is becoming an important subject for the evaluation of food functionality.
Polyphenols derived from grapes act to increase the abundance of Akkermansia in the intestinal tract; as a result, they have been shown to enhance intestinal barrier function and incretin secretion from intestinal endocrine cells.(10,11)
Polyphenols derived from cranberries have also been reported to increase the abundance of Akkermansia, as well as help suppress obesity, insulin resistance, and intestinal inflammation.(12)
These indicate that there is an additional pathway that exerts its function by acting on the gastrointestinal tract without absorption of polyphenols, by influencing the intestinal bacterial flora and acting on intestinal mucosal cells. Masumoto et al.(13) demonstrated that apple-derived macromolecular procyanidins induce an increase in the abundance of intestinal Akkermansia and have anti-inflammatory and anti-metabolism effects in a mouse model of metabolic syndrome.
Administration of macromolecular procyanidins suppressed changes in Inflammation in intestinal mucosa, weight gain, and abnormalities in liver lipid metabolism induced by a high-fat high-sucrose diet.
In addition, 16S rRNA metagenomic analysis showed an improvement in the Firmicutes/Bacteroidetes ratio, as well as an increase in Akkermansia, leading to the anti-inflammatory action in the intestinal tract and the enhancement of the intestinal barrier function.
As far as the functionality of polyphenols has been deemed to contribute to the strong antioxidant effect observed in in vitro experiments, recent results have indicated that relatively poorly absorptive polyphenols directly affect intestinal bacteria and show the possibility that the antioxidant effect is mediated by so-called “good bacteria” such as Akkermansia.
However, polyphenols have not been sufficiently analyzed in human subjects, and the evidence for its involvement in increasing the abundance of Akkermansia has not been sufficient.
Cancer Immunotherapy and Akkermansia
Therapeutic efficacy and its association with the intestinal microbiota were analyzed in 249 patients with lung, kidney, or bladder cancers treated with immune checkpoint inhibitors.(14)
As a result, patients who used antibiotics before and after treatment had a poorer response to the immune checkpoint inhibitor PD-1 antibody and a shorter survival time compared to the patients who did not use antibiotics.
In addition, in the intestine of a patient who responded positively to the immune checkpoint inhibitor, an increase in the abundance of Akkermansia was observed compared to a patient who did not respond positively to the immunotherapy.
It was also confirmed that, using the stool of a patient that responded positively to the immunotherapy, fecal microbiome transplantation in a sterile mouse caused it to respond positively to the anti-PD-1 antibody.
In future cancer immunotherapy, we should obtain detailed genetic information on the cancer tissue, identify the mutation of the mismatch repair gene, select an immune checkpoint inhibitor based on this information, and refer to metagenomic information on the gut microbiota of the patient.
More information: Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study, Nature Medicine, DOI: 10.1038/s41591-019-0495-2 , https://nature.com/articles/s41591-019-0495-2
Journal information: Nature Medicine
Provided by Université catholique de Louvain