Using the gut bacterium Akkermansia muciniphila to treat obese and diabetic patients is now one step closer to becoming a reality, thanks to the work of a group of researchers led by Patrice Cani from the UCL and Willem de Vos from Wageningen University. By using a new cultivation medium and applying pasteurization, these scientists have made the bacterium suitable for oral administration to humans without compromising its beneficial effects. Moreover, they have identified a protein from the outer membrane that is a key factor in the bacterium’s ability to counteract the metabolic disorders associated with obesity and diabetes. The work has been published in the top scientific journal Nature Medicine.
A beneficial bacterium with some limitations
A. muciniphila is one of the most abundant bacteria in the human gut microbiome. Between 1% and 5% of the microorganisms in our intestines belong to this bacterial species. The positive link between A. muciniphila and the prevention of obesity and type 2 diabetes is already well known in the scientific community. Individuals suffering from these diseases have lower abundance of A. muciniphila in their intestinal flora, and feeding live samples of the bacterium to obese and diabetic mice has been shown to improve their metabolic profile.
But until now, therapeutic use of A. muciniphila in humans was still limited by two factors. First, the bacterium needs to be handled under anaerobic conditions because it is highly sensitive to oxygen. Second, the growth medium commonly used for cultivation contains animal mucin, a compound which is not suitable for human consumption. Besides, the main mechanism by which A. muciniphila could exert a positive effect on the metabolism was still unclear.
Turning A. Muciniphila into a therapeutic tool
As a first step in overcoming these limitations, the scientists from UCL and Wageningen University designed an alternative growth medium for A. muciniphila, in which the animal-derived compounds were substituted with a mixture of soy peptone, glucose, threonine, and N-acetylglucosamine. When A. muciniphila is grown in this alternative medium, it is still able to reduce fat mass gain and glucose intolerance in obese and diabetic mice in the same way as when cultivated in the conventional medium.
Pasteurization not only maintains, but even enhances the beneficial effects of A. muciniphila.
With that problem being solved, the researchers focused on finding a way to circumvent the oxygen sensitivity of A. muciniphila. Autoclaving the bacterium before administration was not an option because the high temperatures of this process destroy its beneficial effects. Inspired by previous probiotics research, the scientists decided to try pasteurization, a milder form of heat treatment at 70°C. To their surprise, they found that pasteurization not only maintains, but even enhances the beneficial effects of A. muciniphila. Obese mice fed with pasteurized bacterium show lower glucose intolerance, higher insulin sensitivity, lower concentration of triglycerides in the plasma, lower energy absorption, and smaller adipocyte size compared to mice treated with the live bacterium.
The underlying mechanism
Besides overcoming the hurdles that were limiting the therapeutic use of A. muciniphila, the researchers also gained valuable information about how the bacterium interacts with its host to improve the metabolic profile. By analyzing the proteome of A. muciniphila’s outer membrane, they identified and purified one protein present in abundant quantities. When this protein was isolated and fed to obese and diabetic mice, it partially recapitulated the beneficial effects of A. muciniphila, confirming that is a key factor in the bacterium’s ability to improve the metabolic status of the host.
But what is the underlying mechanism? This protein can interact with Toll-like receptor 2 (TLR2) from epithelial cells of the host’s intestine and, by doing so, it can regulate gut permeability. This ultimately has an effect on various metabolic parameters that are altered in obese and diabetic individuals, like energy absorption at the intestinal level or composition of the urinary metabolome. Moreover, the researchers found that the protein is stable at 70°C, the temperature used for pasteurization. This could explain why pasteurization enhances the beneficial properties of A. muciniphila, since after the treatment, the protein is still active and probably more accessible for interaction with the host cells.
It works for mice, but what about humans?
As a next step, the researchers want to test if A. muciniphila grown in the alternative medium can be safely used to treat humans, and if the positive effects observed in mice can be reproduced. A clinical study is currently being carried out, and the preliminary data already show signs of success. The complete results are expected to be published by the end of 2017.
Plovier et al., 2016. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nature Medicine, doi:10.1038/nm.4236
This article was written by guest columnist Marta Martinez